Cancer Pain: Assessment and Management, Second Edition

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Cancer Pain Drs. Eduardo D. Bruera and Russell K. Portenoy have completely revised and updated the widely respected Cancer Pain: Assessment and Management for the second edition of this unanimously praised book. This is a comprehensive, clinically oriented review of all aspects of the complex and multidimensional problem of cancer pain. The unique characteristics of cancer pain, including pathophysiology, clinical assessment, diagnosis, and pharmacological and nonpharmacological management, are all discussed here in detail. Internationally recognized leaders in cancer pain research have contributed to many new chapters, including those on neuraxial analgesia, hospice practice and institution-based palliative care programs, bone pain, and cancer pain and palliative care in the developing world. Cancer Pain continues to be a scholarly but accessible text that is an essential resource for physicians, nurses, and medical students who treat patients suffering from cancer pain. According to the New England Journal of Medicine, “This book should be in the library of every physician who comes into contact with patients with pain. It is truly superb.” Eduardo D. Bruera, MD, is Chair of the Department of Palliative Care and Rehabilitation Medicine and holds the F. T. McGraw Chair in the Treatment of Cancer at The University of Texas M. D. Anderson Cancer Center in Houston,

Texas. Dr. Bruera is Vice President of the International Association of Hospice and Palliative Care. He is a member of the editorial board of several pain, palliative care, and cancer journals. He has received a number of national and international awards for his clinical and research commitment to the management of pain and other symptoms. Dr. Bruera’s research has focused on clinical trials of pain and other symptoms and on health services research regarding supportive and palliative care. Russell K. Portenoy, MD, is Chairman of the Department of Pain Medicine and Palliative Care and the Gerald J. and Dorothy R. Friedman Chair in Pain Medicine and Palliative Care at Beth Israel Medical Center in New York. He is Professor of Neurology and Anesthesiology at the Albert Einstein College of Medicine. Dr. Portenoy is immediate past president of the American Academy of Hospice and Palliative Medicine and a past president of the American Pain Society. He is Editor-in-Chief of the Journal of Pain and Symptom Management and has been the recipient of the National Leadership Award of the American Academy of Hospice and Palliative Medicine, the Wilbert Fordyce Award for Lifetime Excellence in Clinical Investigation and the Distinguished Service Award from the American Pain Society, and the Founder’s Award from the American Academy of Pain Medicine. Dr. Portenoy’s research has focused on clinical trials of analgesic drugs, opioid pharmacology, symptom measurement, and quality of life assessment.

To Ed, Sofia, and Sebastian Bruera, and to Susan Sussmann and Matthew, Jason, and Allison Portenoy: their love and support make our work possible.

Cancer Pain Assessment and Management Second Edition

edited by

Eduardo D. Bruera, MD

Russell K. Portenoy, MD

The University of Texas M. D. Anderson Cancer Center Houston, Texas

Beth Israel Medical Center and Albert Einstein College of Medicine New York, New York

CAMBRIDGE UNIVERSITY PRESS

Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo, Delhi, Dubai, Tokyo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521879279 © Cambridge University Press 2010 This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2009 ISBN-13

978-0-511-64184-8

eBook (NetLibrary)

ISBN-13

978-0-521-87927-9

Hardback

Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this book to provide accurate and up-todate information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liabilty for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to nformation provided by the manufacturer of any drugs or equipment that they plan to use.

Contents

Contributors Preface Color plates follow page 420 SECTION I MECHANISMS AND EPIDEMIOLOGY 1 Nociception: basic principles Rie Suzuki, Shafaq Sikandar, and Anthony H. Dickenson 2 Pathophysiology of malignant bone pain Juan Miguel Jimenez-Andrade, Monica Herrera, and Patrick Mantyh

vii xi 9 10 3 11 23 12 13

SECTION II EPIDEMIOLOGY AND SYNDROMES 3 Cancer pain epidemiology Irene J. Higginson and Fliss Murtagh 4 Cancer pain syndromes Mervyn Koh and Russell K. Portenoy

5

6

7 8

SECTION III ASSESSMENT The assessment of cancer pain: measurement strategy Karen O. Anderson Multidimensional assessment: pain and palliative care Norma O’Leary, Carol Stone, and Peter G. Lawlor Evaluating pain for children with cancer Patricia A. McGrath and Eric J. Crawford Pain syndromes in cancer survivors Rosemary C. Polomano, Michael Ashburn, and John T. Farrar

14 37 15 53

89

105

130 145

SECTION IV PHARMACOLOGICAL TREATMENT Pharmacology of analgesia: basic principles Charles E. Inturrisi Pharmacogenetic considerations in the treatment of cancer pain P˚al Klepstad Pharmacology of opioid analgesia: clinical principles Carla Ida Ripamonti and Claudia Bareggi Opioid side effects and management Maxine de la Cruz and Eduardo D. Bruera Antipyretic analgesics Burkhard Hinz and Kay Brune Adjuvant analgesic drugs Russell K. Portenoy and Mervyn Koh Neuraxial analgesia Lewis C. Holford and Michael Cousins

SECTION V OTHER INTERVENTIONAL STRATEGIES 16 Neural blockade for cancer pain Rebecca Chan and Oscar de Leon-Casasola 17 Neurosurgical treatment of cancer pain Robert W. Hurley and Fred A. Lenz SECTION VI REHABILITATION AND PSYCHOLOGICAL INTERVENTIONS 18 Psychological interventions for cancer pain Francis J. Keefe, Amy P. Abernethy, Jane L. Wheeler, and Tamara J. Somers

167

180

195 230 255 272 287

315

329

343

v

contents

vi

19 Rehabilitation medicine interventions Jack B. Fu, Ki Y. Shin, and Theresa A. Gillis SECTION VII THE ROLE OF ANTINEOPLASTIC THERAPIES IN PAIN CONTROL 20 Palliative radiotherapy Alysa Fairchild and Edward Chow 21 Palliative systemic antineoplastic therapy Sunil M. Patel and Michael J. Fisch SECTION VIII PAIN IN SPECIAL POPULATIONS 22 Cancer pain management in the chemically dependent patient Steven D. Passik, Lara K. Dhingra, and Kenneth L. Kirsh 23 Cancer pain in children Richard Hain 24 Managing cancer pain in the elderly Marvin Omar Delgado-Guay and David Wollner SECTION IX DIFFICULT PAIN PROBLEMS 25 Cancer pain and depression William S. Breitbart, Wendy G. Lichtenthal, Hayley Pessin, and Gloria C. Lee

354

26 Neuropathic pain Ricardo A. Cruciani, E. Alessandra Strada, and Helena Knotkova 27 Breakthrough pain Sebastiano Mercadante 28 Bone pain Badi El Osta and Eduardo D. Bruera

478

506 515

379 399

29

30 423 31 433

32

444 33

34 457

SECTION X SYSTEMS OF CARE Integrating cancer pain management into hospice practice and institution-based palliative care programs Sandra P. Gomez and Paul W. Walker Pain in medical illness: ethical and legal foundations Pauline Lesage and Russell K. Portenoy Understanding clinical trials in pain research John T. Farrar and Scott D. Halpern Legal and regulatory aspects of opioid treatment: the United States experience June L. Dahl Role of family caregivers in cancer pain management Myra Glajchen Cancer pain and palliative care in the developing world Roberto Wenk, Daniela Mosoiu, and M. R. Rajagopal

Index

535

553 568

583

597

608

627

Contributors

Amy P. Abernethy, MD Division of Medical Oncology Department of Medicine Duke University Medical Center Durham, North Carolina Karen O. Anderson, PhD, MPH Department of Symptom Research Division of Internal Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas Michael Ashburn, MD, MPH Departments of Anesthesiology and Critical Care Medicine, and Pain Medicine and Palliative Care The University of Pennsylvania Philadelphia, Pennsylvania Claudia Bareggi, MD Supportive Care in Cancer Unit IRCCS Foundation National Cancer Institute Milano Milan, Italy William S. Breitbart, MD Department of Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center New York, New York Eduardo D. Bruera, MD Department of Palliative Care and Rehabilitation Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas Kay Brune, PhD Institute of Experimental and Clinical Pharmacology and Toxicology Friedrich-Alexander University, Erlangen Erlangen-Nuremberg, Germany

Rebecca Chan, MD Department of Anesthesiology University of Illinois College of Medicine Chicago, Illinois Edward Chow, MBBS, PhD, FRCPC Department of Radiation Oncology University of Toronto Odette Cancer Centre Sunnybrook Health Sciences Centre Toronto, Ontario, Canada Michael Cousins, MD Pain Management Research Institute University of Sydney at Royal North Shore Hospital St. Leonards, Sydney, Australia Eric J. Crawford, BHSc Department of Anesthesia The Hospital for Sick Children Toronto, Ontario, Canada Ricardo A. Cruciani, MD, PhD Department of Pain Medicine and Palliative Care Beth Israel Medical Center New York, New York June L. Dahl, PhD Department of Pharmacology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Maxine de la Cruz, MD Department of Palliative Care and Rehabilitation Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas

vii

contributors

viii

Oscar de Leon-Casasola, MD Department of Anesthesiology and Pain Medicine Roswell Park Cancer Institute Buffalo, New York Marvin Omar Delgado-Guay, MD Department of Palliative Care and Rehabilitation Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas Lara K. Dhingra, PhD Department of Pain Medicine and Palliative Care Beth Israel Medical Center New York, New York, and Departments of Neurology and Psychiatry and Behavioral Sciences Albert Einstein College of Medicine Bronx, New York Anthony H. Dickenson, PhD Department of Pharmacology University College London London, United Kingdom Badi El Osta, MD Department of Palliative Care and Rehabilitation Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas Alysa Fairchild, BSc, PGDip (Epi), MD, FRCPC Department of Radiation Oncology Cross Cancer Institute University of Alberta Edmonton, Alberta, Canada John T. Farrar, MD, PhD Center for Clinical Epidemiology and Biostatistics and Department of Anesthesiology and Critical Care and Department of Neurology The University of Pennsylvania Philadelphia, Pennsylvania Michael J. Fisch, MD Department of General Oncology The University of Texas M. D. Anderson Cancer Center Houston, Texas Jack B. Fu, MD Department of Palliative Care and Rehabilitation Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas

Theresa A. Gillis, MD The Helen F. Graham Cancer Center Christiana Care Health System Newark, Delaware Myra Glajchen, DSW Institute for Education and Research in Pain and Palliative Care Department of Pain Medicine and Palliative Care Beth Israel Medical Center New York, New York Sandra P. Gomez, MD Department of Palliative Care Memorial Hermann The Woodlands Hospital and The University of Texas M. D. Anderson Cancer Center Houston, Texas Richard Hain, MD Department of Child Health Cardiff University School of Medicine Heath Park, Cardiff, United Kingdom Scott D. Halpern, MD, PhD Center for Clinical Epidemiology and Biostatistics, and Division of Pulmonary, Allergy, and Critical Care Department of Medicine The University of Pennsylvania Philadelphia, Pennsylvania Monica Herrera, MD Department of Pharmacology University of Arizona Tucson, Arizona Irene J. Higginson, FFPHM, PhD, FRCP Department of Palliative Care, Policy and Rehabilitation King’s College London London, United Kingdom Burkhard Hinz, PhD Institute of Toxicology and Pharmacology University of Rostock Rostock, Germany Lewis C. Holford, MD Pain Management and Research Centre University of Sydney at Royal North Shore Hospital St. Leonards, Sydney Australia Robert W. Hurley, MD, PhD Department of Anesthesiology University of Florida Gainesvilla, Florida

contributors Charles E. Inturrisi, PhD Department of Pharmacology Weill Cornell Medical College and The Pain and Palliative Care Service Memorial Sloan-Kettering Cancer Center New York, New York Juan Miguel Jimenez-Andrade, PhD Department of Pharmacology University of Arizona Tucson, Arizona Francis J. Keefe, PhD Division of Medical Psychiatry Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham, North Carolina Kenneth L. Kirsh, PhD Department of Pharmacy Practice and Science University of Kentucky College of Pharmacy and The Pain Treatment Center of the Bluegrass Lexington, Kentucky P˚al Klepstad, MD, PhD Department of Intensive Care St. Olavs University Hospital and Medical Faculty Department of Circulation and Medical Imaging Norwegian University of Science and Technology Trondheim, Norway Helena Knotkova, PhD Department of Pain Medicine and Palliative Care Beth Israel Medical Center New York, New York Mervyn Koh, MBBS, MRCP Section of Palliative Medicine Department of Geriatric Medicine Tan Tock Seng Hospital Novena, Singapore Peter G. Lawlor, MB, MMedSc Our Lady’s Hospice St. James’ Hospital Dublin, Ireland, and Division of Palliative Care Medicine Department of Oncology University of Alberta Edmonton, Alberta, Canada

ix

Gloria C. Lee, MD The State University of New York Downstate College of Medicine Brooklyn, New York Fred A. Lenz, MD Department of Neurology and Neurosurgery Johns Hopkins Hospital Baltimore, Maryland Pauline Lesage, MD Department of Pain Medicine and Palliative Care Beth Israel Medical Center New York, New York Wendy G. Lichtenthal, PhD Department of Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center New York, New York Patrick Mantyh, PhD Department of Pharmacology University of Arizona Tucson, Arizona, and Research Service Veterans Affairs Medical Center Minneapolis, Minnesota Patricia A. McGrath, PhD Departments of Anesthesia and Psychology The Hospital for Sick Children and Department of Anesthesia The University of Toronto Toronto, Ontario, Canada Sebastiano Mercadante, MD Anesthesia and Intensive Care Unit and Pain Relief and Palliative Care Unit La Maddalena Cancer Center and Departments of Anesthesia, Intensive Care, and Emergencies University of Palermo Palermo, Italy Daniela Mosoiu, MD Hospice Case Sperantei Brasov Brasov, Romania Fliss Murtagh, PhD, MRCGP Department of Palliative Care, Policy and Rehabilitation King’s College London London, United Kingdom

contributors

x

Norma O’Leary, MRCPI Department of Palliative Medicine Marie Curie Cancer Centre Newcastle-upon-Tyne, United Kingdom Steven D. Passik, PhD Department of Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center New York, New York Sunil M. Patel, MD Department of General Oncology The University of Texas M. D. Anderson Cancer Center Houston, Texas Hayley Pessin, PhD Department of Psychiatry and Behavioral Sciences Memorial Sloan-Kettering Cancer Center New York, New York Rosemary C. Polomano, PhD, RN, FAAN The University of Pennsylvania School of Nursing and Department of Anesthesiology and Critical Care The University of Pennsylvania Philadelphia, Pennsylvania Russell K. Portenoy, MD Department of Pain Medicine and Palliative Care Beth Israel Medical Center New York, New York, and Departments of Neurology and Anesthesiology Albert Einstein College of Medicine Bronx, New York M. R. Rajagopal, MD Trivandum Institute of Palliative Sciences Trivandum, Kerala, India Carla Ida Ripamonti, MD Supportive Care in Cancer Unit IRCCS Foundation National Cancer Institute Milano Milan, Italy Ki Y. Shin, MD Department of Palliative Care and Rehabilitation Medicine

The University of Texas M. D. Anderson Cancer Center Houston, Texas Shafaq Sikandar, BSc Department of Pharmacology University College London London, United Kingdom Tamara J. Somers, PhD Department of Psychiatry and Behavioral Science Duke University Medical Center Durham, North Carolina Carol Stone, MRCP Palliative Medicine Our Lady’s Hospice Dublin, Ireland E. Alessandra Strada, PhD Department of Pain Medicine and Palliative Care Beth Israel Medical Center New York, New York Rie Suzuki, BSc, PhD Department of Pharmacology University College London London, United Kingdom Paul W. Walker, MD Department of Palliative Care and Rehabilitation Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas Roberto Wenk, MD Programa Argentino de Medicina Paliativa-Fundaci´on FEMEBA Buenos Aires, Argentina Jane L. Wheeler, MS Duke Cancer Care Research Program Duke University School of Medicine Durham, North Carolina David Wollner, MD, FACP, AGSF Department of Palliative Care Metropolitan Jewish Health System Brooklyn, New York

Preface

The years since the publication of the first edition of this volume have witnessed many changes that together may affect the epidemiology, nature, impact, and management of cancer-related pain. The global prevalence of cancer continues to rise, and in most countries, the disease presents as an incurable illness characterized by high prevalence of pain. In developed countries, studies continue to reveal poor assessment, undertreatment, and problems with drug availability or health services delivery that compromise best practice. Although scientific understanding of pain pathophysiology and concurrent elucidation of the multiple systems underlying nociception and pain modulation offers great promise for therapeutics in the future, the community of health professionals continues to struggle with a prevalence and impact of cancer pain far greater than it should be. The rapid development of palliative care in much of the world has increased awareness of the problem and, in some countries, has enhanced access to specialist pain management, but most patients in need do not have access. Without question, there continues to be a huge burden on individuals, on families, and on society at large from inadequately treated cancer pain.

Although a relatively high proportion of patients with pain can be made more comfortable using easily acquired skills in pharmacotherapy, the larger problem requires a deeper understanding of the nature of pain and the broader range of therapies. The purpose of Cancer Pain is to provide a reference for both those who seek the basics and those who seek a scholarly review of the many domains relevant to an in-depth understanding of cancer pain and specialist skills in practice, including syndrome identification and multidimensional assessment, the relationships between pain management and cancer medicine and between pain and other quality of life concerns, the many pharmacologic and nonpharmacologic best practices in pain care, and the diverse needs of special populations. Nothing in the intervening years has altered the comment we made in the first edition of Cancer Pain: It remains our hope that this text will lead to a better understanding of this illness and contribute to continued improvement in care. Eduardo D. Bruera Russell K. Portenoy

xi

SECTION I

MECHANISMS AND EPIDEMIOLOGY

1

Nociception: basic principles rie suzuki, shafaq sikandar, and anthony h. dickenson University College London

Introduction Pain has been a major concern in the clinic for many decades. In recent years, considerable progress has been made with respect to our understanding of both acute and chronic pain mechanisms. This has largely been attributed to advancements in molecular biology and genomic techniques, as well as the use of animal models, which has allowed us to explore mechanisms and networks of neurons involved in pain processes. This has fundamentally altered our understanding of the pathophysiology of pain mechanisms and has led to the hope of development of novel analgesics. The study of the receptor systems involved in the transmission of pain and its modulation involves investigation of processes occurring at the peripheral endings of sensory neurons, as well as central events. The mechanisms of inflammatory, visceral and neuropathic pain are different from those of acute pain, and cancer pain may both overlap and differ in some respects with these broad categories. Furthermore, there is considerable plasticity in both the transmission and modulating systems in these prolonged pain states so that systems change over time. The search for new treatments for these pain states requires the development of valid animal models. For such models to be valid, a number of criteria must be fulfilled. First, the model must provide reproducible and quantifiable behavioral data. Second, the model must produce behaviors in the animal that resemble some of the pain syndromes observed in humans (e.g., allodynia, hyperalgesia). Third, the behavioral data must correlate with pain responses seen and therapies used in humans. Through the use of these animal models, we can broaden our understanding of pain mechanisms and possibly identify or develop potential agents for treatment.

Mechanisms of pain and analgesia The anatomy and physiology of pain The somatosensory primary afferent fibers, which convey sensory information to the spinal cord, can be grouped into several classes according to the transduction properties of the individual nerve fiber. The properties of each afferent fiber are summarized in Table 1.1. The afferent fibers differ in their conduction velocities and degrees of myelination, and can be distinguished by their diameter. The large-diameter A␤-fibers are myelinated by Schwann cells and hence have a fast conduction velocity. This group of nerve fibers innervates receptors in the dermis and is involved in the transmission of low-threshold, non-noxious information, such as touch. The A␦-fiber is less densely myelinated and conveys both non-noxious and noxious sensory information. The unmyelinated C-fiber conveys high-threshold noxious inputs and has the slowest conduction velocity of all three fiber types. On entry into the spinal cord, each primary afferent fiber (A␤-, A␦-, or C-fiber) exhibits a specific termination pattern in the dorsal horn (Fig. 1.1). This has been studied extensively through the use of specific markers. Dorsal root Table 1.1. Classification of somatosensory primary afferent fibers innervating the skin Primary afferent fiber type

Mean diameter (␮m)

Myelination

Mean conduction velocity (m/s)

A␤ A␦ C

6–12 1–5 0.2–1.5

Myelinated Thin myelination None

25–70 10–30 ⬍2.5

3

4

r. suzuki, s. sikandar, and a.h. dickenson

Fig. 1.1. Cross-section of the lumbar spinal cord illustrating the termination sites of afferent fibers in the dorsal horn and the organization of the gray matter into laminae I to X.

afferents send most of their collaterals into the segment of entry. However, there is also a degree of rostrocaudal distribution, and some collaterals may spread to several segments above or below the target segment. Thus, there is an anatomical substrate for the spreading of pain beyond the segment in which it originates. The large-diameter A␤-fiber enters the spinal dorsal horn through the medial division of the dorsal root and terminates in laminae III and IV, where it forms a characteristic termination pattern.1 The densest arborization appears to occur in lamina III. Some also extend to laminae VIII and IX of the ventral horn, where they synapse directly onto motor neurons and form the basis of monosynaptic reflexes.2 The terminals of A␦-fibers, on the other hand, form a plexus at the surface of the spinal cord in laminae I and IIo. Unmyelinated C-fibers enter the spinal cord through the lateral part of the dorsal white matter and terminate in the superficial dorsal horn. Current evidence suggests that lamina II is the main termination area for cutaneous primary afferent C-fibers, whereas that for A␦-fibers is in lamina I.1 These peripheral fibers activate spinal cord neurons, which in turn produce local spinal autonomic and motor reflexes. Spinal neurons can be classified into three broad categories: low-threshold only; nociceptive-specific (NS), in that these cells respond only to noxious mechanical, thermal, and chemical stimuli; and wide dynamic range (WDR) neurons that additionally code innocuous stimuli but increase their activity into the noxious range. The majority of

lamina I nociceptive specific (NS) neurons in the superficial spinal cord are projection neurons that ascend to the parabrachial area, with limited terminations in other brainstem/midbrain regions.3 The parabrachial area is a key supraspinal target implicated in the emotional and autonomic aspects of nociceptive processing. Because these limbic parts of the brain are important in mood, anxiety, fear, the sleep–wake cycle, and central autonomic control, the ability of spinal neurons to contact these zones is a likely basis for the comorbidities that accompany pain. In turn, the parabrachial and cuneiform areas contact the amygdala and hypothalamus and indirectly drive descending modulatory descending pathways. WDR neurons tend to project to areas of the brain that generate the sensory-discriminative components of pain, such as the thalamus and cortex. The activation of spinal neurons therefore produces local motor activity, and the parallel ascending pathways elicit the sensory and affective aspects of pain.4

Pharmacology of pain transmission Peripheral events The transmission of acute pain involves activation of sensory receptors on peripheral C-fibers, the nociceptors, which include a number of sensors for heat, mechanical, and chemical stimuli. However, once tissue damage and inflammation occur, the actions of prostanoids, bradykinin, and

nociception: basic principles

5 painful condition characterized by intolerable burning sensations in the extremities, whereas other mutations in this channel result in paroxysmal extreme pain disorder and loss-of-function mutations produce analgesia.6 Peripheral mechanisms of inflammatory pain

Fig. 1.2. A schematic diagram of a C-fiber showing some of the peripheral mediators of pain and inflammation in the periphery.

5-hydroxytryptamine (5-HT) on their excitatory receptors play a major role in sensitization and activation of C-fibers (Fig. 1.2). Other factors, such as nerve growth factor (NGF) and cytokines, also are important at the peripheral level, and resultant changes in the phenotype of the sensory neurons may be another important process. In common with all nerve fibers, C-fibers need to generate action potentials in response to stimuli, yet these nociceptive fibers have unique sodium channels, whereas some C-fibers are “sleeping”; that is, they do not respond to natural stimuli until after inflammation. Peripheral input that drives pain sensation depends on the presence of voltage-gated sodium channels, and altered sodium channel activity plays an important role in inflammatory and neuropathic pain.5 Voltage-gated Na+ channels propagate action potentials along neurons and spur hyperexcitability after nerve injury. Moreover, based on the efficacy of drugs such as lignocaine and carbamazepine, sodium channels are important targets for drugs, but the ubiquitous nature of the channels leads to low therapeutic windows. Different voltage-gated Na+ channel isoforms, with different kinetic and pharmacological properties, have been delineated in sensory neurons, leading to the potential for more selective agents. The Nav 1.8 and 1.9 ␣ subunits are expressed exclusively in small unmyelinated fibers and are resistant to block by tetrodotoxin (TTX), whereas the Nav 1.7 ␣ subunit, which is susceptible to block by TTX, is expressed in sensory and sympathetic neurons. Tissue and nerve damage may lead to a change in the expression and function of ␣ subunits and a resultant change in neuronal excitability to the detriment of the sensory system. Tellingly, inherited “gain-of-function” mutations in the Nav 1.7 ␣ subunit in humans result in erythermalgia, a

Polymodal C-fiber receptors can be activated selectively by noxious thermal and mechanical stimuli. In the case of activation by noxious heat, we now suspect that the family of transient receptor potential vanilloid channels that also responds to the extract of hot peppers – capsaicin – may be responsible for the generation of action potentials after application of heat. Others within this family are responsive to warming, cooling, and noxious cold. Thus, the peripheral terminals of small-diameter neurons may be excited by a number of applied stimuli and also by endogenous chemical mediators, especially in conditions of tissue damage. These can be released from local non-neuronal cells, the afferent fibers themselves, and products from immune cells triggered by activation of the body’s defense mechanisms. These chemical mediators then interact to cause a sensitization of nociceptors so that afferent activity induced by a given stimulus is increased. This produces primary hyperalgesia, a zone of increased sensitivity to painful stimuli in the center of the damaged tissue.7 One of the most important components in inflammation is the production of arachidonic acid metabolites. Arachidonic acid, a component of cell membranes, is liberated by phospholipase A2 and is subsequently metabolized by two main pathways controlled by two enzymes, cyclooxygenase (COX) and lipoxygenase. This metabolism gives rise to a large number of eicosanoids (leukotrienes, thromboxanes, prostacyclins, and prostaglandins). These chemicals are still poorly understood, but it is clear that they do not normally activate nociceptors directly but, by contrast, reduce the C-fiber threshold and so sensitize them to other mediators and stimuli. The use of both steroids and nonsteroidal antiinflammatory drugs (NSAIDs) is based on their ability to block the conversion of arachidonic acid to these mediators.8 However, these drugs can only prevent further conversion and will not change the effects of eicosanoids that have already been produced. The action of most NSAIDs is to inhibit COX-1, but as this form is the constitutive enzyme, COX-1 inhibition results in the gastric side effects of NSAIDs, whereas their ability to block the inducible COX-2 enzyme appears to be a major contributor to analgesia. The new generation of selective COX-2 inhibitors was thought to have improved therapeutic profiles, as this form of the enzyme is induced at the site of tissue damage

6

r. suzuki, s. sikandar, and a.h. dickenson

and so spares gastric function; however, doubts as to their cardiovascular safety have arisen. Interestingly, COX-2 is normally present in the brain and spinal cord and so may be responsible for some of the central analgesic effects of NSAIDs. Bradykinin is another chemical with important peripheral actions, but as yet it cannot be manipulated in any direct way by drugs. It is a product of plasma kininogens that find their way to C-fiber endings following plasma extravasation in response to tissue injury. Bradykinin receptors have been characterized and here again, there are two forms. The B1 -receptor is constitutively expressed less than the B2 -receptor, but in chronic inflammation, it is upregulated. Pain may arise via the activation of the B2 -receptor, which is abundant in most tissues; this can activate C-polymodal receptors. The response to bradykinin may be enhanced by prostaglandins, heat, and serotonin, indicating the extent of interactions among these peripheral pain mediators.9 After tissue damage, there is an accumulation of hydrogen ions; the pH is lowered in inflammation and ischemia. These protons may activate nociceptors directly via their own family of ion channels and sensitize them to mechanical stimulation. Acid-sensing ion channels are a family of sodium channels that are activated by protons. Of special interest is one type found only in small dorsal root ganglion neurons that are responsible for activation of nociceptors. Mast cells can release histamine, which causes vasodilation, edema, and itch. Adenosine also is involved in inflammatory conditions. Substance P (SP) and calcitonin gene-related peptide (CGRP) released from the peripheral terminals of primary afferents (via axon reflex) cause neurogenic inflammation. These peptides produce vasodilation, plasma extravasation, and mast cell degranulation. Adenosine 5 -triphosphate (ATP) can cause direct nociceptor activation. The vascular changes produced by SP, CGRP, prostaglandins, and bradykinins lead to vasodilation and plasma extravasation that underlie the swelling that accompanies tissue damage.10 Serotonin is released from a number of non-neuronal cells, such as platelets and mast cells, and can produce an excitation of nociceptive afferents via the activation of a large number of receptors (5-HT1A , 5-HT2 , and 5-HT3 ), as well as sensitizing nociceptors, especially to bradykinin. 5HT’s key role, but not its mechanism of action, in the pain associated with migraine and other headaches is well established, but little is known about the actions of this mediator in other noncranial pains. The aura of neurological symptoms and/or signs is thought to be caused by a vascular or a neuronal mechanism, or a combination of the two. One theory suggests that changes in the vasculature are

responsible for causing migraine. A related idea is that peripheral nerves are the source of the problem and then cause the associated vascular changes via release of 5-HT and other inflammatory mediators. A third theory suggests that the primary abnormality is neuronal but originates within the brain itself.11 Sumatriptan, which is commercially available for the treatment of migraine, is an agonist at 5-HT1B and 5-HT1D receptors. It has three distinct pharmacological actions. Stimulation of the presynaptic 5-HT1D receptors on trigeminal A␦-fibers inhibits the release of CGRP, which inhibits dural vasodilation. 5-HT1D receptors on trigeminal C-fibers also are stimulated, inhibiting the release of SP and, therefore, blocking neurogenic inflammation and dural plasma extravasation. A further possible action is a direct attenuation of excitability of trigeminal nuclei, as 5-HT1B/1D receptors in the brainstem are stimulated. Stimulation of these receptors is caused by second-generation triptans that cross the blood–brain barrier, such as zolmitriptan. They all bind to neurons in the trigeminal nucleus caudalis and in the upper cervical cord.12 Direct vasoconstriction is mediated by the stimulation of vascular 5-HT1B receptors. These receptors also are found systemically, and coronary arteries also undergo vasoconstriction. Sumatriptan constricts cerebral arteries, but if the vasculature is normal, this does not affect cerebral blood flow. Other factors, such as NGF and cytokines, also are important at the peripheral level. Changes in the phenotype of sensory neurons may be produced by these mediators. This contributes to the complex changes in the transduction of painful stimuli. Peripheral mechanisms of neuropathic pain After nerve injury, there is considerable plasticity in the peripheral and central nervous system (CNS), which may be related to the pathogenesis of neuropathic pain states. The mechanisms underlying these chronic pain states are heterogeneous. The complex nature of these syndromes is largely responsible for the limited number of therapeutic strategies. The sequence of events that follow peripheral nerve injury, and consequently contribute to the development of neuropathic pain, can be seen at various levels of the nervous system. Nerve injury is associated with anatomical, neurochemical, pharmacological, and electrophysiological changes.13 After a nerve lesion develops, there are alterations in the anatomy of the peripheral nerves; demyelination occurs through phagocytosis by macrophages. A

nociception: basic principles number of neurochemical changes also take place. Studies have reported a complex change in the expression of neuropeptides in the dorsal root ganglia (DRG), including a reduction in the levels of SP and CGRP. In contrast, there is evidence for an upregulation of galanin, as well as for a novel induction of vasoactive intestinal polypeptide and neuropeptide Y. These changes may be related to the degenerative and regenerative processes that take place in the central and peripheral branches of the sensory neuron. Peripheral nerve damage leads to a downregulation of 1.8 and 1.9 sodium channel transcripts in the DRG (despite the translocation, insertion, and clustering of Na+ channels containing these subunits at injury and neuroma sites), with a concomitant upregulation of the embryonic TTX-S ␣ 1.3 subunit.14,15 Various studies suggest that ectopic activities in sensory neurons are mediated by Nav 1.3 ␣ subunits, and not 1.7, 1.8, or 1.9 ␣ subunits. (Interestingly, neuropathic pain develops normally in mice lacking Nav 1.7 and/or 1.8 subunits despite their known involvement in setting mecha nical sensory thresholds.)16 Na+ channels with the 1.3 subunit have the correct biophysical properties to support rapid firing; they are upregulated in all models of neuropathic pain, and their spontaneous firing can be blocked by TTX. One prominent feature of nerve injury is a marked increase in neuronal excitability, which is manifested as abnormal ectopic activities. Ectopic impulses appear to originate from the DRG as well as from the neuroma of the injured peripheral nerve.17 The incidence and level of spontaneous activity depend on several factors, including animal species, time elapsed from injury onset, type of nerve injury, and the nerve studied. One factor contributing to the electrogenesis of ectopic discharges is thought to be the alteration in the expression of voltage-gated sodium channels on peripheral afferents after nerve injury. Immunohistochemical studies have demonstrated that nerve injury induces remodeling of axolemmal sodium channels, and channels have been shown to accumulate in neuromas, especially in regions of demyelination.18 Activation of these previously quiescent channels may therefore induce abnormal repetitive firing in injured neurons and potentially act as ectopic impulse generators. The change in expression of both TTX-S and TTX-R channels implies that the kinetics and voltage-dependent characteristics of sodium currents may be considerably altered in neuropathic pain states. This, together with the pathological accumulation of sodium channels at the neuroma, may promote inappropriate action potential initiation and may form the basis of the therapeutic use of local anesthetics and excitability blockers, such as carbamazepine, for neuropathic pain states.19

7 Another feature of nerve injury is axonal sprouting, whereby injured axons undergo regeneration and reinnervation of target peripheral tissues including the deafferentated territory. In addition, nerve injury can induce adjacent undamaged sensory axons to sprout collateral fibers into an area that has been denervated owing to the nerve lesion over a limited distance (collateral sprouting). However, although studies have reported a structural reorganization of the spinal cord after nerve injury such that the central terminals of axotomized Abeta-fibers sprout into lamina II, an area of the cord that normally processes only C-fiber input,20 technical issues with the tracer refute the suggestion that this is a basis for allodynia.21 Central mechanisms of pain As peripheral nerve fibers become activated by tissue or nerve damage, action potentials are generated in the nerve and arrive in their central endings of the fibers in the spinal cord. Here, the electrical events switch to chemical transmitter release through calcium channels that open in the membrane. As calcium channels are activated, they cause transmitter release, and the transmitters then activate their receptors in the spinal cord, causing important increases in neuronal excitability. The respective neurons then generate action potentials that are passed onto the next nerve cell, transmitter is again released, and the messages pass on upward to many areas of the brain involving thousands and thousands of nerve cells scattered throughout the brain. Whatever the pain state and alterations in function that follow, abnormal peripheral nerve activity will then affect calcium channel function and alter the release of transmitter into the spinal cord. Indeed, numerous studies have shown upregulation of calcium channels after nerve injury, a possible compensation for the loss of normal input produced by the nerve injury. Recent studies with agents that block neuronal voltage-sensitive calcium channels would also suggest that this leads to an increase in central neuronal excitability.22 N-type channels, blocked by omegaconotoxin, appear to be important in behavioral allodynia and play a major role in the neuronal responses to low- and high-threshold natural stimuli and in the C-fiber–evoked central hyperexcitability. Blockers of this channel are considerably more effective after nerve injury.23 Because the channel is voltage operated, these results again suggest increased excitability of the spinal cord neurons after injury. Ziconotide is an example of a drug that works to block calcium channels. Its use is restricted to the spinal route.24 Gabapentin and pregabalin are drugs licensed for neuropathic pain that have analgesic activity in neuropathic pain

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states from varying origins. Recent randomized controlled trials of both drugs, one in patients with postherpetic neuralgia and another in patients with diabetic neuropathy, concluded that the drugs are effective in the treatment of these pain states. The mechanism of action of gabapentin and pregabalin is now clearly established; these drugs interact with calcium channels to reduce the release into the spinal cord of transmitter produced by peripheral pain stimuli, reducing the excitability of neurons that are sending messages to the brain. This interaction occurs through the ability of these compounds to bind to the ␣2 ␦ subunit of calcium channels.22 This, in theory, would lead to a change in the function of all calcium channels if not for the state dependency of these compounds that are able to selectively alter abnormal activity. This appears to result from an upregulation of the ␣2 ␦ subunit in damaged nerve fibers and activity in descending excitatory 5-HT pathways from the brainstem, which then permit actions of the drug on pathological activity while sparing normal function.25 Nociceptive sensory information arriving from primary afferent fibers enters the spinal cord via the dorsal horn. On entering the spinal cord, nociceptive signals undergo considerable convergence and modulation. The pharmacology of the spinal cord is extremely rich and contains a diverse range of neurotransmitters and receptors, which may be excitatory or inhibitory depending on the consequence of their activation and their location on the neuronal circuitry. The transmission of pain therefore can be seen as a complex process involving the interplay between excitatory and inhibitory systems acting at different levels of the CNS. All these systems are subject to plasticity, and alterations in pharmacological systems may occur during pathological conditions.26 In the spinal cord, nociceptive signaling systems undergo convergence and modulation through interactions that involve peripheral inputs, interneurons, and descending controls. One consequence of this modulation is that the relationship between stimulus and response to pain is not straightforward. The response of output cells could be greatly altered via the interaction of various pharmacological systems in the spinal cord. Excitatory transmission The excitatory amino acids glutamate and aspartate have been implicated in the transmission of nociceptive information in acute and chronic pain states.27 Several receptors for glutamate have been identified in the brain and spinal cord, including the ionotropic glutamate receptors (N-methyl-d-aspartate [NMDA], alpha-amino-3-hydroxy-

5-methyl-4-isoxazole-propionic acid [AMPA], kainate) and the metabotropic glutamate receptors. The three ionotropic receptor types have a prominent localization in the superficial dorsal horn (laminae I–III) and in deeper layers (laminae IV–VI). The parallel neuroanatomical distribution of these receptors in laminae I–III of the spinal cord provides support for functional interactions between NMDA and non-NMDA receptors in modulating nociceptive transmission. The excitatory amino acids are found in most sensory fibers, including both large- and small-diameter fibers. In the latter case, they are co-localized with peptides, such as SP. The coexistence of these two transmitters suggests that they are released together in response to a noxious stimulus and thereby contribute to the transmission of pain. Whereas AMPA receptors are activated in response to brief acute stimuli and are involved in the fast events of pain transmission, NMDA receptors are activated only after repetitive noxious inputs, under conditions in which the stimulus is maintained.27 NMDA receptors have been implicated in the spinal events underlying “wind-up,” whereby the responses of dorsal horn neurons are significantly increased after repetitive C-fiber stimulation despite the constant input (Fig. 1.3).28 This increased responsivity of dorsal horn neurons is probably the basis for central hyperexcitability and is responsible for the amplification and prolongation of neuronal responses in the spinal cord.26,29 The NMDA receptor has a heteromeric structure composed of two subunit types: the NR1 subunit and one of four subunits (NR2A–NR2D). It is an ionotropic receptor coupled to a cation channel, which is blocked by physiological levels of Mg2+ at the resting membrane potential. The channel is blocked in a voltage-dependent manner. The receptor can operate only after sufficient repeated depolarization. The removal of the Mg2+ block is mediated by peptides, likely SP and CGRP, which are co-released with glutamate. After a brief acute stimulus, pain transmission from C-fibers is largely mediated by the action of glutamate on AMPA receptors. When the stimulus is sustained or its intensity is increased, however, the action of SP on NK-1 receptors produces sufficient membrane depolarization so that the Mg2+ block can be removed and the NMDA receptor activated.26 SP (and also other peptides in the spinal cord) therefore plays an important role in recruiting NMDA receptors and contributes to the cascade of events leading to the enhancement and prolongation of the neuronal response. Indeed, the administration of SP receptor antagonists has been shown to produce antinociception and decrease spinal excitability.30 Functional modulation of the NMDA receptor can be achieved through actions at various recognition sites.

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Fig. 1.3. Pharmacology of the spinal cord. The diagram depicts many of the transmitters and receptors involved. Action potentials in a peripheral C-fiber, propagated by sodium channels, arrive in the central terminals and open calcium channels. The influx of calcium causes the release of glutamate, SP, and CGRP, which activate their respective receptors on spinal neurons. NMDA receptor activation produces the wind-up depicted in the figure. Plasticity in these systems may result in hyperalgesia and allodynia. The excitatory events can be controlled by activity or drugs acting on opioid, GABA, and adenosine systems.

Potentially, there are several ways in which the effect of released glutamate can be antagonized through NMDA receptor blockade. Numerous studies have investigated the potential use of antagonists acting through the different recognition sites; however, because of the ubiquitous nature of the receptor, it often has been difficult to achieve therapeutic effects at the target site in the absence of adverse side effects. Evidence suggests that drugs acting at the glycine site in particular appear to lack some of the typical NMDA receptor antagonist side effects. In addition, the fact that there are four subtypes of the receptor (NR1/NR2A–NR2D) might allow the production of drugs with selective actions. If these receptors had different distributions, it might be possible to target pain while avoiding forebrain receptors that may mediate problematic side effects. At present, ketamine, which blocks the channel, although not without problems of tolerability, is the most efficacious blocker of NMDAinduced activity. Substantial evidence exists for the involvement of NMDA receptors in various pathological pain states. Studies have demonstrated the effectiveness of NMDA receptor

antagonists in animal models of inflammation,31–33 neuropathic pain,34 allodynia,35 and ischemia.36 Both presurgical and postsurgical administration of antagonists was shown to be effective, suggesting that the induction and maintenance of these ongoing pain states depend on NMDA receptor– mediated events. It is now clear that neuropathic pain states are, at least in part, mediated by NMDA receptor–mediated events based on earlier findings from animal studies.37 After nerve injury, there appears to be a greater contribution of the NMDA receptor system to neuronal activity, and this may play a role in the spinal hyperexcitability that underlies this condition. Neuropathy may produce a prolonged activation of NMDA receptors as a result of a sustained afferent input to the spinal cord, and this may result in a continuous increase in the release of glutamate through upregulated calcium channels. Hence, a greater proportion of channels are likely to be in their open state during neuropathy, and this could enable NMDA channel blockers to exert greater effects as a result of their use-dependency. In the case of inflammation, the sensitization of peripheral nociceptive fibers means that

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a stimulus applied to the periphery will evoke more transmitter release and consequently greater NMDA receptor activation. A number of studies suggest that there is a subsequent complex change in the pattern of the evoked neuronal responses, as well as in the receptive field size of dorsal horn neurons, after nerve injury. Thus, there are important changes in the spinal processing of neuropathic pain. Alterations in the response profile of spinal neurons appear to be modality dependent and are characterized by both increases and decreases in selected peripheral stimuli. It is not clear what underlies this differential plasticity of spinal neurons, although it is likely that the changes result from de novo acquired neuronal responses as well as from alterations in the existing response profiles of spinal neurons.38 Behavioral studies have shown that NMDA receptor activation is required for the induction and maintenance of pain-related behaviors.39 Thus, it is likely that aberrant peripheral activity is amplified and enhanced by NMDA receptor–mediated spinal mechanisms in neuropathic pain. The degree of hyperexcitability after peripheral nerve damage is hard to gauge, as peripheral fibers, central neurons, and pharmacological systems may all change their properties after injury. As the operation of the NMDA receptor/ channel depends critically on the underlying level of excitability, spinal neurons are probably hyperactive and compensate for much of the peripheral nerve damage. Although there is human evidence for the effectiveness of agents acting at the NMDA receptor complex, especially ketamine,37,40 it appears that although some patients get good pain relief, the majority cannot achieve complete pain control because dose escalation is compromised by the narrow therapeutic window; we await strategies that can increase this therapeutic window. Although the extent of the loss of myelinated and unmyelinated fibers after nerve injury is unknown, a large proportion of input is expected to be lost as a result of neuropathy. Despite this marked loss of afferent input, however, the overall changes in the responses of spinal neurons appear to be comparatively small. Hence, this may represent an increase in spinal cord excitability, which could compensate for the loss of afferent drive. The high level and incidence of spontaneous activity seen after nerve injury may be one contributing factor to the global spinal hyperexcitability. This activity may well produce an ongoing level of transmitter release in the spinal cord, which may, in turn, favor hyperexcitability of responses to subsequent evoked stimuli. Furthermore, there may be a drop in the mechanical threshold of spinal neurons after nerve injury, which could

facilitate neuronal activation with a low-intensity stimulus. This, together with an enlargement of neuronal receptive fields, could form the electrophysiological basis for the mechanism underlying the behavioral manifestation of allodynia, hyperalgesia, and spontaneous pain after neuropathy (Fig. 1.4).41 Central inhibitory systems The discovery and use of opium date back many centuries. The roles of the ␮, ␦, and ␬ receptors have been established. Most clinically used drugs act on the ␮ receptor, and the ␦ receptor has remained a target for opioids with fewer potential side effects compared with morphine, although no useful clinical drugs have ensued. The endogenous opioid peptides, the enkephalins, have clear controlling influences on the spinal transmission of pain, whereas the dynorphins have complex actions. Inhibitors of the degradation of the enkephalins have been produced. To date, four opioid receptor subtypes have been cloned and isolated, which include the ␮, ␦, and ␬ receptors42 and the recently identified ORL-1 (opioid receptor–like) receptor (Table 1.2).43 The endogenous opioid peptides for these receptors are endorphin, enkephalin, dynorphin, and nociceptin, respectively. The recently discovered ORL-1 receptor, which exhibits considerable sequence homology with the other three classical opioid receptors, shows unique pharmacological properties because it exhibits only a low affinity for naloxone, a universal opioid receptor antagonist. The endogenous peptide for the receptor has been termed nociceptin, or orphanin FQ, and although its functional role is still somewhat unclear, extensive studies are currently being conducted to elucidate its role in pain modulation.44,45 Overall, this peptide produces spinal analgesia but may well function as an “anti-opioid” at supraspinal sites. The cloning and isolation of opioid receptors were a major breakthrough in understanding the molecular basis of opioid actions, as well as their localization on nerve fibers. The best-described central sites of action of morphine are at spinal and brainstem (midbrain) loci. Autoradiographic and immunohistochemical studies have shown opioid receptors to be localized primarily in the superficial dorsal horn (laminae I–II); a smaller population has been demonstrated in deeper layers.46,47 The relative proportion of opioid receptor subtypes in the rat spinal cord has been reported to be approximately 70%, 20%–30%, and 5%–10% for ␮, ␦, and ␬ receptors, respectively. The majority of these receptors appear to be located on presynaptic terminals of fine afferent

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Table 1.2. Opioid receptors and their ligands Mu

Delta

Kappa

ORL-1

Endogenous agonist

Beta-endorphin Endomorphin

Met-enkephalin Leu-enkephalin

Nociceptin/OFQ

Other Agonists Antagonists

Morphine DAMGO Naloxone

DPDPE DSTBULET Naltrindole Naloxone

Dynorphin A(1−8) Dynorphin A(1−13) Dynorphin B U50488H Naloxone Nor-BNI

Phe1 ␺ (CH2NH) Gly2 NC(1−13) NH2

–

Abbreviations: DAMGO, [D-Ala2, N-Me-Phe4, Gly5-ol] enkephalin; DPDPE, [D-Pen2, D-Pen5]-enkephalin; DSTBULET, Tyr-DSer(OtBu)-Gly-Phe-Leu-Thr; OFQ, orphanin FQ.

Fig. 1.4. An overview of some of the changes that occur after injury to a peripheral nerve together with the types of animal models used to study the mechanisms of neuropathy. A: CCI model, B: PSTL model, C: selective SNL model.

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Fig. 1.5. Spinal analgesic actions of opioids. Transmitter release from the terminals of peripheral sensory C-fibers is controlled by opioids, but not that from A-fibers. Postsynaptic inhibitory controls act to modulate firing of spinal neurons.

fibers. Hence, the predominant presynaptic localization suggests a main action of opioids through the inhibition of transmitter release. Indeed, more than 70% of the total ␮ receptor sites in the spinal cord are localized presynaptically on primary afferent terminals, and only 25% of the receptor population is found on postsynaptic sites, on interneurons, or on dendrites of deep cells in the C-fiber terminal zone.47 Morphine acts on the ␮ receptor, as do most of the clinically used opioid drugs The ␮ receptor is remarkably similar in structure and function in all species studied, so the basic studies will be good predictors for human applications. Genetic differences in the structure of this receptor appear to be one basis for differing requirements for opioid doses in patients.48 The spinal actions of opioids and their mechanisms of analgesia involve 1) reduced transmitter release from nociceptive C-fibers and 2) postsynaptic inhibitions of neurons conveying information from the spinal cord to the brain (Fig. 1.5). The presynaptic action of opioids is the predominant one, and here activation of inhibitory opioid receptors on C-fiber terminals blocks the release of glutamate, SP, and other afferent transmitters. This reduction of transmitter release markedly reduces the activation of spinal pain– transmitting neurons by C-fiber activity. Any activation of these neurons by peripheral activity would be countered

by the postsynaptic opioid receptors that now inhibit firing of the neuron.49 Hence, through the combined effect of these mechanisms, opioids can produce powerful antinociceptive effects, and this has been demonstrated in a large number of studies in various pain states.50,51 Some opioids, such as methadone and ketobemidone, may have additional NMDA-blocking actions and so may be valuable in cases in which morphine effectiveness is reduced, such as in neuropathic pain. However, at the moment, it is hard to know whether this potential nonopioid action is a contributor to the actions of these drugs in patients. It is known that the opioid system is subject to a considerable degree of plasticity after various pain states.42,52 Hence, whereas inflammation results in an overall increase in the analgesic effect of opioids, neuropathic pain states after nerve injury often display decreased opioid sensitivities, leading to difficulties in achieving good opioid analgesia. The issue of opioid responsiveness in neuropathic pain states has been somewhat controversial and a subject of much debate over the past decade. Reports on the efficacy of opioids have been conflicting, and various effects have been reported, ranging from no analgesia53 to adequate pain relief after sufficient dose escalation.54 It is now generally acknowledged, however, that neuropathic pain states are not completely refractory to opioid treatments, and clinical reports have demonstrated beneficial effects in some patients.55 Various factors are responsible for bringing about these changes in opioid actions after

nociception: basic principles nerve injury, including a loss of opioid receptors. This is seen only after complete nerve section and may account for the poor opioid sensitivity of postamputation pains. Less severe nerve damage can increase the levels of certain nonopioid peptides, such as cholecystokinin (CCK) – either spinally or supraspinally – which act as negative influences on opioid actions. Antagonists at the CCKB receptor have predicted actions in enhancing or restoring morphine analgesia.42 Changes after nerve damage may result in hyperexcitability of spinal neurons, against which opioid controls are insufficiently efficacious. The NMDA receptor is a strong candidate for generation of hyperalgesic states in neuropathic and ischemic pain models. An associated reduction in opioid effects frequently has been observed. Transmission of painful messages via the normally innocuous A-fiber population (allodynia) may occur as a result of pathological changes in peripheral and/or central processes. There are no opioid receptors on the central terminals of these fibers, so any inhibition of A-fiber–mediated allodynia could arise only from activation of the smaller population of postsynaptic opioid receptors. This may be the reason for the difficulties of controlling allodynia by opioids. Together with the opioid receptor system, ␥ -aminobutyric acid (GABA) forms another important inhibitory transmitter system within the spinal cord. GABA is found extensively within the CNS and appears to be localized in the superficial dorsal horn (laminae I–III), where it is found mainly within interneurons.26 GABAergic terminals contact A␦- and C-fiber terminals and exert tonic inhibitory controls on excitatory transmission.56 During inflammation, there appears to be an increase in the GABAergic inhibitory control, possibly reflecting a mechanism by which the enhanced neuronal excitability is counteracted.57 In direct contrast, there appears to be a significant decrease in spinal GABA levels after nerve injury.58–60 This has important implications because the loss of endogenous inhibitory controls may disturb the physiological equilibrium between excitatory and inhibitory transmitter systems and contribute to the induction of central hyperexcitability. However, manipulation of GABA is not a therapeutic target because of the ubiquitous roles of this transmitter in many CNS functions. Another inhibitory system includes the adenosine receptor system. The purines, adenosine and ATP, have been implicated in the modulation of nociceptive transmission, both in the periphery and in the CNS.61,62 Receptor sites for adenosine in the spinal cord have been identified in the substantia gelatinosa, where they are localized primarily on

13 intrinsic neurons. Two main subclasses of adenosine receptors (A1 /A2A/B ) have been described so far, and it appears to be predominantly the A1 receptor subtype that plays a major role in inhibiting the nociceptive input in the dorsal spinal cord.63 In support of this, A1 receptor agonists have been shown to inhibit wind-up, an NMDA receptor–mediated event.64 Monoamine systems originate in the midbrain and brainstem and act on the spinal transmission of pain. These systems are important sites of opioid actions located in these 5-HT and noradrenergic nuclei of the brainstem (e.g., midbrain), including the raphe nuclei, the periaqueductal gray matter, and the locus coeruleus.65–67 Opioid receptors in these zones (␮, ␦, and ␬), when activated, alter the level of activity in descending pathways from these zones to the spinal cord. The mechanisms of action of opioids at supraspinal levels are complex but appear to involve a switching on of inhibitory neurons and a turning off of excitatory neurons in the brainstem. This in turn attenuates the activity of spinal neurons through descending pathways. The relative roles of the 5-HT receptors in the spinal cord are yet unknown, but the spinal target for the noradrenaline released from descending pathways are ␣2 receptors that have similar actions and distribution to the opioid receptors.68 Sedation and hypotension with ␣2 agonists presently limit their use as analgesics. Opioid mechanisms at a number of other supraspinal sites (thalamic levels, the amygdala, and the sensory cortex) are likely of relevance to analgesia.48 Sites in the monoamine nuclei, such as the well-demonstrated actions of opioids on noradrenergic transmission in the locus coeruleus and enhancing dopamine release in the ventral tegmental area, are likely associated with reward processes and so relate to dependence.69 Because pain produces aversive psychological effects, it may be that the sensory stimulus “switches off” the neural circuitry that leads to reward and reinforcement. Thus, opioids in the presence of pain may not produce reward, whereas street use of the same drugs in the absence of pain may result in psychological dependence. The relative extent of the unwanted effects caused by selective agonists at the different opioid receptors is of great importance in determining whether non-␮ opioids will have more favorable actions than morphine. There are good indications that the ␦ and ␬ receptor agonists might cause less respiratory depression than ␮ agonists, and that prolonged protection of the enkephalins by the peptidase inhibitors has no dependence liability.70,71 As yet, no drugs have reached the clinic. The lack of dependence also is seen with ␬ agonists but is accompanied by aversive or nonrewarding

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effects that limit the usefulness of these agents in humans.72 Noradrenergic and serotonergic mechanisms of descending inhibition have been extensively described (for reviews, see Bonica2 ), and evidence shows a large degree of plasticity in these systems following injury. However, the past decade has seen a considerable number of descriptions of peripheral, spinal, and supraspinal mechanisms of hyperexcitability in pain pathways. Higher-order cognitive and emotional processes can influence perceived pain, and these also could include anxiety, mood, and attention. Such phenomena are enabled by the convergence of somatic and limbic systems into such descending modulatory systems. Areas in the midbrain and brainstem, such as the periaqueductal gray and the rostroventral medial medulla (RVM), are key structures in the descending modulatory repertoire. Such a system is important as it provides neural networks by which cognitive and emotional states can influence pain processing at the level of the spinal cord.73 In short, these circuits allow the brain to exert some control over spinal pain events. Recent animal studies suggest that in addition to inhibitory systems, there are important descending facilitations that can be engaged by external and internal processes and act to enhance intrinsic spinal mechanisms of pain. Descending controls from the brainstem and midbrain that can control spinal events are also altered by nerve injury. The role of supraspinal modulatory pathways in chronic pain states is supported by a number of recent findings of an enhanced descending facilitatory control of spinal activity in the maintenance stages of nerve injury, and in particular, a 5-HT3 receptor–mediated control on deep dorsal horn neurons following peripheral nerve injury. Ondansetron exerted greater inhibitory effects after spinal nerve ligation (SNL) compared with sham-operated controls, an effect selective for mechanical punctate stimuli, which may be one of the mechanisms whereby mechanical hyperalgesia and allodynia are produced after nerve injury.34 Recent work by Oatway and colleagues (2004)74 demonstrated that ondansetron significantly attenuates mechanical allodynia in a model of spinal cord injury, whereas administration of the 5-HT3 receptor agonist exacerbates pain behavior. A threefold increase in serotonergic fiber immunoreactivity has been reported in this model rostral to the injury site, which may be relevant to the enhanced effectiveness of 5HT3 antagonists after nerve injury. A randomized doubleblind study recently showed that a single intravenous bolus of ondansetron alleviates mechanical allodynia in neuropathic pain patients.75 Similar evidence exists for patients

with fibromyalgia who exhibit diffuse widespread pain.76 One may speculate that a certain intensity of peripheral input is required to increase activity in this excitatory pathway, and the maintenance of central sensitization likely involves distinct mechanisms in peripheral neuropathy and inflammation. Additionally, descending modulatory circuits display time-dependent changes in excitability following tissue injury77 such that RVM neurons undergo a phenotypic switch from excitatory to inhibitory.78 Timerelated changes may therefore also influence the level of activity in this excitatory serotonergic pathway mediated by the RVM so that this pathway may exert selective effects depending on the type of pain, modality, and duration. Given that there is also a descending inhibitory pathway that is partly mediated by noradrenaline, the balance between the dual control by monoamines through descending pathways from the midbrain and brainstem appears to favor excitation. It is therefore likely that the action of antidepressants in neuropathic pain involves alterations in this balance, because the effective drugs share the ability to alter synaptic levels of noradrenaline and serotonin. Mechanisms of visceral pain The ability to perceive pain from internal organs and cutaneous structures is part of the normal sensory repertoire of many animal species. Nevertheless, the neurophysiological basis of visceral sensation has been investigated to a lesser extent than that arising in superficial structures. Underlying reasons for this reside in differences between the nature of pain from visceral organs and from somatic structures, as well as greater complications associated with accessing visceral structures.79 Afferent innervation of viscera forms the peripheral component of the sensory link between the viscera and brain, mediating reflex control of internal organs. Viscera receive dual sensory innervation, comprising the sympathetic system (with spinal afferents) and the parasympathetic system (with vagal and sacral afferents).80,81 The latter is thought to mediate innocuous sensations, including local reflexes and accommodation of hollow organs. However, afferents terminating spinally are thought to mediate noxious sensations, and they share projection pathways similar to those of somatic afferents from the dorsal horn to higher centers. Accordingly, spinothalamic, spinoreticular, and dorsal column pathways have been shown to play an important role in the brain–gut axis. Chronically altered brain–gut interactions may thus contribute to mechanisms underlying autonomic dysregulation of the gut and altered neuronal

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sensitivities to gut stimuli in pathophysiologies such as irritable bowel syndrome (IBS).82 As the gut is innervated by afferents of the autonomic nervous system, visceral pain is often associated with marked autonomic phenomena, including gastrointestinal disturbances and changes in blood pressure and heart rate. Visceral pain is also perceived more diffusely than noxious cutaneous stimulation with respect to location and timing, which is the result of a low density of sensory innervation of viscera and extensive divergence of visceral input within the CNS.83 Moreover, viscerosomatic convergence produces symptoms of referred pain to parietal somatic structures within the same metameric field as the affected organ, often producing secondary hyperalgesia of superficial or deep body wall tissues.84 Opiates are a widely recognized class of compounds that are effective in producing analgesia. Opioid receptors are distributed throughout the CNS and peripherally. The prototypical opiate agonist, morphine, has been shown to reduce pain responses to colorectal distention, and clinically, the ␬ receptor agonist fedotozine is effective in treating abdominal pain and bloating in IBS patients.85,86 Serotonin is an important gastrointestinal signaling molecule that functions as a neurotransmitter used by enteric neurons and is a paracrine messenger for endochromaffin cells that act as sensory transducers.87 The presence of several serotonergic receptor subtypes allows for the investigation of selective drugs to modulate gastrointestinal secretion, motility, and sensation. The 5-HT3 antagonists ondansetron and granisetron are clinically approved for the treatment of IBS to relieve constipation, and the partial 5-HT4 agonist and 5-HT2B antagonist tegaserod effectively increases gastrointestinal secretion and reduces visceral sensitivity. Alosetron has been used in a model of visceral hyperalgesia to demonstrate that 5-HT3 receptors on vagal afferents contribute to a tonic inhibitory control of visceral nociception, whereas 5-HT3 receptors on spinal afferent terminals facilitate visceral nociceptive processing.88

pathophysiology of CIBP has been enabled by the development of mouse, and later rat, models of tumor-induced single bone destruction.90,91 These models parallel the clinical development of CIBP, with an initial painless period, developing gradually to a severe background and movementinduced pain, with the activated osteoblast/osteoclast population leading to abnormal bone modeling and eventually to pathological fracture. Behavioral changes and neurochemical alterations also have been reported in the ipsilateral spinal cord, including an increased expression of glial fibrillary acidic protein, dynorphin, and c-Fos protein.92 By recording second-order neurons in the dorsal horn of the spinal cord using in vivo electrophysiology, it is possible to gauge suprathreshold responses of neurons to peripheral stimuli changes after induction of bone cancer to mechanical, thermal, and electrically evoked stimuli. The superficial dorsal horn is populated predominantly with NS neurons that respond to nociceptive stimuli, compared with WDR neurons, which respond to a wide range of both noxious and innocuous stimuli.93 Establishment of CIBP changes the ratio of neurons so that WDR neurons dominate, suggesting that normally innocuous stimuli can now trigger painful messages, which may explain movement-induced pain and allodynias.91 The phenotype shift seen in the superficial dorsal horn is paralleled by the development of superficial and deep dorsal horn neuronal hyperexcitability to mechanical, thermal, and electrical stimuli, further suggesting an establishment of ongoing central sensitization. Importantly, these lamina I neurons have extensive projections to areas of the midbrain, such as the parabrachial nucleus and periaqueductal gray, as well as areas of the brain concerned with affective/emotional aspects of pain.94 This shift in phenotype of superficial laminae toward WDR neuronal populations implies that areas involved with interpretation of these affective aspects of pain are now being accessed by innocuous stimuli. Plausibly, this may result in tactile stimuli being able to activate pain experience areas of the brain, relating to the distress caused by allodynia.

Mechanisms of bone cancer pain

Animal models of persistent pain

Tumors that metastasize to the bone are commonly associated with a poorly controlled pain state that comprises a background pain and severe pain on moving or weight bearing.89 As the treatment of the underlying cancer has increased in efficacy, the persistence and severity of cancerinduced bone pain (CIBP) has increased, resulting in a loss of quality of life and intractable pain. The elucidation of the

Formalin-induced inflammation Subcutaneous injection of formalin is widely used to study tonic tissue injury–induced changes and has become an established model of inflammatory pain.95 The introduction of formalin into the peripheral receptive field is believed to activate the afferents directly through the activation of

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peripheral chemoreceptors and gives rise to an acute/phasic response. Electrophysiologically, the formalin test is characterized by a typical biphasic response – an early acute phase followed by a prolonged tonic phase. The initial acute phase may last up to 10 minutes after formalin injection, after which activity subsides into a silent interphase.96 This phase is followed by a second tonic phase, which begins approximately 25 minutes after injection. The firing of dorsal horn neurons subsides within an hour. These findings are comparable to those seen behaviorally, in which a similar two-phased paw-licking/flinching response has been observed.95 It has been proposed that the first-phase activity is mediated by the activation of AMPA receptors resulting from an acute afferent barrage in response to formalin. The tonic second phase, by contrast, is a consequence of the sustained afferent input and is produced by a series of biochemical and cellular events (central and peripheral sensitization).33,95 This latter phase is driven centrally by activation of the spinal NMDA receptor.96 Carrageenan-induced inflammation Carrageenan-induced inflammation represents a model of inflammatory cutaneous hyperalgesia. The injection of carrageenan produces rapid development of edema and inflammatory changes, which reach their maximum 3 to 5 hours after administration. The time course of this model is much longer than that seen with formalin inflammation and is maintained up to 72 hours.97 Animals display hyperalgesia to mechanical and thermal stimuli on the injected paw, which is manifested as a decrease in paw withdrawal latency and vocalization threshold. The inflammatory changes that occur in the periphery may have consequences for events at the spinal level. For example, the levels of opioid peptides and transcription markers are elevated after carrageenan inflammation.98 Similarly, the effects of exogenous opioids are enhanced when given spinally,99 and opioids acquire a novel peripheral effect after inflammation.100 Osteoarthritis A chemical model of osteoarthritis pain induced by intraarticular injection of monosodium iodoacetate, an inhibitor of glycolysis, has been developed in which progressive damage to cartilage leads to the slow induction of a pain state.101 This model is more persistent than formalin or carrageenan and exhibits a number of pain-related changes, such as mechanical hypersensitivity, cooling allodynia, and ambulatory-evoked pain that may be referred from the knee to the foot. Studies applying in vivo electrophysiology to models of inflammation showed a higher excitability of

deeper WDR neurons to mechanical stimuli and a contribution of descending pathways to the secondary hyperalgesia seen.102 Interestingly, after inflammation, it appears that the early increased inhibitions may start to fail in the chronic stage.103 Although the role of inflammation is seen most clearly in the earlier stages, the contribution of neuropathy to the longer-term changes in this model in which no further damage can occur appears unlikely, such that osteoarthritis may be an inflammatory pain that switches to a nociceptive pain state. Animal models of neuropathic pain Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Neuropathy can be divided broadly into peripheral and central neuropathic pain, depending on whether the primary lesion or dysfunction is situated in the peripheral nervous system or CNS. In the periphery, neuropathic pain may result from disease or inflammatory states that affect peripheral nerves (e.g., diabetes mellitus, herpes zoster) or, alternatively, may be the result of neuroma formation (amputation, nerve transection), nerve compression (e.g., tumors, entrapment), or other injuries (e.g., nerve crush, trauma).104 Central pain syndromes, by contrast, result from alterations in different regions of the brain or the spinal cord. Examples include a tumor or trauma affecting particular CNS structures (e.g., brainstem and thalamus) or spinal cord injury. Both the symptoms and origins of neuropathic pain are extremely diverse, and this makes the clinical conditions difficult to treat. Current treatment is still inadequate;105 hence, the availability of good animal models is clearly needed. Several models of nerve injury have so far been described, including models of total denervation (dorsal rhizotomy, total nerve section/crush, cryolysis), partial denervation (chronic constriction injury, partial sciatic nerve ligation, selective spinal nerve ligation), and spinal cord injury. Additionally, neuropathy models that involve systemic treatments have also been described (streptozocin-induced diabetic neuropathy).104 Models of partial denervation of the hindpaw Since the introduction of the first animal model of neuropathy involving complete nerve transection,106 models of partial hindpaw denervation based on restricted sciatic nerve injury have been used more frequently. Unlike models of total denervation, such as complete spinal transection or dorsal root rhizotomy, models of partial nerve injury preserve at least some of the sensory information passing into

nociception: basic principles the spinal cord. Three models that are widely used are the chronic constriction injury (CCI) model, partial sciatic tight ligation (PSTL) model, and selective SNL model.107–109 These animal models produce sensory abnormalities in rats, some of which resemble those observed in human neuropathic pain states. CCI model of neuropathy The CCI model, introduced by Bennett and Xie,107 involves the unilateral ligation of the sciatic nerve using chromic gut sutures. Four loose ligatures are placed around the common sciatic nerve, proximal to the trifurcation. The tightness of the ligatures is such that the nerve is barely constricted but not tight enough to obliterate the superficial epineurial vasculature supply. When placed around the nerve, the chromic gut suture may cause chemical irritation and produce an inflammatory reaction, which may contribute to the development of behavioral abnormalities.110 Hence, CCI may represent a model of inflammatory neuropathy. After surgery, rats show spontaneous pain-like behavior, consistent with the presence of ongoing neuropathic pain; they exhibit signs of allodynia and hyperalgesia.107 These abnormal behaviors are maintained up to 90 days after nerve injury. One of the problems associated with this model is the considerable variation in the amount of nerve damage that occurs after the application of the loose ligatures. The variation arises mainly because of the difficulty in placing ligatures with a consistent degree of compression, which could affect the number and type of injured afferent fibers.111 PSTL model of neuropathy Partial denervation of the hindpaw is produced by tightly ligating one third to one half of the common sciatic nerve.108 Similar to the CCI model, the PSTL results in the immediate onset of allodynia and hyperalgesia as well as behavioral signs of spontaneous pain, which persist for several months. Rats exhibit a change in foot posture of the ipsilateral hindpaw and also display signs of guarding behavior. Autotomy has not been observed in this model. One of the problems associated with this model is that the number and type of sciatic nerve axons that are ligated differ among animals, as it is not possible to damage exactly the same proportion of the nerve in each animal. Hence, there may be a considerable degree of variability associated with this model. Selective SNL model of neuropathy Peripheral nerve injury is produced by the unilateral tight ligation of two (L5 and L6) of the three spinal nerves (L4–L6) that make up the sciatic nerve.109 Selective SNL

17 (L5/L6) produces allodynia and hyperalgesia on the ipsilateral hindpaw, which persist for several weeks (5–10 weeks). Rats often exhibit signs of spontaneous pain and also display guarding behavior of the ipsilateral hindpaw. Autotomy is not observed in this model. Compared with the other two models of sciatic nerve injury,107,108 this model produces less variability among experiments because the same spinal nerves (L5/L6) are ligated in each animal. The only potential variability may arise from differences among individual rats in the proportion of the sciatic nerve contributed by its three spinal segments. One key feature of this model is that the location of the injured fibers is in spinal segments completely separate from the uninjured fibers.109 Hence the DRG, which contains the injured nerves, is separated from the neighboring DRG, which contains intact neurons. This allows us to selectively manipulate inputs from injured and intact fibers to spinal segments in an independent manner. This ability is unique to this model of nerve injury because in the CCI and PSTL models, the injured and intact primary afferent neurons are mixed within all the DRG innervating the sciatic nerve territory. Models of central pain Xu and colleagues112 developed a model of central pain that involves ischemic spinal cord injury induced photochemically by laser irradiation. The model produces allodynialike behaviors whose severity can be titrated by changing the duration of the light exposure. Models of diabetic neuropathy Various models have been developed recently to study the complications associated with the clinical condition of diabetes mellitus. The most widely used is the streptozocininduced diabetes produced by a single injection of streptozocin, which results in an insulin-dependent diabetic neuropathy.113 Studies have shown that the pharmacological characteristics of this model correspond well to the clinical experience from patients with painful diabetic neuropathy, thus making it a useful model to study the mechanisms underlying this condition.114 Use of present animal models of pain: benefits and problems The development of animal models has contributed to the understanding of the mechanisms underlying clinical pain

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states. Animal models may enable the replication of some of the symptoms associated with human disease and have been invaluable in providing information about the pathophysiological processes occurring after inflammation or nerve injury. Furthermore, animal models have contributed to the clinical management of various pain states by providing information about the therapeutic value of existing drugs, as well as revealing potential novel targets. Despite the apparent benefits of these animal models, it is important to be aware of some of the limitations and problems associated with their use. One must be cautious when extrapolating data from animal studies for clinical application. Although animal models produce behavioral responses that resemble those of various human pain states, it is not clear how these behavioral features correspond to the human perception of pain. We can only assume that the behavioral manifestation of the animal represents a similar clinical presentation of the pain in a patient. Another limitation of an animal model is that it is not possible to distinguish or discriminate the different types of pain sensations of the animal. Whereas clinicians can rely on descriptions given by patients to determine the clinical characteristic of the pain (e.g., “burning” pain or “shooting” pain), information from animal studies is confined to observations made on physical features and behavioral responses that are suggestive of pain. A question one needs to bear in mind when using animal models is: Which model relates to which clinical condition? Although some animal models represent specific clinical conditions (trigeminal CCI-induced neuropathy and diabetic neuropathy model), others are not as specific. Furthermore, even when the model appears to have a close resemblance to a specific condition, it is difficult to determine whether it represents the same pathological entity as that seen in patients and whether it would always respond to the same pharmacological interventions to the same extent. Hence, the direct clinical application of animal findings may not necessarily be straightforward. Nevertheless, the development of animal models has substantially improved our understanding of pain processes and has generally translated well to patients in terms of pain states and a rational basis for treatment. It is hoped that the continued interactions between the preclinical and clinical experts will lead to further progress in the fight against pain.

Acknowledgments The authors thank Dr. Vesa Kontinen for his contribution to the figures in this article.

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circuitry after inflammation. J Neurophysiol 87:750–60, 2002. Terayama R, Guan Y, Dubner R, Ren K. Activity-induced plasticity in brain stem pain modulatory circuitry after inflammation. Neuroreport 11:1915–9, 2000. Arendt-Nielsen L. Induction and assessment of experimental pain from human skin, muscle and viscera. In: Jensen TS, Turner JA, Wiesenfeld-Hallin Z, eds. Proceedings of the 7th World Congress on Pain. Progress in pain research and management, vol 8. Seattle: IASP Press, 1997, pp 393– 425. Jaenig W, Morrison JFB. Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. In: Cervero F, Morrison JFB, eds. Progress in brain research. New York: Elsevier, 1986, pp 87–114. Roman C, Gonella J. Extrinsic control of digestive tract motility. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven, 1987, pp 507–54. Mayer EA. Emerging disease model for functional gastrointestinal disorders. Am J Med 107:12S–19S, 1999. Procacci P, Zoppi M, Maresca M. Clinical approaches to visceral sensation. In: Cervero F, Morrison JFB, eds. Visceral sensation, progress in brain research, vol. 67. Amsterdam: Elsevier, 1986, pp 21–8. Hardy JD, Wolff HG, Goodell H. Experimental evidence on the nature of cutaneous hyperalgesia. J Clin Invest 29:115, 1950. Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterol Motil 16(Suppl 2):17–28, 2004. Dapoigny M, Abitbol J, Fraitag B. Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome. A multicenter dose-response study. Dig Dis Sci 40:2244–9, 1995. Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132:397–414, 2007. Bradesi S, Lao L, McLean PG, et al.: Dual role of 5-HT3 receptors in a rat model of delayed stress-induced visceral hyperalgesia. Pain 130:56–65, 2007. Mercadante S. Recent progress in the pharmacotherapy of cancer pain. Expert Rev Anticancer Ther 1:487–94, 2001. Honore P, Rogers SD, Schwei MJ, et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 98:585–98, 2000. Urch CE, Donovan-Rodriguez T, Dickenson AH. Alterations in dorsal horn neurones in a rat model of cancer-induced bone pain. Pain 106:347–56, 2003. Schwei M, Honore P, Rogers S, et al. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci 19:10886–97, 1999. Urch CE, Dickenson AH. In vivo single unit extracellular recordings from spinal cord neurones of rats. Brain Res Brain Res Protoc 12:26–34, 2003.

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94. Todd AJ. Anatomy of primary afferents and projection neurones in the rat spinal dorsal horn with particular emphasis on substance P and the neurokinin 1 receptor. Exp Physiol 87:245–9, 2002. 95. Dubuisson D, Dennis S. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4:161–74, 1977. 96. Haley JE, Sullivan AF, Dickenson AH. Evidence for spinal N-methyl-d-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res 518:218–26, 1990. 97. Winter C, Risley E, Nuss G. Carrageenan-induced edema in hindpaw of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med 111:544–7, 1962. 98. Iadarola M, Brady L, Draisci G, et al. Enhancement of dynorphin gene expression in spinal cord following experimental inflammation: stimulus specificity, behavioural parameters and opioid receptor binding. Pain 35:313–26, 1988. 99. Stanfa LC, Sullivan AF, Dickenson AH. Alterations in neuronal excitability and the potency of spinal mu, delta and kappa opioids after carrageenan-induced inflammation. Pain 50:345–54, 1992. 100. Stein C, Millan M, Shippenberg T, et al. Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat. Neurosci Lett 84:225–8, 1988. 101. Combe R, Bramwell S, Field MJ. The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats? Neurosci Lett 370:236–40, 2004. 102. Xu M, Kim CJ, Neubert MJ, Heinricher MM. NMDA receptormediated activation of medullary pro-nociceptive neurons is required for secondary thermal hyperalgesia. Pain 127:253– 62, 2007. 103. Danziger N, Weil-Fugazza J, Le Bars D, Bouhassira D. Alteration of descending modulation of nociception during the course of monoarthritis in the rat. Pain 127:253–62, 2007. 104. Ralston D. Present models of neuropathic pain. Pain Rev 5:83– 100, 1998. 105. Gilron I, Watson CP, Cahill CM, Moulin DE. Neuropathic pain: a practical guide for the clinician. CMAJ 175:265–75, 2006. 106. Wall PD, Devor M, Inbal R, et al. Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 7:103–113, 1979. 107. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107, 1988. 108. Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43:205–18, 1990. 109. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355–63, 1992. 110. Kawakami M, Weinstein JN, Spratt KF, et al. Experimental lumbar radiculopathy. Immunohistochemical and quantitative

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demonstrations of pain induced by lumbar nerve root irritation of the rat. Spine 19:1780–94, 1994. 111. Carlton SM, Dougherty PM, Pover CM, et al. Neuroma formation and numbers of axons in a rat model of experimental peripheral neuropathy. Neurosci Lett 131:88–92, 1991. 112. Xu X, Hao J, Aldskogius H, et al. Chronic pain related syndrome in rats after ischemic spinal cord lesion: a possible

animal model for pain in patients with spinal cord injury. Pain 48:279–90, 1992. 113. Ahlgren SC, Levine JD. Mechanical hyperalgesia in streptozotocin-diabetic rats. Neuroscience 52:1049–55, 1993. 114. Courteix C, Eschalier A, Lavarenne J. Streptozocin-induced diabetic rats: behavioural evidence for a model of chronic pain. Pain 53:81–8, 1993.

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Pathophysiology of malignant bone pain juan miguel jimenez-andrade, monica herrera, and patrick mantyh University of Arizona

Introduction Currently, more than 10 million people are diagnosed with cancer every year, and by 2020, it is estimated that 20 million new cases will be diagnosed each year.1,2 In 2005, cancer caused 7.6 million deaths worldwide.3 In the United States, cancer is a major health problem, being the second leading cause of death. Currently, 25% of U.S. deaths are cancer related.4 Cancer-associated pain may be present at any time during the course of the disease, but the frequency and intensity of cancer pain tend to increase with advancing stages of cancer. In patients with advanced cancer, 62%–86% experience significant pain, which is described as moderate to severe in approximately 40%–50% and as very severe in 25%–30%.5 Bone cancer pain is the most common pain in patients with advanced cancer; two thirds of patients with metastatic bone disease experience severe pain.6,7 Most common tumors, including those of the breast, prostate, thyroid, kidney, and lung, have a remarkable affinity to metastasize to bone.7 Currently, the factors that drive bone cancer pain are poorly understood; however, several recently introduced models of bone cancer pain not only are providing insight into the mechanisms that drive bone cancer pain, but are guiding the development of novel mechanism-based therapies to treat the pain and skeletal remodeling that accompany metastatic bone cancer. As analgesics can also influence disease progression, findings from these studies may lead to therapies that have the potential to improve the quality of life and survival of patients with skeletal malignancies.

The challenge of bone cancer pain Although bone is not a vital organ, most common tumors have a strong predilection for bone metastasis. Tumor

metastases to the skeleton are major contributors to morbidity and mortality in metastatic cancer. Tumor growth in bone results in pain, hypercalcemia, anemia, increased susceptibility to infection, skeletal fractures, compression of the spinal cord, spinal instability, and decreased mobility, all of which compromise the patient’s survival and quality of life.7,8 Once tumor cells have metastasized to the skeleton, tumor-induced bone pain is usually described as dull in character, constant in presentation, and gradually increasing in intensity with time.9 As bone remodeling progresses, severe spontaneous pain frequently occurs,9 and given that the onset of this pain is both acute and unpredictable, this component of bone cancer pain may be particularly debilitating to the patient’s functional status and quality of life.8,9 Breakthrough pain, which is an intermittent episode of extreme pain, may occur spontaneously or, more commonly, is induced by movement of or weight bearing on the tumor-bearing bone(s).10 Currently, the treatment of pain from bone metastases involves the use of multiple complementary approaches, including radiotherapy, surgery, chemotherapy, bisphosphonates, calcitonin, and analgesics.6,9 However, bone cancer pain is one of the most difficult of all persistent pains to fully control,9 as the metastases generally are not limited to a single site and the analgesics most commonly used to treat bone cancer pain, nonsteroidal anti-inflammatory drugs9 and opioids,9,11–13 are limited by significant adverse side effects.14,15 The onset of clinically apparent bone metastases marks a crucial moment in the natural history of cancer, sharply decreasing expected survival (on average, 12 months for prostate cancer patients after the diagnosis of bone metastasis).16 However, the length of survival continues to increase for cancer patients,17 so to maintain the patient’s quality of life and functional status, it is essential that new therapies be developed that can be administered over several years 23

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to control bone pain without the side effects commonly encountered with the currently available analgesics. In the last decade, the first animal models of bone cancer pain were developed. In terms of tumor growth, bone remodeling, and bone pain, these models appear to mirror several aspects of human bone cancer pain.18–22 Information engendered from these models has begun to provide insight into the mechanisms that generate and maintain bone cancer pain. Nevertheless, what remains unclear is how the primarily osteolytic animal models (which have been the most-used models to date) compare with common osteoblastic tumors that avidly metastasize to bone with regard to bone remodeling and tumor-induced bone pain. This chapter examines the similarities and differences between a primarily osteolytic sarcoma tumor and a primarily osteoblastic prostate tumor in terms of bone destruction, bone formation, tumor growth, macrophage infiltration, osteoclast and osteoblast number, and type and severity of bone cancer-related pain. Additionally, it discusses the remodeling of the sensory innervation of bone in osteolytic and osteoblastic bone cancer models.

growth factor expression and response properties, which in part underlie the development of peripheral sensitization so that normally non-noxious sensory stimulation is now perceived as noxious stimuli, resulting in a chronic pain state. This chapter focuses on the involvement of sensory neurons in the generation and maintenance of tumor-induced pain. However, it should be stressed that following cancerinduced injury to sensory neurons, areas of the spinal cord and central nervous system involved in the processing of somatosensory information also undergo a variety of neurochemical and cellular changes, known as central sensitization, that facilitate the transmission and conscious appreciation of both noxious and non-noxious sensory information. Thus, during the development of cancer, there is probably a slow but progressive neurochemical and cellular remodeling of both the peripheral and central nervous systems that inhibits, facilitates, or otherwise alters the transmission of somatosensory information from the damaged peripheral sensory fibers to the cerebral cortex, resulting in an altered and unwanted perception of both noxious and non-noxious sensory information.

Pain transmission Primary afferent sensory neurons are the gateway by which sensory information from peripheral tissues is transmitted to the spinal cord and brain, and these sensory neurons innervate every organ of the body except the brain. The cell bodies of sensory fibers that innervate the head and body are housed in the trigeminal and dorsal root ganglia (DRG), respectively, and can be divided into two major categories: 1) large-diameter myelinated A-fibers and 2) smalldiameter unmyelinated C-fibers and finely myelinated Afibers (Fig. 2.1). Large-diameter myelinated A␤-fibers originating in skin, joints, and muscles normally conduct non-noxious stimuli including fine touch, vibration, and proprioception. In contrast, most small-diameter sensory fibers are specialized sensory neurons known as nociceptors. Nociceptors have the remarkable ability to detect a wide range of stimulus modalities, including those of physical and chemical nature, by expressing an extremely diverse repertoire of receptors and transduction molecules that can sense forms of noxious stimuli, including thermal, mechanical, and chemical, albeit with varying degrees of sensitivity (Fig. 2.1). These unmyelinated C-fibers and finely myelinated A sensory neurons are involved in generating the chronic pain that accompanies many cancers. Following tissue injury induced by the tumor or tumor-associated cells, many nociceptors alter their pattern of neurotransmitter, receptor, and

Tumor growth, skeletal remodeling, and pain induced by primarily osteolytic or osteoblastic tumors When primarily osteolytic 2472 murine osteosarcoma tumor cells are injected and confined to the intramedullary space of the femur, these tumor cells grow in a highly reproducible fashion as they proliferate, replacing the hemopoietic cells in the bone marrow.20–22 Eventually, the entire marrow space is homogeneously filled with tumor cells and tumor-associated inflammatory/immune cells. In contrast, following injection and confinement of the primarily osteoblastic angiotensin-converting enzyme (ACE)-1 prostate cells into the mouse femur, the tumor cells are present in small clonal colonies throughout the marrow space of the femur, and these small colonies of osteoblastic tumor cells are separated from each other by extensive matrices of newly formed woven bone (Fig. 2.2). With regard to bone remodeling, injection of osteosarcoma cells to the femur induces predominant destruction along the entire bone, including the proximal and distal heads as well as the diaphysis. In sharp contrast, prostate tumor cells induce significant formation of new woven bone at the proximal and distal heads of the femur as well as the diaphysis of the bone (Fig. 2.2). The marked bone formation induced by prostate cancer cells also is accompanied by bone destruction, giving the tumor-bearing femur a unique

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Osteoclast Fig. 2.1. Primary afferent sensory nerve fibers involved in generating bone cancer pain. Primary afferent neurons innervating the body have their cell bodies in the DRG and transmit sensory information from the periphery to the spinal cord and brain. Myelinated A-fibers (A␤) containing large-diameter cell bodies, which project centrally to the dorsal column nuclei and deep spinal cord, are involved in detecting non-noxious sensations including light touch, vibration, and proprioception. Unmyelinated C-fibers and thinly myelinated A␦-fibers contain small-diameter cell bodies that project centrally to the superficial spinal cord. These fibers are involved in detecting multiple noxious stimuli (chemical, thermal, and mechanical). Box: Nociceptors use several different types of receptors to detect and transmit signals about noxious stimuli that are produced by cancer cells (yellow), tumor-associated immune cells (orange), or other aspects of the tumor microenvironment. There are multiple factors that may contribute to the pain associated with cancer. The TRPV1 and ASICs detect extracellular protons produced by tumor-induced tissue damage or abnormal osteoclast-mediated bone resorption. Several mechanosensitive ion channels may be involved in detecting high-threshold mechanical stimuli occurring when distal aspects of sensory nerve fiber are distended from mechanical pressure due to the growing tumor or as a result of destabilization or fracture of bone. Tumor cells and associated inflammatory (immune) cells produce a variety of chemical mediators, including prostaglandins (PGE2 ), NGF, endothelins, bradykinin, and extracellular adenosine 5 -triphosphate (ATP). Several of these proinflammatory mediators have receptors on peripheral terminals and can directly activate or sensitize nociceptors. (See color plate.)

scalloped appearance when assessed by microcomputed tomography (␮CT) or with traditional histological methodology; this appearance is similar to that observed in human patients with prostate tumor metastases.23 The concurrent bone destruction and formation in the prostate cancer model is quite distinct from that observed in tumors such as sarcoma21,24 or breast,25 in which the tumor is primarily osteolytic as bone destruction predominates.21,24 This mixed bone remodeling in the prostate

tumor–bearing femurs is characterized by an increase in a) the number of osteoclasts throughout the intramedullary space that drive osteolytic bone remodeling and b) the number of macrophages scattered throughout the tumor and remaining hematopoietic spaces in the bone. In the sarcoma bone cancer pain model, there is an upregulation in the number of osteoclasts and macrophages (a twofold greater increase in macrophages than in the prostate cancer line). However, it is the increase in the number of osteoblasts

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behaviors correlate with the progressive tumor-induced bone destruction or bone formation that ensues and appears to mimic the condition in patients with primary or metastatic bone cancer.

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Fig. 2.2. Bone remodeling and tumor growth in 2472 sarcoma– and ACE-1 prostate carcinoma–injected femurs have different characteristics depending on the osteolytic or osteoblastic component of the tumor cells as assessed by ␮CT imaging and hematoxylin and eosin staining. Sham-injected femurs present a relative absence of bone formation or bone destruction (A, D). The 2472 sarcoma–injected femurs display a primarily osteolytic appearance visible as regions absent of trabecular bone at the proximal and distal heads (B) as well as replacement of normal hematopoietic cells by tumor cells (E). The ACE-1 prostate carcinoma–injected femurs mainly present an osteoblastic appearance, which is characterized by pathologic bone formation in the intramedullary space (C) surrounding pockets of tumor cells that generate diaphyseal bridging structures (F). A–F: Scale bar, 0.5 mm. T, tumor; H, normal hematopoietic cells; WB, ACE-1-induced woven bone formation. (See color plate.)

found throughout the tumor-bearing intramedullary space that ultimately separates prostate tumors from the primarily osteolytic bone tumors, in which few osteoblasts are observed and little or no bone formation occurs. In these developed models, baseline, spontaneous, and evoked pain behaviors were assessed in the hind limb following tumor cell injection into the intramedullary space of the femur. Ongoing and movement-evoked pain–related behaviors increased in severity with time. These pain

Numerous studies have demonstrated that the periosteum is densely innervated by both sensory and sympathetic fibers26–28 and that it receives the greatest density of nerve fibers per area.29 With a combination of minimal decalcification and antigen amplification techniques, it also has been demonstrated that the bone marrow, mineralized bone, and periosteum all receive significant innervation by both sensory and sympathetic nerve fibers (Fig. 2.3).30–32 Because sensory and sympathetic neurons are present within the bone marrow, mineralized bone, and periosteum and all aspects of the bone are ultimately affected by fractures, ischemia, or the presence of tumor cells, sensory fibers in any of these compartments may play a role in the generation and maintenance of bone cancer pain. By examining the changes in the sensory innervation of bone induced by the primarily osteolytic sarcoma cells, investigators observed sensory fibers at and within the leading edge of the tumor in the deep stromal regions of the tumor. Additionally, these sensory nerve fibers displayed a discontinuous and fragmented appearance, suggesting that following initial activation by the osteolytic tumor cells, the distal processes of the sensory fibers ultimately were injured by the invading tumor cells. In contrast, examination of the sensory innervation of bone following injection of the primarily osteoblastic prostate cancer cells suggests that there is simultaneous injury and sprouting of sensory fibers in the bone. In the sarcoma-injected animals, there was expression of activating transcription factor (ATF)-3 in the nucleus of sensory neurons that innervate the femur (Fig. 2.4). ATF3 is a member of the ATF/CREB family of transcription factors, which is not expressed at detectable levels in normal sensory neurons or in sensory neurons following peripheral inflammation but is strongly expressed in sensory neurons following injury to peripheral nerves in neuropathic pain models.33 It is likely that the expression of ATF-3 in sensory neurons of tumor-bearing animals is a result of peripheral nerve destruction within the tumor-bearing femur.34 This tumor-induced injury of sensory nerve fibers in the sarcoma model also was accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic

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Fig. 2.3. Sensory innervation of mouse bone. A ␮CT three-dimensional image of a mouse femur illustrating the areas used for analysis of bone innervation (A). Low-power confocal photomicrograph of the proximal head of the mouse femur where the CGRP-positive (+) fibers are bright white and are present in the marrow and surround the trabeculae (white arrowhead, B). The inset in the top right of part B shows the average diameter of individual fibers in a bundle of CGRP fibers found in the marrow. High-power photomicrographs of CGRP expressing fiber in the marrow (C) and periosteum (D). Note that the CGRP+ nerve fibers are in close proximity to blood vessels within the haversian canal system, whereas in the periosteum, CGRP+ nerve fibers form a dense net-like meshwork. With permission from Mach et al.29

Fig. 2.4. ATF-3 and galanin are upregulated in primary sensory neurons that innervate the tumor-bearing femur 14 days following injection of osteolytic sarcoma cells into the intramedullary space of the femur. Neurons in the sham-vehicle L2 DRG express low levels of ATF-3 (A) or the neuropeptide galanin (C), whereas 14 days following injection and confinement of sarcoma cells to the marrow space, there is a marked upregulation of both ATF-3 (B) and galanin (D) in sensory neurons in the L2 DRG ipsilateral to the tumor-bearing bone. Many sensory neurons that show an upregulation of galanin in response to tumor-induced injury of sensory fibers in the bone also show an upregulation of ATF-3 in their nucleus (compare parts E and F, arrows). These data suggest that tumor cells invading the bone injure the sensory nerve fibers that normally innervate the tumor-bearing bone. A–D: Scale bar, 200 ␮m; E and F: scale bar, 100 ␮m. With permission from Peters et al.24 (See color plate.)

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A

even when the tumor is confined within the bone, a component of bone cancer pain is the result of tumor-induced injury to primary afferent nerve fibers that normally innervate the tumor-bearing bone.

Skeletal remodeling and acidosis in bone cancer pain

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Fig. 2.5. Confocal images showing the increase in the astrocyte marker GFAP in a mouse with bone cancer pain in the right femur. Coronal sections of the L4 spinal cord 21 days following injection of osteolytic sarcoma cells into the intramedullary space of the femur. In part A, GFAP is bright orange; in parts B and C, GFAP is green and the neuronal nuclei (NeuN) staining (which labels neurons) is in red. A low-power image (A) shows that the upregulation of GFAP is almost exclusively ipsilateral to the femur with the intraosseous tumor. Higher magnification of GFAP contralateral (B) and ipsilateral (C) to the femur with cancer shows that on the ipsilateral side, there is marked hypertrophy of astrocytes, characterized by an increase in both the size of the astrocyte cell bodies and the extent of the arborization of their distal processes. Additionally, this increase in GFAP (green) is observed without a detectable loss of neurons, as NeuN (red) labeling remains unchanged. A: Images, from 60-␮m thick tissue, are projected from six optical sections acquired at 4-␮m intervals with a 20× lens; scale bar, 200 ␮m. B and C: Images are projected from 12 optical sections acquired at 0.8-␮m intervals with a 60× lens; scale bar, 30 ␮m. Modified from Schwei et al.22 (See color plate.)

protein (GFAP; Fig. 2.5) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral DRG, and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur.24,35,36 Similar neurochemical changes have been described following peripheral nerve injury and in other noncancerous neuropathic pain states.37 Chronic treatment with gabapentin in the sarcoma model also did not influence tumor growth, tumor-induced bone destruction, or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but did attenuate both ongoing and movement-evoked bone cancer–related pain behaviors.24 These results suggest that

Recent experiments in a murine model of bone cancer pain have reported that osteoclasts play an essential role in cancer-induced bone loss and that osteoclasts contribute to the etiology of bone cancer pain.21,38 Osteoclasts are terminally differentiated, multinucleated, monocyte lineage cells that resorb bone by maintaining an extracellular microenvironment of acidic pH (4.0–5.0) at the osteoclastmineralized bone interface.39 Tumor-induced release of protons and acidosis may be particularly important in the generation of bone cancer pain. Both osteolytic (bonedestroying) and osteoblastic (bone-forming) cancers are characterized by osteoclast proliferation and hypertrophy.40 Bisphosphonates, a class of antiresorptive compounds that induce osteoclast apoptosis, also have been reported to reduce pain in patients with osteoclast-induced skeletal metastases.41–43 In a recent study of the bisphosphonate alendronate in the sarcoma model, a reduction in the number of osteoclasts and in osteoclast activity was noted, as evidenced by the reduction in tumor-induced bone resorption and in the number of osteoclasts displaying the clear zone at the basal bone-resorbing surface that is characteristic of highly active osteoclasts.44 In this model, alendronate also attenuated ongoing and movement-evoked bone cancer pain and the neurochemical reorganization of the peripheral and central nervous systems while promoting both tumor growth and tumor necrosis. These results suggest that in bone cancer, alendronate can simultaneously modulate pain, bone destruction, tumor growth, and tumor necrosis. Osteoprotegerin (OPG) is a secreted soluble receptor that is a member of the tumor necrosis factor receptor family.45 This decoy receptor prevents the activation and proliferation of osteoclasts by binding to and sequestering OPG ligand (also known as receptor for activator of nuclear factor-␬B ligand [RANKL]).45–48 OPG has been shown to decrease pain behaviors in the sarcoma model of bone cancer.38 These results suggest that a substantial part of the actions of OPG seems to result from inhibition of tumorinduced bone destruction via a reduction in osteoclast function. This reduction of osteoclast function in turn inhibits the neurochemical changes in the spinal cord that are thought to be involved in the generation and maintenance

pathophysiology of malignant bone pain of cancer pain, which demonstrates that excessive tumorinduced bone destruction is involved in the generation of bone cancer pain. The finding that sensory neurons can be directly excited by protons or acid originating from cells such as osteoclasts in bone has generated intense clinical interest in pain research.49,50 Studies have shown that subsets of sensory neurons express different acid-sensing ion channels.51,52 The two major classes of acid-sensing ion channels (ASICs) expressed by nociceptors are transient receptor potential vanilloid (TRPV1)53,54 and ASIC3.49,51,55 Both these channels are sensitized and excited by a decrease in pH. Tumor stroma56 and areas of ischemic necrosis57 such as that observed in the 2472 or ACE-1 prostate bone cancer model typically exhibit lower extracellular pH than surrounding normal tissues. As inflammatory cells invade tumor stroma, they release protons that generate local acidosis. The large amount of apoptosis that occurs in the tumor environment also may contribute to the acidotic environment. It has been shown that TRPV1 is present on a subset of sensory neuron fibers and on those that innervate the mouse femur (Fig. 2.1). TRPV1 antagonist or disruption of the TRPV1 gene results in a significant attenuation of both ongoing and movement-evoked nocifensive behaviors in a model of bone cancer pain.36 Previous studies also have shown that in the 2472 model, administration of a TRPV1 antagonist retains its efficacy at early, middle, and late stages of tumor growth.36 The ability of a TRPV1 antagonist to maintain its analgesic potency with disease progression is probably influenced by the fact that sensory nerve fibers innervating the tumor-bearing mouse femur maintain and upregulate the expression of TRPV1, even as tumor growth and tumor-induced bone destruction progresses.58 All together, these results suggest that the TRPV1 channel plays a role in the integration of nociceptive signaling in a severe pain state.

29 Prostaglandins Cancer cells and tumor-associated macrophages have been shown to express high levels of cyclooxygenase (COX) isoenzymes, leading to high levels of prostaglandins.75–79 Prostaglandins are lipid-derived eicosanoids that are synthesized from arachidonic acid by COX isoenzymes COX-1 and COX-2. Prostaglandins have been shown to be involved in the sensitization and/or direct excitation of nociceptors by binding to several prostanoid receptors expressed by nociceptors (Fig. 2.1).80 Studies have shown in the sarcoma model of bone cancer pain that chronic inhibition of COX-2 activity with selective COX-2 inhibitors resulted in significant attenuation of bone cancer pain behaviors as well as many of the neurochemical changes suggestive of both peripheral and central sensitization.21 In addition, prostaglandins have been shown to be involved in tumor growth, cell survival, and angiogenesis;81–87 therefore, besides having the ability to block cancer pain, COX-2 inhibitors are also capable of retarding tumor growth within bone.21 Chronic administration of a selective COX-2 inhibitor significantly reduced tumor burden in sarcoma-bearing bones, which may in turn reduce factors released by tumor cells capable of exciting primary afferent fibers.65 Acute or chronic administration of a selective COX-2 inhibitor significantly attenuated both ongoing and movement-evoked pain. Whereas acute administration of a COX-2 inhibitor presumably reduces prostaglandins capable of activating sensory or spinal cord neurons, chronic inhibition of COX-2 also appears to simultaneously reduce osteoclastogenesis, bone resorption, and tumor burden. Together, suppression of prostaglandin synthesis and release at multiple sites by selective inhibition of COX-2 may synergistically improve the survival and quality of life of patients with bone cancer pain.

Endothelins

Tumor-derived products in generation of bone cancer pain The tumor stroma is made up of many different cell types apart from cancer cells, including immune cells such as macrophages, neutrophils, and T lymphocytes. These cells secrete a variety of factors that have been shown to sensitize or directly excite primary afferent neurons, such as prostaglandins,59,60 tumor necrosis factor-␣,61–64 endothelins,65,66 interleukin-1 and -6,61,67,68 epidermal growth factor,69 transforming growth factor-␤,70,71 and plateletderived growth factor.72–74 Receptors for many of these factors are expressed by primary afferent neurons.

Endothelins (ET-1, -2, and -3) are a family of vasoactive peptides expressed at high levels by several types of tumors, including those that arise from the prostate.66 Clinical studies have shown a correlation between the severity of pain and plasma levels of endothelins in prostate cancer patients.88 Endothelins might contribute to cancer pain by directly sensitizing or exciting nociceptors, as a subset of small unmyelinated primary afferent neurons express endothelin A receptors (ETA Rs) (Fig. 2.1).89 Furthermore, direct application of endothelin to peripheral nerves induces activation of primary afferent fibers and an induction of pain-related behaviors.90 Like prostaglandins, endothelins

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produced by cancer cells also are thought to be involved in regulating angiogenesis91 and tumor growth.92 In the sarcoma model, acute or chronic administration of the ETA R selective antagonist ABT-627 significantly attenuated ongoing and movement-evoked bone cancer pain. Chronic administration of ABT-627 also reduced several neurochemical indices of peripheral and central sensitization without influencing tumor growth or bone destruction.93 As tumor expression and release of ET-1 has been shown to be regulated by the local environment, locationspecific expression and release of ET-1 by tumor cells may provide insight into the mechanisms that underlie the heterogeneity of bone cancer pain that is frequently observed in humans with multiple skeletal metastases. Kinins Previous studies have shown that bradykinin and related kinins are released in response to tissue injury and that these kinins play a significant role in driving acute and chronic inflammatory pain.94 The action of bradykinin is mediated by two receptors termed B1 and B2 . Whereas the B2 receptor is constitutively expressed at high levels by sensory neurons, the B1 receptor is normally expressed at low but detectable levels by sensory neurons, and these B1 receptors are significantly upregulated following peripheral inflammation and/or tissue injury.95 Tumor metastases to the skeleton induce significant bone remodeling with accompanying tissue injury, which presumably induces the release of bradykinin. It has been demonstrated that both bone cancer-induced ongoing and movement-evoked nocifensive behaviors were reduced following the pharmacologic blockade of the B1 receptor.96 Nerve growth factor One important concept that has emerged over the past decade is that in addition to nerve growth factor (NGF) being able to directly activate sensory neurons that express the trkA receptor, NGF modulates expression and function of a wide variety of molecules and proteins expressed by sensory neurons that express the trkA or p75 receptor. Some of these molecules and proteins include neurotransmitters (substance P and calcitonin gene-related protein [CGRP]), receptors (bradykinin R), channels (P2×3, TRPV1, ASIC3, and sodium channels), transcription factors (ATF-3), and structural molecules (neurofilaments and the sodium channel anchoring molecule p11) (Fig. 2.1).97,98 Additionally, NGF has been shown to modulate the trafficking and

insertion of sodium channels such as Nav 1.899 and TRPV1100 in the sensory neurons as well as modulating the expression profile of supporting cells in the DRG and peripheral nerves, such as nonmyelinating Schwann cells and macrophages.101 Therefore, anti-NGF antibody therapy may be particularly effective in blocking bone cancer pain, as NGF appears to be integrally involved in the upregulation, sensitization, and disinhibition of multiple neurotransmitters, ion channels, and receptors in the primary afferent nerve and DRG fibers that synergistically increase nociceptive signals originating from the tumor-bearing bone. Two recent studies in which the same analgesic therapy was used in the primarily osteolytic 2472 sarcoma and the primarily osteoblastic ACE-1 prostate bone cancer model demonstrated not only that administration of an anti-NGF antibody was highly efficacious in reducing both early- and late-stage bone cancer pain–related behaviors, but that this reduction in pain-related behaviors was greater than that achieved with acute administration of 10 or 30 mg/kg of morphine sulfate.19,35 In light of these findings, the mechanisms that contribute to the efficacy of anti-NGF in blocking sarcoma or prostate tumor–induced bone pain remain a critical matter that requires further investigation.

Conclusions For the first time, animal models of cancer pain are now available and effectively mirror the clinical picture observed in humans with bone cancer pain. Information generated from these models has begun to provide insight into the mechanisms that generate and maintain bone cancer pain and has helped target potential mechanism-based therapies to treat this chronic pain state. It is noteworthy that in these models, analgesics such as bisphosphonates, OPG, and COX-2 inhibitors appear to influence disease progression in the tumor-bearing bone. Together, these and other studies using models of bone cancer suggest that it may be possible to develop novel mechanism-based therapies that not only reduce tumor-induced bone pain, but perhaps provide added benefit in synergistically reducing disease progression. Successful development and clinical use of these therapies not only may have a positive impact on survival, but also may improve the cancer patient’s quality of life.

Acknowledgments This work was supported by National Institutes of Health grants NS23970 and NS048021 and a Merit Review from the Veterans Administration.

pathophysiology of malignant bone pain

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SECTION II

EPIDEMIOLOGY AND SYNDROMES

3

Cancer pain epidemiology irene j. higginson and fliss murtagh King’s College London

Introduction Cancer pain afflicts millions of people worldwide every year, yet it can be well or completely controlled in 80%– 90% of patients.1–3 Exactly how many of the estimated 6.6 million people worldwide who died from cancer last year4 experienced pain at any one time is difficult to ascertain. The reasons for this are discussed in the following text. Nevertheless, in spite of the major advances in pain control over the past 15 years, cancer-related pain continues to be a major international public health problem.5–21 Although pain is recognized as an extremely common symptom in patients with cancer, studies to date show a wide variation in the reported prevalence.22–24 A systematic review of 19 studies recording the prevalence of pain in cancer found pain reported in 35%–96% of patients.25 Three main factors influence this variation: 1. Difficulty in making generalizations to different health care settings or different patient groups because of variation in the design of prevalence studies26,27 2. Inherent difficulties in assessing the presence or absence of pain, particularly because no one “gold standard” assessment system exists, exacerbated by attempts to grade the severity of cancer pain in a variety of ways 3. Difficulty in defining the type of pain,28 because pain associated with cancer has features of both chronic and acute pain and can be either the direct or indirect result of the cancer29,30 Pain and cancer are not synonymous.31 Evaluation of pain in advanced cancer is primarily clinical and is based on pattern recognition. Attention to detail is necessary to prevent inappropriate treatment.32 Comprehensive pain assessment is important, but initial treatment with analgesics should not be withheld until this has been carried out.31 There are

many reasons that pain remains unrelieved, associated with the patient or family, and the doctor or nurse.

Definition and diagnosis The definition of pain Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”33 By definition, pain is subjective, and each person’s interpretation depends on experiences in earlier life. There is no definitive way to distinguish pain occurring in the absence of tissue damage from pain resulting from damaged tissue.34 Not only is it a sensation in a part or parts of the body, but it is also “always unpleasant and therefore an emotional experience.”33 Pain is a complex and unique experience. In addition to its physiological basis, it can be affected by situational factors and by psychological processes including emotion, cognition, and motivation. The perception of pain is therefore modulated by the patient’s mood, the patient’s morale, and the meaning of pain for the patient.31 Moreover, the situational and psychological factors are all susceptible to cultural, ethnic, and linguistic influences.31,35 Recent qualitative exploration comparing black Caribbean and white U.K. cancer patients suggests that pain is interpreted in varied ways – sometimes as a test, a punishment, or a challenge, which alters the patient’s attitude toward pain and pain treatment.36 Difficulties in cancer pain assessment There are several problems associated with cancer pain classification in epidemiology. Study designs are often limited and not generalizable for the reasons given in the following paragraphs. Variation among studies makes it difficult to combine data effectively.25 37

38 First, pain is usually studied in health care settings rather than in communities of people. Therefore, the prevalence estimates relate to a group of patients referred to a specific service (e.g., a pain clinic). For example, the study carried out by Coyle37 reviewed later in this chapter was performed in patients referred to the Supportive Care Program of the Pain Service at the Memorial Sloan-Kettering Cancer Center. The patients studied were a subgroup of 90 problematic patients whose management “taxes the clinical skills and compassion of practitioners, as well as the psychological and financial resources of the patient and family.” Hence, although this study provided detailed insight into the management and symptomatology of this particular population, there are obvious limitations in making generalizations from a population who are all experiencing intractable pain. Some studies include only patients who have pain. Although these give valuable information on pain syndromes, mechanisms, and treatment, they do not give prevalence estimates (see, e.g., Lin,38 who examined relationships between disclosure and pain management, or Uki et al.,39 who examined the utility of a pain assessment tool). Second, measures of pain are not constant among studies. Although severity and its impact on patient function are both critical to assessment, severity is the main factor that determines the impact of pain.40,41 Failure to assess the severity of pain and the variety of methods used for its categorization compound the difficulties in assessment. Further work is needed to develop systematic assessments of pain, which can be used in routine care and for epidemiological monitoring. Third, pain in cancer is not a well-defined entity.28 A patient may have several pains, which in turn can have features of both acute and chronic pain. Although the site of the tumor influences the characteristics of the pain and the type of intervention,42 the situation is complicated because the definition of cancer pain also incorporates the pathology of pain (e.g., nociceptive or neuropathic,29 pain related to the cancer [bedsores], pain related to the cancer treatment [postoperative scar pain], or pain caused by a concurrent disorder [spondylosis]).43 In addition to these problems in assessment, in some instances the incidence of pain is determined from records of analgesic use. These estimates are likely to be lower than would have been obtained if pain had been systematically assessed. Aspects of assessment First of all, the physician must believe the patient’s report of pain and initiate discussions about pain. The assessment

i.j. higginson and f. murtagh should define the nature and extent of the underlying disease, evaluate concomitant problems (physical, psychological, and social) that may contribute to patient distress, and clarify the goals of care.44 The assessment should thereby clarify the pain characteristics and syndrome, infer the putative mechanisms that may underlie the pain, and determine the impact of the pain on function and psychological wellbeing.44 If necessary, additional investigations should be carried out to clarify uncertainties in the assessment.45 When selecting a mode of measuring pain severity, the response mode must be41 1) sufficiently graded to identify changes, 2) clear to both subjects and investigators, and 3) easy to score. Visual analogue, verbal descriptor, and numeric rating scales have been used in the clinical setting to assess pain severity and have been shown to approach equivalency in their results.46 Numeric rating scales have been endorsed for use in trials and practice because they are easier to understand and to score.47 These have also been shown to be less affected by language or cultural interpretation of pain severity. A study using multidimensional scaling to compare the rating of pain’s interference in four countries revealed two dimensions to the reporting of pain irrespective of pain severity or cultural or linguistic background35 – activity and affect. Activity was defined in terms of walking, work, general activity, and sleep. Affect is related to functions such as relationships with others, mood, and enjoyment of life.35 The research program of the European Palliative Care Research Collaboration is studying the methods of assessment and management of three symptoms – pain, depression, and cachexia. The pain assessment work package is seeking to develop a uniform agreed-on and validated method to assess pain across the collaborative. It is studying pain intensity and the extent to which pain interferes with activities – although pilot work has found high correlations between these two aspects.48 The results of this collaborative will be very valuable in unifying assessment across research studies and in practice. Some general assessment tools include pain alongside other symptoms and problems and thus can be valuable in monitoring pain. As more and more standardized assessment tools become available,49 comparisons between settings may become feasible. Such measures include the Edmonton Symptom Assessment System,50 the Palliative Care Outcome Scale,51 the Support Team Assessment Schedule,52 the Memorial Symptom Assessment Scale,53 and the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire,54 as well as standard quality-of-life measures such as the SF-36 and the EQ-5D, used in health economic studies.

cancer pain epidemiology Assessment also may be carried out by interview, either with the patient or, in certain situations, with the assistance of the family. Whether an assessment is carried out by the physician, the nurse, or the patient will obviously affect the data collected. In a study validating a staff-rated outcome measure for use in palliative care, staff were found to underrate the level of pain and family or caregivers overrated the level of pain as compared with the patient’s self-report of pain.52 However, in a recent validation of the Palliative Outcome Scale caregiver version, lay caregivers showed substantial agreement with patients’ self-ratings.55 The limitations of each method of measurement need to be understood and noted when reporting cancer pain prevalence data, because the methods used will affect the outcomes of the study. Another key factor in measuring the prevalence of pain is the time period of assessment. Assessments range from pain now, to pain during the past 24 hours, to pain in the past 1, 2, or even 6 months. Any binary scale of pain present/absent will lead to a higher prevalence if a longer time period of assessment is included. (Compare responses to “Have you had pain in the past 24 hours?” with those to “Have you had pain in the past month?”). Graded scales (such as a 0–4 scale) do not have as many problems in interpretation as a result of changes in the period of assessment, because patients tend to average their experience over time. The classification of cancer pain is a controversial issue. Ventafridda and Caraceni56 suggest the following: 1. Every study involving patients with cancer pain and analgesic treatments should provide a precise description of the symptoms, including details of all clinical and instrumental diagnostic criteria. 2. A classification of pain according to the definition of somatic, visceral, and nerve pains should separate differentiation, neuropathic, or dysesthetic pain from nerve trunk pains. 3. Temporary patterns of pain and their precipitating factors should always be specified. This classification reflects an ideal situation and would overcome many of the problems encountered when reviewing the prevalence estimates in this area. However, simple clinical tools are now available to help in the classification of neuropathic pain, which is one of the key pains to differentiate because of the different outcomes and management. For example, the Leeds Assessment of Neuropathic Symptoms and Signs57 has now been validated for use in cancer.58 Unfortunately, the primary data do not allow us to classify the studies of cancer pain in this way; therefore, we are restricted to making generalizations from studies, with caveats attached.

39

Prevalence of cancer pain To determine the prevalence of cancer pain, a systematic literature review involving four stages was undertaken: literature searching and study retrieval, the assessment of studies for inclusion on the basis of relevance and design, data extraction, and data synthesis59 (See cancer pain, 1st ed., Chapter 2, cancer pain epidemiology). This review has been updated for this chapter, using other reviews and a PubMed search. Thus, in addition to the earlier review, Medline and PubMed were searched to 2008. The databases were searched using the words cancer pain as the main search term in the title, abstract, or key words of an article. Inclusion/exclusion and data extraction The criteria for including studies in this review were defined based on the work of Portenoy,24 who proposed using two related sets of survey data to provide epidemiological estimates of cancer pain prevalence. Hence, a study was included in the review if the article reported the prevalence of cancer pain in a clearly defined cancer population, which was derived from: 1. A survey on the natural history of the neoplasm that included information on pain 2. The preliminary stage of a broader study on pain management or cancer service evaluation In addition, a seminal review article by Bonica60 was included because the original studies in this review were especially difficult to locate (because of the age and location mainly of the unpublished gray literature), and the data from some would not have been included otherwise. Studies were excluded if they selected only patients who had pain, or were historical accounts, personal opinions, or case studies. Because of the problems of varied measurement, a metaanalysis of the data could not be carried out. Data extracted from the published studies were reviewed as a whole (Tables 3.1 and 3.2) and are synthesized in the text. Prevalence of pain A total of 64 studies met the criteria for inclusion in the review (Tables 3.1 and 3.2). It became apparent that although cancer pain is prevalent at all stages of the disease and may often be the first symptom of cancer, it is more common in advanced and terminal cancer. For this reason, studies focusing on people with cancer at all stages or who are newly diagnosed (Table 3.1) are considered

i.j. higginson and f. murtagh

40 Table 3.1. The prevalence of cancer pain in general cancer populationsa Study type Prospective survey Prospective survey Prospective survey

Disease definition and tumor type General cancer population General cancer population Breast, prostate, colon, or rectum and three gynecological tumors

Sample size

Prevalenceb

540 397 237

r 29% (specified by site) r 38% (60% of the terminal patients) r 72%

667

r 18% to 49% had had pain as an early r r r r

Prospective survey

Lung, pancreas, prostate, and uterine cervix

536

r r

Prospective survey

General cancer population

240

r r r r r

Quasi–meta-analysis Retrospective patient record survey

General cancer population General cancer population

Prospective survey

Newly diagnosed general cancer population

Prospective survey

General cancer population with intractable pain

Prospective study Prospective survey

Prostate, colon, breast, or ovarian cancer patients Ovarian cancer patients

14,417 35,683

r r r r

240

r r

1635

r r

symptom (specified by site) 48% had had pain in the past month Due to the cancer in 56% and 17% with metastatic or nonmetastatic disease, respectively Mean scores for worst pain: 4.0 (SD 3.6) to 6.7 (SD 7.1)c Mean scores for average pain: 2.5 (SD 3.5) to 5.7 (SD 2.1)c 64% with typical pain (specified by site) 30% with slight pain, 30% with moderate pain, 4% with very bad pain 19% had very bad worst pain 45% Mean score for present intensity, 2.9 (SD 2.5)c Mean score for most severe pain in past week, 7.2 (SD 2.4) 28% maximal interference, 55% extensive interference 51% of patients at all stages 74% of advanced/terminal patients 32.6% overall In 11.4% before treatment, 24.9% in curative stage, 48.7% in conservative stage, 71.3% in terminal stage 35%; a total of 28% still had pain 46% had pain related to the cancer, 67% had pain secondary to cancer or its treatment, 18% had unrelated pain 99% with continuous pain, 1% with incident or breakthrough pain 3% mild, 11% moderate, 33% severe, 49% very severe/maximal 64% (specified by site)

243

r

151

r 42% r 62% had had pain preceding diagnosis or

Reference Foley, 197922 Trotter et al., 198184 Daut & Cleeland, 198240

Greenwald et al., 198785

Dorrepaal et al., 198990

Bonica, 199060 Hiraga et al., 199161

Vuorinen, 199363

Grond et al., 199426

Portenoy et al., 199473 Portenoy et al., 199470

recurrence

r Mean severity of pain in general was r r Prospective survey

Advanced general cancer population

369

r r r r

Prospective cross-sectional multicenter survey

general cancer population

605

r r r

moderate, mean severity for worst pain was severe 40% experienced any pain almost constantly, 21% experienced worst pain almost constantly Median duration of worst or only pain was 2 weeks (range ⬍1–756 weeks) 54% with cancer-related pain Mean score for average daily pain, 3.6 (SD 2.2) (between mild & moderate) Mean number of hours per day in pain, 9.2 (SD 9.1) Mean number of days per week in pain, 4.2 (SD 2.8) 57% (specified by site), 65% of whom had metastatic disease 69% rated pain as significant (score of 5 or more)c 54% rated average pain significant

Glover et al., 1995106

Larue et al., 199576

cancer pain epidemiology

Study type Descriptive survey (unclear whether it was cross-sectional or prospective)

Disease definition and tumor type Ambulatory patients with breast cancer

41

Sample size 97

Prevalenceb

Reference

r 64% r 73% of which was cancer-related r Mean score for average daily pain, 3.4

Miaskowski & Dibble, 1995107

(SD 2.3) (mild to moderate)

r Mean number of hours per day in pain, 8.9 (SD 10.1)

r Mean number of days per week in significant pain, 3.8 (SD 3.0)

Prospective survey

Pain clinic cancer population

2266

r 85% caused by cancer, 17% treatment r r

Prospective study

Randomized controlled trial

General cancer population, all with pain

383

General cancer population

438

r r

r r

Retrospective cross-sectional study Prospective survey

General cancer population Patients with recurrent breast or gynecologic cancers

13,625 114

r

r 70% of patients with breast cancer and r r

Prospective study

Newly diagnosed general cancer population

296

r r

Cross-sectional study

General cancer population General cancer population, all with pain requiring opioid medication

217

r

1095

r

Prospective cross-sectional international survey

r r r

Prospective longitudinal study

Patients with cancers of the head and neck

93

related, 9% associated with cancer disease, 9% unrelated 77% had an average pain intensity of severe or worse on previous day 30% had one pain, 39% had two pains, 31% had three or more pains Patients had a mean of 1.8 pain locations, and mean pain duration of 14.2 months (SD 33.4) Mean present pain intensity on a numeric rating scale (maximum score 10) was 3.3 (SD 2.3), mean average pain intensity over previous week was 4.9 (SD 2.1) Pain score – mean 9.9 in treatment group and 11.1 in control group (range 0–40) Prevalence – 42% in treatment group and 36% in control group at pretest and 39% in both groups at posttest 29% reported daily pain

r r r

63% of patients with gynecologic cancer had had at least a little pain over the past 4 weeks 51% had mild to moderate pain 62% stated their pain interfered with their ability to function 38% had cancer-related pain Of these, 65% had significant worst pain (i.e., worst pain level scores ≥5 on a 10-point scale), and 31% had significant average pain (i.e., average pain level scores ≥5 on a 10-point scale) 64% had pain at some time in the past 2 weeks Mean duration of pain, 5.9 months (SD 105) 67% reported worst pain intensity over past day was ≥7 on a 10-point numeric scale 25% experienced two or more pains 80% had pain due to the cancer, 18% had treatment-related pain 48% had pain at admission, 8% severe, 14% in the shoulder 25% had pain at 12 months, 3% severe, 37% in the shoulder 26% had pain at 24 months, 3% severe, 26% in the shoulder

Grond et al., 1996108

de Wit et al., 1997109

Elliott et al., 1997110

Bernabei et al., 1998111 Rummans et al., 1998112

Ger et al., 199864

Wells et al., 1998113 Caraceni & Portenoy, 1999114

Chaplin & Morton, 1999115

(continued)

i.j. higginson and f. murtagh

42 Table 3.1 (continued) Study type Prospective study

Secondary analysis of prospective data from four studies, including a clinical trial Prospective survey

Prospective study

Disease definition and tumor type General cancer population, all with pain

Sample size 593

Prevalenceb

Reference

r 64% nociceptive pain, 5% neuropathic

Grond et al., 1999116

pain, 31% mixed

r Mean intensity on a numeric rating scale

Patients with primary lung cancer or cancer metastatic to bone

125

General cancer population (in- and outpatients)

240

Patients with pancreas cancer, all with pain

50

(maximum score 100) at admission was 66 (nociceptive), 70 (neuropathic), and 65 (mixed), reducing to 26, 28, and 30 after 3 days, and 18, 21, and 17 at the end of the survey r 72% had pain r McGill pain questionnaire total score – mean 19.7 (SD 12.5), range 0–53

r 59% had pain (67% of inpatients, 47% r r r

Prospective survey

Prospective survey Population-based survey Prospective survey

Prospective survey Prospective survey

Cross-sectional survey

a

of outpatients) Of in-patients, 64% of those with pain had a malignant pain syndrome, 23% a non-malignant pain syndrome, and 11% mixed The 36 patients in group 1 scored 5.4 (SD 0.54) on a pain visual analogue scale (maximum score possible, 10) The 14 patients in group 2 scored 7.6 (SD 0.88) 51.5% had pain, as assessed by physician interview using a structured questionnaire; 29.3% of these had pain thought to be related to the tumor 35.7% had cancer-related pain, as identified by screening questions at interview 61.6% had cancer-related pain as identified by self-completed questionnaire 53% had pain 22% had pain, which they reported as “quite a bit” or “very much”

Berry et al., 1999117

Chang et al., 2000118

Rykowski & Hilgier, 2000119

258

r

263

r

Randomly selected patients from the cancer population General cancer population attending oncology outpatient clinics Hospitalized cancer patients

1555

r

480

r r

1392

r 61% had pain, identified using EORTC

Rustoen et al., 2003124

General cancer population attending oncology outpatient clinics General cancer population, including oncology in- and outpatients

480

QLQ-C30, with almost 30% reporting moderate or severe pain r 54% had pain r Severe pain was reported by 35% and moderate pain by 35.4% of patients

Hsieh, 2005125

178

r 50% had pain during the previous 24

General cancer population hospitalized for at least 24 hours General cancer population

hours, identified using the Brief Pain Inventory; moderate to severe pain occurred in 50% of patients surveyed, with 23% reporting severe pain and 33% reporting severe impairment in their ability to work due to pain

Ripamonti et al., 2000120

Beck & Falkson, 2001121 Liu et al., 2001122 Lidstone et al., 2003123

Reyes-Gibby et al., 2006126

Studies are listed in order of publication date. Percentages for severity breakdowns may not equal overall percentages quoted because of missing values. c 0 = no pain, 10 = worst pain as assessed by a pain rating scale. d Period of terminal care = period of care from end of active treatment to the patient’s death (median time 9 weeks). e Scores relate to hours of pain multiplied by a severity coefficient; values can range from 0 to 240. Study types Survey: the main purpose of the study was to survey pain or symptom prevalence. Study: there may have been other reasons for the study, e.g., as a service evaluation or an evaluation of management/control. b

cancer pain epidemiology

43

Table 3.2. The prevalence of cancer pain in patients with advanced or terminal disease, or who are at the end of lifea Study type Retrospective record review and interviews with general practitioners and caregivers Retrospective interview study Prospective survey

Disease definition and tumor type

Sample size

Prevalenceb

Reference

Patients who had died from cancer of the pharynx, breast, bronchus, stomach, colon, rectum

279

r 62%

Ward, 197465

Bereaved caregivers of advanced general cancer population Far-advanced general cancer population, all in pain

165

r 36% had no to mild pain, 31% had

Parkes, 197866

100

r r r r

Prospective study Prospective evaluation study Prospective study

Terminal general cancer population or their primary caregivers Advanced general cancer population Terminal general cancer population

1754

r r

256

r

60

Retrospective record review but with prospective data collection

Advanced, clinically challenging cancer patients

90

Prospective study

Advanced general cancer population Terminal general cancer population Advanced general cancer population

65

Prospective study Prospective survey

r Mean scores 53.5 (SD 37.5) and 41.9 (SD r r r

120 78

moderate pain, 33% had severe to very severe pain Only 41% had all their pain caused directly by the cancer 90% had had pain for ⬎4 weeks, 57% of these for ⬎16 weeks For those who had pain for ⬎8 weeks, 77% had severe to excruciating pain 80% had more than one pain, 34% of these had four or more 69% 19% mild, 21% discomfort, 16% distressing, 7% horrible, 5% excruciating 53%

r

29.1) for home care and hospital care patients, respectivelye 100% 27% mild, 19% mild to moderate, 34% moderate, 20% moderate to severe Major limitation for 94% of those rating pain as moderate to severe 68% rated pain as a problem

r 100% r 71% (specified by site) r 24% mild, 40% moderate, 36% severe r 60% had one main site of pain, 35% had

Twycross & Fairfield, 198272

Morris et al., 1986127 McIllmurray & Warren, 1989128 Ventafridda et al., 1989129 Coyle et al., 199037

Higginson et al., 1990130 Ventafridda et al., 1990131 Simpson, 199171

two, 5% had three or more

Retrospective record review

Advanced cancer population

110

r 69% r 34% related to the primary cancer, 43%

Retrospective record review

Advanced general cancer population who died on the unit Bereaved caregivers or informants of people who had died from cancer Advanced general cancer population over 65 years of age Lung cancer patients General advanced cancer population

100

r 99%

Fainsinger et al., 199199

383

r 87% in 1969 r 84% in 1987

Cartwright, 199167

239

r 58% with discomfort/pain r 12% mild, 18% discomfort, 17% distress,

Stein & Miech, 1993132

52 1000

r 88% r 83% with pain r Ranked as most severe symptom out of 30

Chan & Woodruff, 199195

related to metastatic disease

Retrospective interview study Retrospective record review Prospective study Prospective study

7% horrible, 6% excruciating

Mercadante et al., 1994133 Donnelly et al., 1996134

common symptoms

Prospective survey Retrospective interview study Prospective study

Advanced general cancer population Bereaved caregivers of general cancer population Far-advanced general cancer population

125 2018 98

r 74% r Over 25% r 88% r 64%

Ellershaw, 199574 Addington-Hall & McCarthy, 199568 Shannon et al., 1995135 (continued)

i.j. higginson and f. murtagh

44 Table 3.2 (continued) Study type Prospective survey

Disease definition and tumor type Advanced general cancer population,all in pain

Sample size 111

Prevalenceb

Reference

r 46% had all pain caused by the cancer, 29%

Twycross et al., 1996136

r r Prospective study Prospective study Retrospective study

Advanced cancer population Advanced general cancer population Caregivers of general cancer population

1640 695 170

r r r r r r

Retrospective cross-sectional survey Prospective study

Retrospective cohort study

Advanced general cancer population

100

Advanced general cancer population

3577

Advanced cancer patients who subsequently died

223

r r r r r r r r r r

Prospective study

Advanced cancer patients admitted to hospice

232

Retrospective case note review

Patients referred to palliative care services – hospice, community, hospital, and outpatient (95% with cancer; of these, 71% had advanced disease) Patients with metastatic cancer or stage IV lymphoma in hospital for ⬎72 hours for complications not treatment In- and outpatients with metastatic or recurrent cancer

400

Cross-sectional survey

Prospective survey

a

66

r r r r r r r

had associated pains, 5% had pain related to the treatment Median score of 4 for average pain, median score of 6 for worst painc 85% had ⬎1 pain, ⬎40% of these had four or more 72% (specified by site) 24% mild, 30% moderate, 21% severe 70% (specified by site) 54% mild or moderate, 16% severe or overwhelming 86% stated pain was a problem, 61% reported a great deal or quite a bit of pain, 25% had some or little pain 82% reported data on pain relief intervention, 46% of which made pain stop/get better, 56% of which made pain a little better or had no effect or made it worse 77% had current pain Majority had mild pain 76% had regular analgesics for their pain 70.3% had pain at referral Mean intensity on a visual analogue scale (maximum score 10) was 4.4 at referral, 2.5 at 1 week, 2.3 in the last week of life Pain reported in 66% of all abstracted patient visits 13.2% of patients never had a documented pain complaint 19% had pain complaints documented at each visit Presence of metastases not significantly associated with presence of pain Hospice programs differed in the proportion of visits for which pain was reported (75%, 64%, and 48%) 81% had pain at the time of admission Pain severity worsened in the 48 hours before death (prevalence not reported) 64% had pain at first assessment In the hospice, 62% of patients had pain In the community setting, 56% had pain In the hospital service, 63% had pain In the outpatient service, 75% had pain

r 78% of patients had pain (assessed using the

Vainio et al., 1996137 Higginson & Hearn, 199727 Bucher et al., 199969

Chung et al., 1999138 Mercadante, 1999139

Nowels & Lee, 1999140

Chiu et al., 2000141 Potter et al., 2003142

Tranmer et al., 2003143

Memorial Symptom Assessment Scale)

655

r 70.8% had some pain in the previous 24

Yun et al., 2003144

hours r 63.3% rated their pain at 5 or higher on a visual analogue scale of 0–10

Studies are listed order of publication date. Percentages for severity breakdowns may not equal overall percentages quoted because of missing values. c 0 = no pain, 10 = worst pain as assessed by a pain rating scale. d Period of terminal care = period of care from end of active treatment to the patient’s death (median time, 9 weeks). e Scores relate to hours of pain multiplied by a severity coefficient; values can range from 0 to 240. Study types Survey – the main purpose of the study was to survey pain or symptom prevalence. Study – there may have been other reasons for the study, e.g., as a service evaluation or evaluation of management/control. b

cancer pain epidemiology separately from those concentrating on patients with advanced or terminal disease (Table 3.2). The prevalence of pain at all stages and in early disease Thirty-four studies reported on the prevalence of pain in the general adult cancer population (i.e., studies usually at a varying stage of presentation) (Table 3.1). After three studies of patients in pain were excluded by virtue of their attending pain clinics or similar programs, the studies gave a combined weighted mean prevalence of pain of 35%, range 18%–85%. Note, however, that this estimate includes three low estimates determined from the use of analgesics alone as a measure of pain prevalence (Foley:22 29% and 38%; Hiraga et al.:61 33%). In addition, Elliott et al.62 reported a prevalence of 18% among pediatric patients with current or past malignancy. Excluding these studies would provide a weighted mean prevalence of pain of 41%, range 29%–85%. There is little evidence on the prevalence of pain at or around the time of diagnosis. Vuorinen63 reported 35% of newly diagnosed patients had experienced pain in the past 2 weeks; Daut and Cleeland40 reported that 18%–49% of patients had had pain as an early symptom of the disease. Ger et al.64 found that 38% of newly diagnosed cancer patients had pain. Prevalence of pain in advanced cancer Thirty studies reported data on pain prevalence in the advanced or terminal cancer population (Table 3.2). In the majority of cases, the data are for point prevalence estimates, obtained at referral to a particular service. Period prevalence estimates mainly related to pain over the past week, and occasionally the past 2 weeks or month. As a result of the variation in methods of measuring and reporting the data, the values were simply combined to provide a crude overall mean prevalence based on the number of patients in each study and the number reported to be experiencing pain (i.e., a weighted estimate). The combined weighted mean prevalence of pain was 75%, range 53%– 100%. There was no relationship between prevalence and study sample size. Five studies had used retrospective data collected from bereaved caregivers of patients with cancer or from other informants who could provide information on particular patients.65–69 Obviously, there are limitations to these data in that the interviews with the bereaved caregivers or informants are subject to recall bias, as well as being subjective assessments. Overall, the estimates were slightly higher than those for patient reports. Reports from the Regional Studies for the Care of the Dying67,68 provided period

45 prevalence estimates of pain in “the last year of life” at three time points: 87% in 1969, 84% in 1987, and 88% in 1995. The studies by Ward65 and Parkes66 considered pain in “the period of terminal illness” and gave a pain prevalence of 62%–64%. Bucher et al.69 reported that 86% of patients had a problem with pain in the last 4 weeks of life. These prevalence estimates may be higher than patient reports because of the longer period included (e.g., last year of life), because bereaved caregivers overestimate pain compared with patient assessments, or because samples were biased by nonresponse from patients with the most severe pain. The prevalence of pain by primary tumor site Table 3.3 combines some studies that provided prevalence data on pain in more than one cancer type in the general adult cancer population. These show a wide range in reported prevalence by tumor site, but the cancers with more than 70% of patients with pain reported in more than one study are: r r r r

Head and neck (mean 80%, range 67%–91%) Genitourinary (mean 77%, range 58%–90%) Esophagus (mean 74%, range 71%–77%) Prostate (mean 74%, range 56%–94%)

One hundred percent of patients with advanced multiple myeloma70 and with advanced sarcoma71 were experiencing pain. Portenoy et al.70 found that 42% of ovarian cancer patients had pain. This evidence must be viewed with caution, as the data are from only one study for each cancer type; however, it does illustrate the extent of the problem. Cancers of the blood are said to have little pain associated with the disease, particularly in the early stages. This opinion could be substantiated by the evidence from the study by Foley,22 which reported only 5% of patients with leukemia experiencing pain. Nevertheless, the range of pain prevalence values for lymphoma was 20%–87%; hence, pain in cancers of the blood should not be underestimated. The severity and effect of pain The various stages of disease considered and the methods of measurement make it difficult to summarize the data in the tables to provide valid estimates of the prevalence of severe pain, or the proportion of pain affecting or dominating the daily life of patients. However, it is obvious by looking qualitatively at the data that there is a great deal of unrelieved pain at referral to all the services carrying out these studies.

e

d

c

b

a

80%

5%

85%

40%

70%–75% 20%

52% 45%

40%; 14%

59%; 39%

0%; 35%

47%; 40%

75%; 30%

64%; 40%

Daut & Cleeland, 198240,b

72%

56%

71% 56%

Greenwald et al., 198785

100%

20%

83% 50%

50%–71%

88% 50%

50% 17%

Simpson, 199171

67%

62%

68%

60%

Portenoy et al., 199470

100%

83%

87% 91% 71% 77% 85% 90% 85%

79%

94%

89%

Donnelly et al., 1995145

67%

56%

58% 35%

56% 58%

Larue et al., 199576

74%

71%

83%

78% 74% 83% 90% 87% 79%

Vainio & Auvinen, 1996137

68%

74% 74%

76% 71%

Higginson & Hearn, 199727

91%

100%

60% 87%

79%

70% 78%

Chiu et al., 2000141

53%e

52%

58%

40% 38%

62% 68%

Lidstone et al., 2003123

10 8 5 6 6 5 5 4 5 3 2 3 2 1 1 1 2 1 1 1 1 1 1 2

Number of studies

See Tables 3.1 and 3.2 for further details on each study (Donnelly et al.,145 Simpson,71 Vainio & Auvinen,137 and Higginson & Hearn27 report on advanced cancer populations). Metastatic disease; nonmetastatic disease-N.B. An overall percent was determined for each cancer type from the original article, not given here. Calculated using the overall % values where necessary. Cervix/cervix-vagina/uterine cervix. Brain tumors.

Breast Lung Prostate Genitourinary Lymphoma Colorectal Gastrointestinal Cervixd Head and neck Ovary Esophagus Pancreas Uterine corpus Bladder Bone Carcinomatosis Central nervous system Kidney Leukemia Melanoma Multiple myeloma Oral cavity Sarcoma Stomach

Tumor site

Foley, 197922

Table 3.3. Prevalence of pain by primary tumor sitea

40–89 17–74 56–94 40–90 20–87 40–79 40–68 33–87 67–91 46–71 71–77 72–100 30–90 – – – 50–53 – – – – – – –

Range of %

cancer pain epidemiology In the study by Grond et al.26 of patients referred to a pain clinic, patients experiencing very severe or maximal pain complained more frequently of insomnia, sweating, vomiting, and paresis. In this study, the use of strong opioids was associated with a higher prevalence of anorexia, constipation, nausea, neuropsychiatric symptoms, vomiting, urinary symptoms, and paresis. Studies assessing the number of pains a patient is experiencing have shown that a large proportion of patients have two or more distinct kinds or causes of pain, reflecting the complexity of disease associated with malignancy.31,71–73 High-risk groups When considering risk factors for cancer pain, it is important to be clear which “type” of cancer pain is under investigation. In this section, pain associated with direct tumor involvement is discussed. Pain associated with the cancer therapy, such as postoperative pain syndromes, or pain syndromes related or unrelated to the cancer itself, such as myofascial pains or constipation, are not considered here. With increases in chemotherapy in cancer, however, they are of growing prevalence and importance. The evidence shows that the prevalence of pain varies according to the site of the cancer and the stage of the disease. Although there are limitations to the data, as discussed earlier, it is possible to draw several conclusions as to who is more likely to be at risk. Patients reported as more likely to experience pain may be those with primary tumors of the head and neck, the genitourinary system, the esophagus, and the prostate (mean prevalence values for these tumors from more than one study were more than 70%). In addition, the higher prevalence estimates found for patients with far-advanced cancer would indicate that these patients are more likely to be experiencing pain at referral to a service than those at earlier stages of the disease. Daut and Cleeland40 found that more pain is usually associated with metastatic than nonmetastatic disease. For example, 64% of patients with metastatic breast cancer had pain, compared with 40% of patients with nonmetastatic disease, a pattern that is consistent throughout cancer types. This may be related to stage of disease. Age is not necessarily associated with a greater number of symptoms in cancer,26 and there is no evidence as to whether age is a predictor of pain in cancer patients. There is some suggestion that pain may be lower among elderly people, but it is not clear whether this is a result of physiological changes, different cultural systems, or ageism.

47 There is no evidence on whether specific psychological factors predispose to the initial onset of pain. However, the effect of pain on increasing psychological distress has been well documented, and it is likely that patients with unresolved psychosocial problems will experience more frequent or more intense pain compared with those patients who are not experiencing psychological distress, according to the models of “suffering” and “total pain.” The severity of pain is determined by the previously mentioned factors combined with the method of pain control therapy administered, and whether it has been appropriate to the needs of the individual patient. The continued reports of high levels of pain prevalence on referral to cancer services suggest that pain is important and in some instances not being managed as well as it should be.27,74–76 Health professionals should not assume that patients previously receiving care elsewhere have adequate pain control.

Challenges for the future in the epidemiology of cancer pain The reality of addressing cancer pain control, coupled with the increasing number of people living to older ages and living longer with cancer, makes reducing the prevalence of pain at any stage of the disease process of paramount importance. Collaboration is needed with the nonmedical sectors of society to ensure that palliative care becomes an integral part of patient care.77 Just as important as research in the purely medical aspects of pain and palliative care are the social, economic, and cultural attitudes toward pain, suffering, and the terminally ill.78–85 This is especially true as the proportion of caregivers declines relative to the growing number of patients who need care.3 Much more work is needed to study the epidemiology of pain in palliative care and community populations, rather than in specialist centers, but using standardized assessments and longitudinal studies so that the pattern of changes in pain can be understood over time. Further work is also needed on meanings and treatment of pain in different cultural populations and among older people. As cancer treatments change, so may the nature and prevalence of pain in cancer, and this will require careful assessment.86–88 The gap between what is possible in pain control and what is achieved is a result of:1,89–102 1. A lack of awareness that established methods already exist for cancer pain management

48 2. A lack of systematic teaching of medical students, doctors, nurses, and other health care workers about cancer pain management 3. Fears about addiction in both cancer patients and the wider public if strong opioids are more readily available for medical purposes 4. The nonavailability of necessary pain relief drugs in many parts of the world 5. The use of special “triplicate prescription” forms for controlled drugs, which discourages the use of strong opioids 6. A lack of concern by governments Quality improvement guidelines for the treatment of acute pain and cancer pain were published by the American Pain Society Quality of Care Committee in 1995,103 building on guidelines published by others.78–81,104,105 There are five key elements to the guidelines for improving quality of care for people with acute or cancer pain: 1. Ensuring that a report of unrelieved pain raises a “red flag” that attracts clinicians’ attention 2. Making information about analgesics convenient where orders are written 3. Promising patients responsive analgesic care and urging them to communicate pain 4. Implementing policies and safeguards for the use of modern analgesic technologies 5. Coordinating and assessing implementation of these measures Clinicians often do not recognize how frequently pain remains untreated or inadequately managed.23 It should not be assumed that if a person has been receiving cancer care or treatment in a health care setting, their pain is being adequately controlled.27,82 Continual assessment of the response of the patient’s pain complaint is essential to ensure continuous pain control and to prevent breakthrough pain.83,87 As other chapters in this textbook show, there are now approaches to ensure the development of systems to better manage cancer pain. There is also a need for training and education, a key function of the specialist in palliative care. Health care professionals in all health care settings need to monitor pain and know how to treat cancer pain effectively. References 1. Grond S, Zech D, Schug SA, et al. Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life. J Pain Symptom Manage 6:411–22, 1991.

i.j. higginson and f. murtagh 2. Zech DF, Grond S, Lynch J, et al. Validation of World Health Organization guidelines for cancer pain relief: a 10year prospective study. Pain 63:65–76, 1995. 3. Stjernsward J, Colleau SM, Ventafridda V. The World Health Organization Cancer Pain and Palliative Care Program. Past, present, and future. J Pain Symptom Manage 12:65–72, 1996. 4. World Health Organization. The World Health Report, 1996. Fighting disease, fostering development. Executive summary. Geneva: World Health Organization, 1996. 5. Allende S, Carvell HC. Mexico: status of cancer pain and palliative care. J Pain Symptom Manage 12:121–3, 1996. 6. Cherny NI. Israel: status of cancer pain and palliative care. J Pain Symptom Manage 12:116–17, 1996 7. Erdine S. Turkey: status of cancer pain and palliative care. J Pain Symptom Manage 12:139–40, 1996. 8. Fernandez A, Acuna G. Chile: status of cancer pain and palliative care. J Pain Symptom Manage 12:102–3, 1996. 9. Goh CR. Singapore: status of cancer pain and palliative care. J Pain Symptom Manage 8:431–3, 1993. 10. Larue F, Fontaine A, Brasseur L, Neuwirth L. France: status of cancer pain and palliative care. J Pain Symptom Manage 12:106–8, 1996. 11. Laudico AV. The Philippines: status of cancer pain and palliative care. J Pain Symptom Manage 8:429–30, 1993. 12. Lickiss JN. Australia: status of cancer pain and palliative care. J Pain Symptom Manage 12:99–101, 1996. 13. Merriman A. Uganda: status of cancer pain and palliative care. J Pain Symptom Manage 12:141–3, 1996. 14. Moyano J. Colombia: status of cancer pain and palliative care. J Pain Symptom Manage 12:104–5, 1996. 15. Soebadi RD, Tejawinata S. Indonesia: status of cancer pain and palliative care. J Pain Symptom Manage 12:112–15, 1996. 16. Strumpf M, Zenz M, Donner B. Germany: status of cancer pain and palliative care. J Pain Symptom Manage 12:109–11, 1996. 17. Sun WZ, Hou WY, Li JH. Republic of China: status of cancer pain and palliative care. J Pain Symptom Manage 12:127–9, 1996. 18. Takeda F. Results of field-testing in Japan of the WHO draft interim guideline on relief of cancer pain. Pain Clinic 1:83–9, 1986. 19. Wenk R, Ochoa J. Argentina: status of cancer pain and palliative care. J Pain Symptom Manage 12:97–8, 1996. 20. Zylicz Z. The Netherlands: status of cancer pain and palliative care. J Pain Symptom Manage 12:136–8, 1996. 21. Zhang H, Gu WP, Joranson DE, Cleeland C. People’s Republic of China: status of cancer pain and palliative care. J Pain Symptom Manage 12:124–6, 1996. 22. Foley KM. Pain syndromes in patients with cancer. In: Bonica JJ, Ventafridda V, eds. Advances in pain research and therapy. New York: Raven Press, 1979, pp 59–75. 23. Bonica JJ. Treatment of cancer pain: current status and future needs. In: Fields HL, ed. Advances in pain research and therapy, vol 9. New York: Raven, 1985, pp 589–616. 24. Portenoy RK. Cancer pain. Epidemiology and syndromes. Cancer 63(11 Suppl):2298–307, 1989.

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64. Ger LP, Ho ST, Wang JJ, Cherng CH. The prevalence and severity of cancer pain: a study of newly-diagnosed cancer patients in Taiwan. J Pain Symptom Manage 15:285–93, 1998. 65. Ward AWM. Terminal care in malignant disease. Soc Sci Med 8:413–20, 1974. 66. Parkes CM. Home or hospital? Terminal care as seen by surviving spouses. J R Coll Gen Pract 28:19–30, 1978. 67. Cartwright A. Changes in life and care in the year before death 1969–1987. J Public Health Med 13:81–7, 1991. 68. Addington-Hall JM, McCarthy M. Dying from cancer: results of a national population-based investigation. Palliat Med 9:295–305, 1995. 69. Bucher JA, Trostle GB, Moore M. Family reports of cancer pain, pain relief, and prescription access. Cancer Pract 7:71–7, 1999. 70. Portenoy RK, Kornblith AB, Wong G, et al. Pain in ovarian cancer patients. Prevalence, characteristics, and associated symptoms. Cancer 74:907–15, 1994. 71. Simpson KS. The use of research to facilitate the creation of a hospital palliative care team. Palliat Med 5:122–9, 1991. 72. Twycross RG, Fairfield S. Pain in far-advanced cancer. Pain 14:303–10, 1982. 73. Portenoy RK, Thaler HT, Kornblith AB, et al. Symptom prevalence, characteristics and distress in a cancer population. Qual Life Res 3:183–9, 1994. 74. Ellershaw JE, Peat SJ, Boys LC. Assessing the effectiveness of a hospital palliative care team. Palliat Med 9:145–52, 1995. 75. Larue F, Colleau SM, Fontaine A, Brasseur L. Oncologists and primary care physicians’ attitudes toward pain control and morphine prescribing in France. Cancer 76:2375–82, 1995. 76. Larue F, Colleau SM, Brasseur L, Cleeland CS. Multicentre study of cancer pain and its treatment in France. BMJ 310:1034–7, 1995. 77. Stjernsward J, Koroltchouk V, Teoh N. National policies for cancer pain relief and palliative care. Palliat Med 6:273–6, 1992. 78. Portenoy RK. Report from the International Association for the Study of Pain Task Force on cancer pain. J Pain Symptom Manage 12:93–6, 1996. 79. Max M. American Pain Society quality assurance standards for relief of acute pain and cancer pain. In: Bond MR, Charlton JE, Woolf CJ, eds. Proceedings of the VI World Congress on Pain. Amsterdam: Elsevier, 1990. 80. Jacox A, Carr DB, Payne R. Special report. New clinical practice guidelines for the management of pain in patients with cancer. N Engl J Med 330:651–5, 1994. 81. Foley KM, Portenoy RK. World Health OrganizationInternational Association for the Study of Pain: joint initiatives in Cancer Pain Relief. J Pain Symptom Manage 8:335–9, 1993. 82. Kaasa S, Malt U, Hagen S, et al. Psychological distress in cancer patients with advanced disease. Radiother Oncol 27:193–7, 1993. 83. Cassell EJ. The relief of suffering. Arch Intern Med 143:522– 3, 1983.

i.j. higginson and f. murtagh 84. Trotter JM, Scott R, Macbeth FR, et al. Problems of the oncology outpatient: role of the liaison health visitor. Br Med J (Clin Res Ed) 282:122–4, 1981. 85. Greenwald HP, Bonica JJ, Bergner M. The prevalence of pain in four cancers. Cancer 60:2563–9, 1987. 86. Bruera E, Macmillan K, Hanson J, MacDonald RN. The Edmonton staging system for cancer pain: preliminary report. Pain 37:203–9, 1989. 87. Bruera E, Schoeller T, Wenk R, et al. A prospective multicenter assessment of the Edmonton Staging System for cancer pain. J Pain Symptom Manage 10:348–55, 1995. 88. Portenoy RK, Foley KM, Inturrisi CE. The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions. Pain 43:273–86, 1990. 89. Cleeland CS. The impact of pain on the patient with cancer. Cancer 54(11 Suppl):2635–41, 1984. 90. Dorrepaal KL, Aaronson NK, van Dam FS. Pain experience and pain management among hospitalized cancer patients. A clinical study. Cancer 63:593–8, 1989. 91. World Health Organization. Cancer pain relief. 3–74. Geneva: World Health Organization, 1986. Available from http://www.who.int/cancer/palliative/en. 92. Zenz M, Willweber-Strumpf A. Opiophobia and cancer pain in Europe. Lancet 341:1075–6, 1993. 93. Vainio A. Treatment of terminal cancer pain in France: a questionnaire study. Pain 62:155–62, 1995. 94. Takeda F. Japan: status of cancer pain and palliative care. J Pain Symptom Manage 12:118–20, 1996. 95. Chan A, Woodruff RK. Palliative care in a general teaching hospital. 1. Assessment of needs. Med J Aust 155:597–9, 1991. 96. Cherny NI, Catane R. Professional negligence in the management of cancer pain. A case for urgent reforms. Cancer 76:2181–5, 1995. 97. Cherny NI, Coyle N, Foley KM. Suffering in the advanced cancer patient: a definition and taxonomy. J Palliat Care 10:57–70, 1994. 98. Au E, Loprinzi CL, Dhodapkar M, et al. Regular use of a verbal pain scale improves the understanding of oncology inpatient pain intensity. J Clin Oncol 12:2751–5, 1994. 99. Fainsinger R, Miller MJ, Bruera E, et al. Symptom control during the last week of life on a palliative care unit. J Palliat Care 7:5–11, 1991. 100. Foley KM. The treatment of cancer pain. N Engl J Med 313:84–95, 1985. 101. Goldberg R, Guadagnoli E, Silliman RA, Glicksman A. Cancer patients’ concerns: congruence between patients and primary care physicians. J Cancer Educ 5:193–9, 1990. 102. Kelsen DP, Portenoy RK, Thaler HT, et al. Pain and depression in patients with newly diagnosed pancreas cancer. J Clin Oncol 13:748–55, 1995. 103. American Pain Society Quality of Care Committee. Quality improvement guidelines for the treatment of acute pain and cancer pain. JAMA 274:1874–80, 1995.

cancer pain epidemiology 104. Stjernsward J, Teoh N. Current status of the Global Cancer Control Program of the World Health Organization. J Pain Symptom Manage 8:340–7, 1993. 105. Stjernsward J, Stanley K, Koroltchouk V. WHO guidelines for cancer pain relief. Cancer Nurs 10(Supp 1):135–7, 1987. 106. Glover J, Dibble SL, Dodd MJ, Miaskowski C. Mood states of oncology outpatients: does pain make a difference? J Pain Symptom Manage 10:120–8, 1995. 107. Miaskowski C, Dibble SL. The problem of pain in outpatients with breast cancer. Oncol Nurs Forum 22:791–7, 1995. 108. Grond S, Zech D, Diefenbach C, et al. Assessment of cancer pain: a prospective evaluation in 2266 cancer patients referred to a pain service. Pain 64:107–14, 1996. 109. de Wit R, van Dam F, Zandbelt L, et al. A pain education program for chronic cancer pain patients: follow-up results from a randomized controlled trial. Pain 73:55–69, 1997. 110. Elliott TE, Murray DM, Oken MM, et al. Improving cancer pain management in communities: main results from a randomized controlled trial. J Pain Symptom Manage 13:191– 203, 1997. 111. Bernabei R, Gambassi G, Lapane K, et al. Management of pain in elderly patients with cancer. JAMA 279:1877–82, 1998. 112. Rummans TA, Frost M, Suman VJ, et al. Quality of life and pain in patients with recurrent breast and gynecologic cancer. Psychosomatics 39:437–45, 1998. 113. Wells N, Johnson RL, Wujcik D. Development of a short version of the Barriers Questionnaire. J Pain Symptom Manage 15:294–7, 1998. 114. Caraceni A, Portenoy RK; a working group of the IASP Task Force on Cancer Pain. An international survey of cancer pain characteristics and syndromes. Pain 82:263–74, 1999. 115. Chaplin JM, Morton RP. A prospective, longitudinal study of pain in head and neck cancer patients. Head Neck 21:531–7, 1999. 116. Grond S, Radbruch L, Meuser T, et al. Assessment and treatment of neuropathic cancer pain following WHO guidelines. Pain 79:15–20, 1999. 117. Berry DL, Wilkie DJ, Huang H-Y, Blumenstein BA. Cancer pain and common pain: a comparison of patient-reported intensities. Oncol Nurs Forum 26:721–6, 1999. 118. Chang VT, Hwang SS, Feuerman M, Kasimis BS. Symptom and quality of life survey of medical oncology patients at a veterans affairs medical center: a role for symptom assessment. Cancer 88:1175–83, 2000. 119. Rykowski JJ, Hilgier M. Efficacy of neurolytic celiac plexus block in varying locations of pancreatic cancer. Anesthesiology 92:347–54, 2000. 120. Ripamonti C, Zecca E, Brunelli C, et al. Pain experienced by patients hospitalized at the National Cancer Institute of Milan: research project “towards a pain-free hospital.” Tumori 86:412–18, 2000. 121. Beck SL, Falkson G. Prevalence and management of cancer pain in South Africa. Pain 94(1):75–84, 2001. 122. Liu Z, Lian Z, Zhou W, et al. National survey on prevalence of cancer pain. Chin Med Sci J 16:175–8, 2001.

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123. Lidstone V, Butters E, Seed PT, et al. Symptoms and concerns amongst cancer outpatients: identifying the need for specialist palliative care. Palliat Med 17:588–95, 2003. 124. Rustoen T, Fossa SD, Skarstein J, Moum T. The impact of demographic and disease-specific variables on pain in cancer patients. J Pain Symptom Manage 26:696–704, 2003. 125. Hsieh RK. Pain control in Taiwanese patients with cancer: a multicenter, patient-oriented survey. J Formos Med Assoc 104:913–19, 2005. 126. Reyes-Gibby CC, Ba DN, Phi YN, et al. Status of cancer pain in Hanoi, Vietnam: a hospital-wide survey in a tertiary cancer treatment center. J Pain Symptom Manage 31:431–9, 2006. 127. Morris JN, Mor V, Goldberg RJ, et al. The effect of treatment setting and patient characteristics on pain in terminal cancer patients: a report from the National Hospice Study. J Chron Dis 39:27–35, 1986. 128. McIllmurray MB, Warren MR. Evaluation of a new hospice: the relief of symptoms in cancer patients in the first year. Palliat Med 3:135–40, 1989. 129. Ventafridda V, De Conno F, Vigano A, et al. Comparison of home and hospital care of advanced cancer patients. Tumori 75:619–25, 1989. 130. Higginson I, Wade A, McCarthy M. Palliative care: views of patients and their families. BMJ 301:277–81, 1990. 131. Ventafridda V, Ripamonti C, De Conno F, et al. Symptom prevalence and control during cancer patients’ last days of life. J Palliat Care 6:7–11, 1990. 132. Stein WM, Miech RP. Cancer pain in the elderly hospice patient. J Pain Symptom Manage 8:474–82, 1993. 133. Mercadante S, Armata M, Salvaggio L. Pain characteristics of advanced lung cancer patients referred to a palliative care service. Pain 59:141–5, 1994. 134. Donnelly S, Walsh D, Rybicki L. The symptoms of advanced cancer: identification of clinical and research priorities by assessment of prevalence and severity. J Palliat Care 11:27–32, 1996. 135. Shannon MM, Ryan MA, D’Agostino N, Brescia FJ. Assessment of pain in advanced cancer patients. J Pain Symptom Manage 10:274–8, 1995. 136. Twycross R, Harcourt J, Bergl S. A survey of pain in patients with advanced cancer. J Pain Symptom Manage 12:273–82, 1996. 137. Vainio A, Auvinen A; with members of the Symptom Prevalence Group. Prevalence of symptoms among patients with advanced cancer: an international collaborative study. J Pain Symptom Manage 12:3–10, 1996. 138. Chung JW, Yang JC, Wong TK. The significance of pain among Chinese patients with cancer in Hong Kong. Acta Anaesthesiol Sin 37:9–14, 1999. 139. Mercadante S. Pain treatment and outcomes for patients with advanced cancer who receive follow-up care at home. Cancer 85:1849–58, 1999. 140. Nowels D, Lee JT. Cancer pain management in home hospice settings: a comparison of primary care and oncologic physicians. J Palliat Care 15:5–9, 1999.

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141. Chiu TY, Hu WY, Chen CY. Prevalence and severity of symptoms in terminal cancer patients: a study in Taiwan. Support Care Cancer 8:311–13, 2000. 142. Potter J, Hami F, Bryan T, Quigley C. Symptoms in 400 patients referred to palliative care services: prevalence and patterns. Palliat Med 17:310–14, 2003. 143. Tranmer JE, Heyland D, Dudgeon D, et al. Measuring the symptom experience of seriously ill cancer and noncancer hospitalized patients near the end of life with the Memorial

i.j. higginson and f. murtagh Symptom Assessment Scale. J Pain Symptom Manage 25:420–9, 2003. 144. Yun YH, Heo DS, Lee IG, et al. Multicenter study of pain and its management in patients with advanced cancer in Korea. J Pain Symptom Manage 25:430–7, 2003. 145. Donnelly S, Walsh D, Rybicki L. The symptoms of advanced cancer: identification of clinical and research priorities by assessment of prevalence and severity. J Palliat Care 11:27–32, 1995.

4

Cancer pain syndromes b,c mervyn koh a and russell k. portenoy a b c

Tan Tock Seng Hospital, Beth Israel Medical Center, and Albert Einstein College of Medicine

Introduction The reported prevalence of cancer pain varies across studies and is highly influenced by the population evaluated, stage of disease, and treatment setting. The overall prevalence is between 33% and 50%1 and is considerably higher – above 70%–among those with advanced disease.2 Chronic pain adversely affects all domains of quality of life, including physical functioning and well-being, mood and coping, and social interactions.3–5 Pain may be a focus on problematic communication with health professionals6,7 or contribute to distress through its association with disease progression or recurrence. Although not an independent predictor of poor prognosis,8 uncontrolled pain has been linked to suicidal ideation.9,10 Although pain is widely regarded to be a significant problem in oncology, management continues to be compromised by under-recognition and undertreatment. Good pain control may reduce hospitalizations, physician and emergency room visits, and overall health care costs,11 and should be considered a best practice in cancer care. Effective control of pain and other symptoms is the foundation for the array of psychological and spiritual processes that together assist the patient in coping with the rigors of the disease and its treatment.12,13 The latter processes, in turn, may contribute to symptom relief, an observation underscored by the diversity of effective nonpharmacological approaches to pain treatment.14,15

Pain assessment and classification Given the high prevalence of cancer pain and its potential for profound adverse consequences, all patients with active disease should be routinely screened for pain. Those who report pain require a more comprehensive assessment, the

goals of which include clarification of both the nature of the pain and its impact on quality-of-life domains. The varied nature of cancer pain has led to the development of classification approaches. Pain can be categorized by key descriptors, such as those related to temporal characteristics (acute vs. chronic), or by factors identified through a more comprehensive assessment, such as predominating pain mechanisms, underlying etiology, or identified syndrome. The distinction between acute and chronic pain is highly salient.16 Acute pain is typically associated with a specific event or injury and has a duration that extends from seconds to a few weeks. When sudden or due to a frightening event, it usually is associated with anxiety and signs of sympathetic hyperactivity, such as tachycardia and hypertension. In contrast, chronic pain may be defined simply in terms of duration, usually as pain persisting for 3 months or longer, or more specifically as pain that continues for more than 1 month after healing of a precipitating lesion, persists or recurs over months, or occurs in association with a lesion that is unlikely to remit or heal. Chronic pain often is associated with depressed mood and vegetative signs, such as disturbances in sleep, appetite, or vitality. Most patients with chronic cancer pain have recurrent superimposed episodes of acute pain. These are known generically as “breakthrough pains” (sometimes termed “episodic pains”) and are now recognized as clinically important problems in their own right. Breakthrough cancer pain is associated with a more severe pain syndrome, more pain-related adverse effects, and higher cost of care.17 Classification by inferred mechanism also has become widely accepted, notwithstanding the reality that the designated categories – most importantly “nociceptive” pain and “neuropathic” pain – simplify extremely complex mechanisms18,19 and represent a best clinical guess about

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54 pathophysiology that cannot be directly ascertained. In particular, these labels are viewed as clinically valuable for treatment selection. Nociceptive pain is perceived to be sustained by ongoing activation of afferent pathways by tissue injury. It is subdivided into somatic pain (associated with injury to skin, soft tissues, and bone) and visceral pain (due to injury to visceral structures). Somatic nociceptive pain often is well localized and described as sharp, aching, and/or throbbing. Visceral nociceptive pain related to obstruction of a hollow viscus often is diffuse and may be crampy or gnawing; when related to other factors, such as stretch of an organ capsule or tumor invasion of parenchyma or connective tissues, it may be well localized and aching, sharp, or throbbing. Neuropathic pain is caused by damage or dysfunction of the central or peripheral nervous systems. It may or may not be dysesthetic, a term referring to an “abnormal” uncomfortable sensation like burning or electric shocks. Abnormalities on the sensory examination that may or may not occur in association with the pain include allodynia (pain from an innocuous stimulus), hyperalgsia (relatively increased pain from a noxious stimulus), and hyperpathia (exaggerated pain response, often with spreading, aftersensation, and intense emotional reaction).20

m. koh and r.k. portenoy Table 4.1. Acute pain syndromes associated with the cancer or related disorders Acute pain directly related to cancer Rupture of hepatocellular carcinoma Pathological fractures from metastases (vertebral or long bones) Acute intestinal/biliary/ureteric obstruction/perforation Acute pain associated with infections Herpes zoster and postherpetic neuralgia Acute pain associated with thrombotic events Deep vein thrombosis – upper and lower extremities Superior vena cava obstruction

cancer pain syndromes has clear value as part of the broader approach to assessment.

Acute pain syndromes Acute cancer pain may be related to a complication of the disease or a related disorder (Table 4.1), to a diagnostic or therapeutic intervention (Table 4.2), or to an antineoplastic therapy (Table 4.3). In contrast to chronic pain, acute pain is more often related to iatrogenic factors than to the disease. Acute pain directly attributed to cancer

Syndromic classification The systematic effort to describe cancer pain syndromes reflects an effort to further codify and explicate these varied characteristics. A syndrome is a constellation of symptoms, signs, and related findings that together identify a clinically recognizable phenomenon. Cancer pain syndromes may be either acute or chronic. They may be related broadly to a direct effect of cancer itself, a complication of cancer treatment (surgery, interventional procedures, chemotherapy, or radiotherapy), or factors unrelated to the cancer or its therapy. In two large studies involving more than 1000 cancer patients, the reported prevalence of pain directly due to cancer was 85%–93% and the prevalence of treatment-related pain was 17%– 21%.21,22 More than one third of patients had multiple causes of pain. A syndrome may be linked with specific etiologic or prognostic findings, thereby guiding decisions about the nature and urgency of further evaluation. Specific treatment approaches may be suggested once a syndrome is noted. Knowledge about cancer pain syndromes may speed diagnosis of the patient’s medical status and provide needed time to explore quality-of-life domains. In short, an understanding of the characteristics that define acute and chronic

Rupture of hepatocellular carcinoma Cancers may rarely present as acute pain emergencies. Acute hemorrhage into a hepatocellular carcinoma is an example. This syndrome, which is characterized by severe Table 4.2. Acute pain syndromes associated with diagnostic and therapeutic interventions Acute pain associated with diagnostic interventions Lumbar puncture and post–lumbar puncture headache Arterial or venous blood sampling Endoscopy and biopsy Endometrial biopsy Transrectal prostate biopsy Percutaneous biopsy Bone marrow biopsy Acute postoperative pain Acute pain caused by other therapeutic interventions Pleurodesis/chest tube insertions Percutaneous biliary stents Abdominal paracentesis Tumor embolization Suprapubic catheterization Nephrostomy insertion Acute pain associated with analgesic techniques Injection pain Opioid hyperalgesia syndrome Epidural injection pain

cancer pain syndromes Table 4.3. Acute pain syndromes associated with anticancer therapies Acute pain associated with chemotherapy infusion techniques Intravenous infusion pain – Venous spasm – Chemical phlebitis (vinorelbine, 5-FU) – Vesicant extravasation – Anthracycline-associated flare reaction Hepatic artery infusion pain Intraperitoneal chemotherapy abdominal pain Intravesical chemotherapy pain Acute pain associated with chemotherapy toxicity Mucositis Headaches – Intrathecal methotrexate meningitic syndrome – l-Asparaginase–associated dural sinus thrombosis – Transretinoic acid headache Acute painful peripheral neuropathy and plexopathy Arthralgia and myalgia Steroid pseudorheumatism Palmar–plantar erythrodysesthesia syndrome Postchemotherapy acute limb ischemia 5-FU–induced angina Postchemotherapy gynecomastia Steroid-induced perineal discomfort Transretinoic acid–induced diffuse bone pain Acute pain with hormonal therapy Lutenizing hormone–releasing factor tumor flare in prostate cancer Hormone-induced pain flare in breast cancer Acute pain with immunotherapy Interferon-induced acute pain Acute pain associated with growth factors Colony-stimulating factor–induced bone pain Acute pain associated with radiotherapy Incident pain associated with positioning Oropharyngeal mucositis Early-onset brachial plexopathy Acute radiation enteritis or proctitis Acute vertebral bone pain after radiation Acute and subacute radiation myelopathy Acute pain associated with radiopharmaceuticals Flare of bone pain

right upper quadrant pain, may be life threatening and require surgery or other invasive therapies.23 Pathological fractures The sudden onset of back or limb pain may be the result of pathologic fracture. The proximal femur is the most common site affected, and breast, lung, and prostate cancers and multiple myeloma are the most prevalent tumor types.24,25 Acute organ obstruction or perforation Biliary or ureteric obstruction due to intra-abdominal cancers also may present with acute severe pain. Relief of the obstruction through surgery or stenting, if possible and consistent with the goals of care, can provide prompt analgesia.

55 Acute pain associated with infections Acute herpetic neuralgia Herpes zoster infections occur at an increased rate among cancer patients who are immunocompromised, particularly those with head and neck cancers or lymphoproliferative malignancies, and in patients who have undergone bone marrow transplantation.26–28 Pain or itch usually precedes the rash by days, and the dermatomal location of the infection is often associated with the site of malignancy.27 Acute zoster arises in previously irradiated dermatomes more than in nonirradiated sites; a study of irradiated breast cancer patients showed a three- to fivefold increase in incidence of herpes zoster compared with those who were not irradiated.29 Most patients with acute zoster should be treated with an antiviral drug, which reduces the risk of a generalized eruption and may provide analgesia. Prophylactic low-dose acyclovir in patients who are receiving immunosuppressants after bone marrow transplantation reduces the risk of herpes zoster.30

Acute pain associated with vascular events Pain due to acute thrombosis Cancer often produces a prothrombotic state. Fifteen percent to 25% of deep vein thrombosis is attributable to cancer.31 It can be the presenting sign of malignancy and is the second leading cause of death in those with metastatic disease.32,33 Patients with advanced pelvic tumors,34 pancreatic cancer,35 gastric cancer, advanced breast cancer,36 and brain tumors37 are at the greatest risk for thrombosis. Chemotherapy and hormonal therapy increase the risk further. Lower-extremity deep vein thrombosis presents with pain and swelling of the lower limbs. Pain is variable, however, and may be limited to a dull cramp or diffuse heaviness. The most common site of pain is the calf. Physical examination reveals swelling, warmth, and dilation of superficial veins, with pain induced by stretching.38 The diagnosis is commonly confirmed by ultrasound. Anticoagulation with low molecular weight heparin, which has become popular because of ease of administration, the lack of laboratory monitoring, and the relatively low risk of adverse events and drug interactions,39 may or may not yield analgesia. An inferior vena cava filter may be inserted in selected patients (usually those with a contraindication to anticoagulation) to prevent clot migration and pulmonary embolism, and presumably would be less likely to address pain than anticoagulation. Rarely, deep venous thrombosis may progress to phlegmasia cerulea dolens,40 a syndrome characterized

56 by severe pain, extensive edema, and cyanosis of the legs. Gangrene may occur if the obstruction is not relieved. Deep venous thrombosis in the upper extremity is uncommon.41 The diagnosis is suggested by edema, dilated collateral circulation, and pain.42 Extrinsic compression of venous outflow by tumor is the most common cause. Anticoagulation may control damage to vessels; however, pain and swelling may persist secondary to the extrinsic compression.43 Superior vena cava obstruction Although superior vena cava obstruction may be associated with intense pain, pain is a less common symptom than dyspnea, swelling of the face and neck, and dilated neck and chest wall veins. When pain occurs, it may be related to headache or to vascular congestion of the head or neck. Superior vena cava syndrome is usually caused by extrinsic compression from tumor or enlarged mediastinal lymph nodes. Most patients have a known cancer, usually non– small cell lung cancer (50%), small cell lung cancer (25%), lymphoma, or metastases. Intravascular devices such as stents and pacemakers account for one third of all cases.44 CT scan with contrast usually provides the diagnosis. Treatment includes steroids and urgent vascular stenting or radiotherapy; diuretics are not useful.44

m. koh and r.k. portenoy pressure, which is transmitted rostrally and leads to relief of the headache. The use of caffeine for either prophylaxis or treatment of post–lumbar puncture headaches was recently reviewed and reported not to be useful.51 Needle biopsies Although needle biopsies typically produce fleeting pain, the discomfort occasionally is severe and more prolonged. For example, a prospective study showed that 16% of patients reported pain of moderate or greater severity during transrectal ultrasound-guided prostate biopsy.52 The site of prostate biopsy influences pain severity, with mid and apical biopsies more painful than base biopsies. Several anesthetic methods, such as seminal vesicle–prostatic base blockade and intraprostatic and apical–rectal blocks, have been shown to reduce pain of the procedure.53 The application of EMLA cream (a eutectic mixture of lidocaine and prilocaine) before the procedure has also been shown to reduce pain.54 Bone marrow biopsies are often painful, and local anesthetic (lidocaine) should be given as standard protocol before the procedure, barring allergies. In addition, deep sedation with a short-acting opioid, a benzodiazepine, or propofol also is becoming increasingly used, particularly in children, and studies have shown no significant adverse sequelae with these drugs.55

Acute pain associated with diagnostic interventions Lumbar puncture headache Headache after lumbar puncture is positional, occurring with upright posture and often worsening as this position is maintained. The syndrome results from leakage of cerebrospinal fluid through the defect in the dural sheath; intracerebral veins are dilated.45 There is a decrease in the incidence of lumbar puncture headache when a small-gauge needle is used with longitudinal insertion of the needle bevel.45–47 If headache occurs, it commonly starts within hours of the procedure. Patients usually describe it as a dull occipital discomfort that radiates to the frontal region or to the shoulders.47,48 If pain escalates, it may be accompanied by diaphoresis and nausea. Lumbar puncture headache typically resolves without specific treatment, typically within 1 week after onset.49 Routine management includes bed rest, hydration, and analgesics. If the headache does not resolve within days, it may be treated with an epidural blood patch.50 In this approach, blood is withdrawn under sterile conditions and promptly injected into the epidural space. The mechanism for the benefit produced by the patch is unknown, but it has been proposed that a blood clot may increase intraspinal

Acute pain associated with therapeutic interventions Postoperative pain Acute pain following surgery requires prompt and adequate treatment.56,57 The usual approach involves systemic administration of an opioid analgesic. Patient-controlled analgesia can be delivered intravenously or through an epidural catheter. It provides analgesia comparable to regularly scheduled, nurse-administered therapy58 and offers patients greater control. Numerous other strategies for postoperative pain management, including sophisticated regional anesthetic techniques, may be available in settings with the potential for referral to pain specialists. Postoperative pain resolves over days to weeks, depending on the extent of the surgery. Persistent postoperative pain typically indicates the need for further evaluation for the possibility of infection or a tumor-related complication. Local treatment of cervical intraepithelial neoplasia Cervical intraepithelial neoplasia (CIN) often is treated by large loop excision of the transformation zone. This procedure may be painful, so local anesthetic should be given beforehand.59 One study observed that self-administration

cancer pain syndromes of inhalation anesthetics also can be used for analgesia.60 Cryosurgery also is used in the management of CIN. This procedure may produce an acute cramping pain syndrome. The duration of the freeze period is directly proportional to the severity of pain. It has been noted that a prophylactic nonsteroidal anti-inflammatory drug is not helpful.61 Other interventions A variety of other interventions may cause acute severe pain. Pain during and after tumor embolization may be very intense and prolonged, and at times may require regional anesthesia for relief.62 Chemical pleurodesis63 also causes acute severe pain, and one study noted that significant pain reduction may follow the use of a multidisciplinary approach, includuing house staff and nursing education of the patient, premedication with parenteral morphine, and thorough infiltration with local anesthesia.64 Other procedures, such as percutaneous biliary drainage, suprapubic catheter insertions, percutaneous nephrostomy tube insertions, and abdominal paracentesis, also may be painful unless adequate local anesthesia is provided. Acute pain after analgesic interventions Opioid therapy as a potential cause of pain An evolving experimental literature has described the phenomenonology and mechanisms of opioid-induced hyperalgesia (OIH) and provided a scientific parallel to the observation that occasional patients develop escalating pain as systemic or intraspinal opioid doses increase.65,66 In contrast to animal models, however, a change in the pain experienced by patients may be related to increasing nociception associated with more tissue injury, to psychological factors, or to drug-related changes such as metabolite accumulation or drug–drug interactions. As a result of this complexity, it is difficult to determine the extent to which OIH is clinically significant. At this time, concern about OIH should not inhibit the appropriately aggressive use of these drugs in patients with moderate to severe cancer pain. If dose escalation is associated with poor pain control, or even increases in pain, the strategy for analgesia must be changed, irrespective of the potential mechanisms that may be underlying the change. Use of another opioid in this situation should not be avoided. It is likely that future clinical studies will further clarify the importance of this phenomenon. Other interventions Subcutaneous or intramuscular injections may be painful. For example, intradermal and subcutaneous injection of lidocaine causes a transient burning pain before the

57 lidocaine takes effect.67 Intramuscular opioid administration is particularly painful, and this route of administration generally should be avoided.68 Although subcutaneous injection may be painful, particularly with large volumes and some drugs, such as methadone,69 this route of drug delivery usually is acceptable. Patients with advanced illness who develop pain with subcutaneous injection potentially may benefit from the addition of a small amount of a corticosteroid to the injectate.70 In addition to the rare occurrence of pain and hyperalgesia associated with high intraspinal doses of an opioid, which is presumed to be a spinal form of OIH,71 epidural drug delivery may cause compression or irritation of nerve roots, leading to back, pelvis, or leg pain.72 The latter problem may not necessitate discontinuation of treatment if repositioning of the cathether, or the use of a slower delivery rate of a more concentrated drug formulation, resolves the problem. Acute pain associated with chemotherapy infusion techniques Intravenous infusion pain Venous spasm, chemical phlebitis, anthracycline-associated flares, and vesicant extravasations may cause pain at the site of chemotherapy infusion. Venous spasm may be lessened by the application of a warm compress or by a slower infusion rate. It is not accompanied by inflammation. Chemical phlebitis may be caused by chemotherapeutic agents such as vinorelbine;73 reducing the infusion time of vinorelbine does not appear to significantly reduce phlebitis.74 5-Fluorouracil (5-FU) also has been implicated as a cause of phlebitis, and a small study of 32 patients showed that local application of ketoprofen gel may reduce the incidence and severity of this problem.75 Venous irritation and phlebitis also occur with nonchemotherapeutic agents such as potassium chloride infusions and hyperosmolar solutions. Anthracyclines such as doxorubicin cause a venous flare reaction, which manifests with local urticaria and pain.76 Vesicant extravasation produces extreme pain along with linear erythema, desquamation, and ulceration.77 Hepatic artery infusion pain Intra-arterial chemoembolization for hepatocellular carcinoma or hepatic metastases potentially can cause severe abdominal pain. If the infusion is stopped, the pain typically disappears, and some patients tolerate reinfusion at a slower rate.78 In addition, intra-arterial lidocaine given before and during the procedure has been shown to reduce postprocedural pain and opioid requirements.79

58 Intraperitoneal chemotherapy pain Intraperitoneal chemotherapy is used for treatment of gynecological cancers and can cause abdominal pain in up to 50% of patients, with half experiencing pain severe enough to warrant opioid therapy.80 In the absence of infection, severe pain presumably is secondary to chemical serositis.81 Serositis may follow treatment with mitoxantrone,82 doxorubicin,83 or paclitaxel.84 The presence of fever or leukocytosis in blood and peritoneal fluid suggests infectious peritonitis.85 The incidence of peritonitis fortunately is low, about 3.6% in a study of gynecological cancer patients.86 Intravesical chemotherapy or immunotherapy Bladder irritability characterized by frequency and/or painful micturition may be caused by the administration of intravesical bacillus Calmette-Gu´erin therapy for transitional cell carcinoma.87 Intravesical doxorubicin and gemcitabine also have been used to treat transitional cell carcinoma and can cause a painful cystitis, severe abdominal pain, and bladder erosions.88,89 Acute pain associated with chemotherapy toxicity Mucositis The most common acute painful complication associated with systemic chemotherapy is mucositis. Mucositis typically occurs 5–7 days after intensive chemotherapy. The incidence varies with the drug regimen, concurrent therapies, and host factors; it is virtually universal among hematological cancer patients undergoing myeloablative chemotherapy before bone marrow transplantation.90 The chemotherapeutic agents that are strongly associated with the development of mucositis include methotrexate, 5-FU, and doxorubicin.91 The pathophysiology of mucositis involves both direct toxicity due to the production of local inflammatory cytokines (interleukin-1 and tumor necrosis factor) and myelosuppression leading to mucosal denudation and oral ulcers. The clinical syndrome ranges from mild to severe, and those who are severely affected may have intense pain, deep or confluent ulcers, and superinfection with Candida, herpes simplex, and other organisms. Patients commonly cannot eat or drink comfortably, and malnourishment occurs unless nutrition is artificially supported. Grading systems for oral mucositis have been developed. The World Health Organization has a five-level system: 1) grade 0 – no mucositis; 2) grade 1 – painless ulcer, erythema, or mild sensitivity; 3) grade 2 – painful erythema or ulcer that does not interfere with food intake; 4) grade 3 – confluent ulcers that interfere with the ability to take solid

m. koh and r.k. portenoy food; and 5) grade 4 – severe symptoms requiring enteral or parentral support.92 The data supporting some therapies are poor, including those for allopurinol mouthwash, granulocyte-macrophage colony–stimulating factor (CSF), and immunoglobulins,93 and these interventions are not used clinically. Cryotherapy, or simply putting ice chips in the mouth immediately before 5-FU infusion and leaving it for 30 minutes, has been shown to reduce the incidence of mucositis by up to 50%.94 The ice chips presumably cause local vasoconstriction, which reduces the concentration of 5-FU reaching the oral mucosa. Recently, keratinocyte growth factor was shown to significantly reduce mucositis in hematological cancer patients undergoing intensive chemotherapy.95 Numerous other therapies, including the mixture of lidocaine, diphenhydramine hydrochloride, and aluminium hydroxide suspension (often called “magic mouthwash”); sucralfate; chlorhexidine; tetrachlorodecaoxide; and benzydamine, have no confirmed efficacy in preventing or reducing the duration of mucositis.93 Nonetheless, oral coating therapies often are tried in an effort to identify a local approach that may be perceived as soothing during more severe periods of pain. When moderate to severe pain begins, parenteral opioid therapy should be provided. Chemotherapy-induced headaches Headache is common after treatment with intrathecal methotrexate for leukemia or leptomeningeal disease. Pain may be associated with vomiting, nuchal rigidity, fever, irritability, and lethargy. There may be an associated cerebrospinal fluid pleocytosis. The syndrome may last for several days or longer, and may or may not occur with repeated administration.96,97 l-Asparaginase, which is used in the treatment of acute lymphoblastic leukemia, induces thrombosis of cerebral veins or dural sinuses in 1%–2% of patients. The drug presumably reduces the efficiency of fibrinolysis, a process dependent on asparagine, but the reason for the cerebral localization of the thrombotic complications is unknown. The syndrome presents as severe headaches or focal neurological deficits.98 Headaches also may occur during treatment with transretinoic acid therapy, which is used for acute promyelocytic leukemia. The syndrome may be associated with pseudotumor cerebri or occur in tandem with transitory diffuse bone pain.99,100 Painful peripheral neuropathy Many chemotherapeutic agents damage peripheral nerve, and acute painful neuropathy is a complication of some.

cancer pain syndromes Diverse types of neuropathy, including painful mononeuropathy (such as a painful jaw syndrome) and painful polyneuropathy, first were described following treatment with vinca alkaloids, especially vincristine.101 Other neurotoxic agents were identified subsequently, including paclitaxel, which damages myelinated nerve;102 oxaliplatin, which also enhances peripheral nerve excitability;103 thalidomide, which damages axons;104 and cisplatin, which induces dorsal root ganglion apoptosis.105 These drugs typically produce dose-dependent effects and present with paresthesias and dysesthesias, such as burning pain, in the distribution of the injured nerves.106 In some cases, the presentation is relatively acute, and the syndromes that result are transitory, gradually improving after treatment is stopped or the dose reduced. Some patients, however, develop chronic neuropathic pain, and a larger number manifest long-term abnormalities on neurological examination. Intra-arterial administration of some chemotherapies also may lead to acute focal neuropathies. For example, painful lumbosacral or brachial plexopathy may occur within 48 hours of cisplatin infusion into the iliac or brachial arteries, respectively.107,108 Arthralgia and myalgia Acute arthralgia and myalgia are reported by as many as 20% of patients treated with paclitaxel.109 The cause of these symptoms is unknown. They occur soon after chemotherapy administration and typically last up to a week, and sometimes longer. Acute arthralgia and myalgia also can complicate abrupt withdrawal or tapering of a corticosteroid, typically after prolonged therapy.110 This syndrome is known as steroid pseudorheumatism. The mechanism is not understood. Reintroduction of the steroid at a higher dose, followed by a more gradual taper, usually reduces the pain.111 Palmar–plantar erythrodysesthesia and other cutaneous toxicities Palmar–plantar erythrodysesthesia syndrome (also known as hand–foot syndrome) manifests as a painful rash on the palms and soles following administration of specific chemotherapies. The rash may progress to bulla formation and desquamation. The syndrome has been associated with continuous low-dose infusions of 5-FU112 and oral 5-FU precursor (cepacitabine),113 liposomal doxorubicin,114 and cytarabine.115 It is usually self-limiting and may be attenuated by coadministration of pyridoxine. If the syndrome is severe, chemotherapy dose reduction or a change to a different agent may be warranted.

59 Many chemotherapies can cause skin lesions, but the problem of cutaneous toxicity was relatively uncommon until the advent of the epidermal growth factor receptor inhibitors. These drugs cause serious cutaneous toxicity, which may be treatment limiting, and pain may be a component of the resulting syndromes.116 The treatment is symptomatic. Postchemotherapy acute limb ischemia Bleomycin, vinblastine, and cisplatin are known to cause Raynaud’s phenomenon or transient ischemia of the toes.117 This syndrome has been reported in the treatment of AIDS patients with Kaposi’s sarcoma.118 5-Fluorouracil–induced angina Both 5-FU and cepacitabine increase the risk of cardiac ischemic episodes, which presumably result from vasospasm. These episodes of angina are more common among patients with known coronary artery disease.119,120 Postchemotherapy gynecomastia Chemotherapy for testicular cancer and sometimes other neoplasms may be associated with an acute, painful gynecomastia.121 The syndrome typically is transitory. In the population with testicular cancer, the differential diagnosis is focused on the possibility of tumor-related gynecomastia.122 Steroid-induced perineal burning Acute perineal burning and shooting pain have been described immediately (within 30 seconds) after intravenous steroid infusion.123 Dose does not seem to influence the effect, which has been described with dexamethasone ranging from 8–100 mg.124 Diffuse bone pain Severe bone pain has been known to occur with transretinoic acid.125 The mechanism behind this syndrome is not well appreciated. As described previously, this pain may or may not be associated with drug-induced headache. Acute pain syndromes after hormonal therapy Flare syndrome in prostate cancer Lutenizing hormone-releasing hormone analogues, commonly used for the treatment of prostate cancer, may cause an “acute flare” syndrome, which is characterized by increased bone pain. Structural changes associated with the pain may increase the risk of cord compression or bladder outlet obstruction.126,127 Treatment also increases the risk

60 of a complication related to hypercoagulability. The mechanism of the flare, which is believed to involve a transient luteinizing hormone and testosterone surge, is reflected in a transitory rise in prostate-specific antigen that starts approximately 2 days after injection and can last almost a month.128 The concomitant administration of steroidal and nonsteroidal antiandrogens reduces this flare effect.129 Flare syndrome in breast cancer A similar flare reaction also may occur in women with metastatic breast cancer after the initial administration of tamoxifen. This syndrome manifests as diffuse musculoskeletal pain, skin erythema, change in liver function studies, and hypercalcemia.130 Aromatase inhibtors also have been shown to cause joint pains (47%) and muscle aches in these patients.131 Acute pain associated with immunotherapy and growth factors Interferon-associated myalgia and arthralgia Patients who receive interferon may experience myalgias, arthralgias, and headache. These symptoms may be accompanied by fever and severe fatigue and appear shortly after initial dosing. They typically decrease in severity after repeated dosing. Acetaminophen given before treatment may be useful in reducing pain intensity.132 In addition, painful vascular effects such as Raynaud’s phenomenon and digital ulceration also have been reported with interferon treatment for leukemia.133 Acute pain associated with growth factors CSFs stimulate the production, maturation, and function of blood elements. Bone pain, fever, headache, arthralgias, and myalgias may follow treatment with granulocyte– macrophage CSF, granulocyte CSF, and interleukin3.134,135 Erythropoietin injection also may cause pain at the subcutaneous injection site.136 Acute pain associated with radiotherapy Radiotherapy-induced acute mucositis Oropharyngeal mucositis occurs with doses above 1000 cGy to the head and neck. Pain may escalate to a point at which patients are unable to eat. The pain from the mucositis can linger several weeks after completion of the radiotherapy.137 Several newer interventions, such as using lowenergy helium-neon laser,138 and improvements in technical aspects of radiotherapy, such as three-dimensional conformal radiation and intensity-modulated radiotherapy, may

m. koh and r.k. portenoy further reduce the incidence of mucositis.139 The treatment of radiation-induced mucositis is similar to that of chemotherapy-induced mucositis; amifostine also has been recommended for the prevention of mucositis in head and neck cancer patients undergoing radiotherapy. Radiation-induced acute plexopathy Although new methods of radiotherapy appear to have substantially reduced the incidence, retrospective studies have documented the existence of an acute, transient brachial plexopathy associated with radiation.140 Most patients experience symptoms during radiotherapy or immediately after completion. Patients usually present with paresthesias, pain, and weakness in the shoulder, arm, and hand. The syndrome is usually self-limited but may progress over a period of weeks. Radiation-induced acute enteritis Patients undergoing abdominal radiation may experience abdominal cramps, nausea, and vomiting,141 which may occur within hours after radiation but classically happen 1–2 weeks after radiotherapy.142 Similarly, pelvic radiotherapy may produce tenesmoid pain with diarrhea, mucus discharge, and bleeding.143 Although current methods of radiotherapy have reduced the incidence and severity of these syndromes, the risk exists for all those undergoing radiotherapy that includes intestinal viscera in the irradiated field. Increased risk is associated with advanced age, concomitant chemotherapy, and having postoperative rather than preoperative radiotherapy.144 The syndrome usually is self-limited. Acute pain after radiation of spinal metastasis Radiation to a vertebral metastasis is associated with a “painful flare” reaction in as many as one third of patients.145 Any increase in pain mandates a careful assessement to exclude the possibility of neoplastic progression at the site. Radiation that includes spinal cord also may result in acute or subacute neurological syndromes, both of which may be prominently characterized by pain. The acute syndrome usually involves worsening at sites of existing spinal cord injury. The subacute type takes the form of Lhermitte’s sign, shock-like pains in the neck or back that may be precipitated by spinal movement and may radiate into one or more extremity. The syndrome usually begins weeks after treatment and disappears after several months.146 Newer methods of radiotherapy, such as the use of lower or hyperfractionated doses, may reduce the incidence of this syndrome.147,148

cancer pain syndromes Acute pain due to radiopharmaceuticals Radiopharmaceutical drugs, such as strontium-89 and samarium-153, are systemically administered beta-emitting compounds that are taken up by bone in areas of osteoblastic activity and have been developed as a treatment for malignant bone pain.149 A flare response after initial treatment occurs in as many as 20% of patients and is characterized by intense worsening of bone pain for a period of days.150

Chronic pain syndromes Approximately three quarters of chronic cancer pain syndromes result from the direct invasion of pain-sensitive structures by the neoplasm. This pain can be subclassified into nociceptive somatic (Table 4.4), nociceptive visceral Table 4.4. Nociceptive somatic pain syndromes related to the tumor Bone pain Multifocal bone pain – Bone metastases – Bone marrow expansion (hematological malignancies) – Oncogenic osteomalacia Vertebral syndromes – Atlantoaxial destruction and odontoid fracture – C7–T1 syndrome – T12–L1 syndrome – Sacral syndrome Back pain secondary to spinal cord compression Pain syndromes to pelvis and hip – Pelvic metastases – Hip joint syndrome Base-of-skull metastases – Orbital syndrome – Parasellar syndrome – Middle cranial fossa syndrome – Jugular foramen syndrome – Occipital condyle syndrome – Clivus syndrome – Sphenoid sinus syndrome Soft tissues Headache and facial pain Ear and eye pain syndromes – Otalagia – Eye pain Muscles – Muscle and soft tissue pain – Cramps Others – Pleural pain Paraneoplastic syndromes – Hypertrophic pulmonary osteoarthropathy – Tumor-related gynecomastia – Paraneoplastic pemphigus – Paraneoplastic Raynaud’s phenomenon

61 (Table 4.5), or neuropathic (Table 4.6). Chronic pain also may result from the therapies administered to treat the disease (Table 4.7), or from disorders unrelated to the disease or its treatment. Table 4.5. Nociceptive visceral pain syndromes related to cancer Hepatic distention syndrome Midline retroperitoneal syndrome Chronic intestinal obstruction Peritoneal carcinomatosis Malignant perineal pain Adrenal pain syndrome Ureteric obstruction Table 4.6. Neuropathic pain syndromes directly related to cancer Leptomeningeal metastases Painful cranial neuralgias Glossopharyngeal neuralgia Trigeminal neuralgia Painful radiculopathy Cervical plexopathy Malignant brachial plexopathy Malignant lumbosacral plexopathy Sacral plexopathy Panplexopathy Painful peripheral mononeuropathies Tumor-related mononeuropathy Paraneoplastic painful peripheral neuropathy Table 4.7. Chronic pain syndromes related to anticancer treatments Chronic pain associated with chemotherapy Painful peripheral neuropathy Raynaud’s syndrome Bony complications of long-term steroids – Avascular (aseptic) necrosis of femoral or humeral head – Vertebral compression fractures Chronic pain associated with hormonal therapy Chronic gynecomastia Osteoporotic compression fractures Chronic pain associated with surgery Postmastectomy syndrome Post–radical neck dissection pain Post-thoracotomy pain Post-thoracotomy frozen shoulder Postsurgery pelvic floor pain Stump pain Phantom pain Chronic postradiation pain syndromes Radiation-induced brachial plexopathy Chronic radiation myelopathy Chronic radiation enteritis and proctitis Lymphedema pain Burning perineum syndrome Osteoradionecrosis

62

Tumor-related somatic pain syndromes Tumor spread to bone, joint, muscle, or connective tissue can cause persistent somatic pain.151 Bone metastases are the most common cause of chronic pain in cancer patients,152 and the spine is the most common area of involvement.153 Two thirds of patients with bone metastases experience pain or disability.154 Bone pain may be caused by direct invasion of nociceptive afferent nerves that invest bone tissue, secondary pathological fracture, or damage to adjacent sites, such as epidural spinal cord compression. Most metastatic deposits are not painful, and the factors – mechanical or chemical – that may convert a painless metastasis to a painful one are unknown.24

Multifocal bone pain Widespread bony metastases may cause multifocal bone pain. Bone scintigraphy typically is positive in regions corresponding to the pain. The patient usually reports deep aching that may be continuous or related to movement or position. Movement-associated breakthrough pain, which is also called “incident” pain, often is prominent and a major source of physical disability. Hematogenous malignancies rarely produce a bone marrow expansion syndrome.155 This syndrome may produce intense multifocal pain without abnormality on bone scintigraphy. It may herald the recurrence of disease or the transition of a chronic leukemia to acute leukemia. The diagnosis requires examination of bone marrow. Oncogenic osteomalacia is a rare condition in which mesenchymal tumors inhibit resorption of phosphorus and vitamin D synthesis, leading ultimately to osteomalacia.156 Multifocal bone pain and fractures may result.

Vertebral bone pain syndromes More than two thirds of vertebral metastases are located in the thoracic spine; lumbosacral (20%) and cervical (15%) metastases account for the remainder.157 Localized mechanical back pain with tenderness on palpation is the usual presenting syndrome. Back and neck pain may signal invasion of the epidural space, and early treatment of this complication is the most important reason to recognize and evaluate the vertebral syndromes (see the following text). Bone pain syndromes related to the spine have been well described and exemplify the value of syndrome identification in guiding the assessment and management of chronic pain.

m. koh and r.k. portenoy Atlantoaxial destruction and odontoid fracture Nuchal or occipital pain that often radiates over the posterior aspect of the skull is a typical presentation of destruction of the atlas or fracture of the odontoid process. This type of pain is exacerbated by neck flexion.158 The syndrome may evolve into compression of the spinal cord with subluxation at the cervicomedullary junction. Patients usually present with insidious neurological deficits in one or more extremities. Upper-extremity involvement is more prominent at early stages. MRI is probably the best method of imaging this region of the spine. Posterior stabilization surgery may be useful for pain relief and preventing further neurological deterioration.159 C7–T1 syndrome A patient with tumor invasion of a C7 or T1 vertebra may experience pain in the interscapular region. This referral pattern may lead to a missed diagnosis if imaging is performed solely at the site of pain. The phenomenon implies that patients with progressive interscapular pain should have radiographic evaluation of both the cervical and thoracic spine. T12–L1 syndrome A patient with T12 or L1 vertebral metastases may experience referred pain at the ipsilateral iliac crest or sacroiliac joint. Imaging procedures directed at pelvic bone also may miss the metastatic lesion. Sacral syndrome Pain radiating to buttocks, perineum, or posterior thighs may indicate destruction of the sacrum.160 This pain typically is exacerbated by sitting. Lateral spread of tumor from the sacrum is one of the causes of a malignant “pyriformis syndrome.” Tumor involvement of the pyriformis muscle also may arise from direct spread of pelvic cancers or intrapelvic metastases. The syndrome may present with buttock and posterior thigh or leg pain, which increases with specific maneuvers. These are known as the pyriformis signs and include pain flare with passive internal rotation of the hip or isometric resistance of voluntary internal hip rotation. Compression of the sciatic nerve as it penetrates the pyriformis can produce pain down the leg and into the foot, and motor or sensory signs consistent with a sciatic mononeuropathy.161 Epidural spinal cord or cauda equina compression Back or neck pain may herald epidural compression of the spinal cord or cauda equina, which together are the second

cancer pain syndromes most common neurological complication of cancer.162 In one study, spinal cord compression was the cause of up to 2.5% of admissions in all cancer patients who died.163 The common etiologies include breast (21%), lung (24%), and prostate (20%) cancers.164 Epidural compression usually is caused by posterior extension of a vertebral body metastasis into the epidural space. On occasion, tumor extends from the posterior arch of the vertebra or grows through the intervertebral foramen from a paraspinal location. Rarely, an intraspinal metastasis causes the complication. Epidural spinal cord or cauda equine compression almost always presents as back or neck pain. Although as many as 50% of patients also have neurological signs at presentation,165,166 pain usually precedes neurological impairment by weeks or months. Diagnosis of epidural disease when pain is the sole complaint or neurological complications are minimal is crucial so that effective treatment may begin. Indeed, back or neck pain in a patient with known vertebral metastases should be viewed as a potential signal of epidural extension and should initiate a thoughtful plan of care focused on monitoring over time, imaging of the epidural space, or both. The decision to definitively image the epidural space may be based on clinical grounds or the findings on spinal imaging studies that do not specifically depict the epidural space. MRI is the preferred approach to definitive imaging of the epidural space.167,168 It is less invasive than myelography and offers similar sensitivity and specificity.169 Clinically, additional imaging of the epidural space should be considered if 1) back or neck pain is associated with any evidence of radiculopathy or myelopathy, or 2) back or neck pain has characteristics that suggest higher risk, including pain progression over time, pain with recumbency, pain that is worse with cough or other Valsalva maneuvers, or pain that is associated with a shooting component down the back and possibly into an extremity (Lhermitte’s sign). Radiographically, the decision to image the epidural space, or not, may be guided by findings on plain radiography, CT scanning, or bone scintigraphy. A plain radiograph that demonstrates vertebral collapse or pedicle erosion, or a CT scan that reveals damage to the cortical bone along the posterior wall of the vertebral body, is suspicious for epidural extension; if these findings are absent, the risk of epidural extension is less. Similarly, although a positive bone scintigram at the site of focal pain is not specific enough to significantly help in decision making about definitive imaging of the epidural space, a negative bone scintigram at the site greatly reduces the likelihood of malignant infiltration of the epidural space. None of the

63 imaging studies are absolute determinants, and the information provided by each should be used to stratify risk of epidural disease and clarify the plan for additional evaluation or monitoring. Even a negative bone scintigram at a site of pain, which clearly reduces the risk of epidural disease, does not exclude the complication; paraspinal neoplasms, such as lymphoma arising from paraverbebral lymph nodes or paravertebral nodal metastases, can grow through the intervertebral foramen and produce cord or cauda compression without inducing enough bone damage to affect bone scintigraphy. If MRI is performed with the intention of definitive imaging of the epidural space, a study of the total spine should be considered whenever the patient has known metastatic sites of disease at spinal sites remote from the pain (e.g., a bone scintigram with multiple vertebral lesions). In this setting, there is sufficient risk that occult epidural extension will be uncovered that the more extensive study is justified. The evaluation of back pain as a potential harbinger of epidural disease is important because early treatment of epidural disease usually is effective in limiting adverse neurological consequences. A corticosteroid, conventionally dexamethasone, is useful in reducing “cord edema”and has been shown to improve pain and neurological functioning in the short term, particularly when used together with radiotherapy.170 The use of high-dose versus moderate-dose steroids remains controversial, with one small study showing a nonsignificant (25% vs. 8%, P = 0.22) advantage of a 100-mg bolus of dexamethasone over a 10-mg bolus after 1 week, albeit with a higher rate of toxicity.171 Another study showed that more than 10% of patients receiving high-dose dexamethasone experienced serious gastric side effects.172 Interestingly, there is one report suggesting that patients with good motor function at the start of radiotherapy may not gain added benefit with steroids.173 The definitive treatment of epidural compression is either surgical decompression or radiotherapy. Radiotherapy usually is the first-line consideration. The dose and frequency of radiation vary, and there appears to be no optimum dose.164,174 In those who are medically fit for surgery, operations of various types may be considered when there has not yet been a tissue diagnosis, the tumor is known to be radioinsensitive, there is clinically significant segmental instability, neurological signs are progressing rapidly or progressing during radiation, the tumor has recurred in a previously radiated field, or there is a single lesion that is readily accessible through a posterior or posterolateral approach. Surgical complications may be common in some populations and have been reported in one study to include

64 a 13% 30-day postoperative mortality and a 54% postoperative complication rate.164 Pelvic and hip metastases Metastases to the pelvis may involve the ischium, pubis, or sacroiliac area. Pain and tenderness over the site of the lesion may be debilitating. Local referral can produce a large region of deep aching pain that typically has a milder continuous component and a severe movement-associated breakthrough pain. These lesions typically are treated with radiotherapy, but interventional pain strategies or surgery may be considered in some cases.175 Local extension of bone tumors in the pelvis can cause a coexisting painful plexopathy or mononeuropathy (see later), and as described previously, tumor invasion of deeper structures also may result in a malignant pyriformis syndrome. Metastases involving the hip joint may present as hip or inguinal pain on walking or as pain in the knee or thigh. Base-of-skull metastases Neoplastic injury to the base of the skull may occur from local extension of nasopharyngeal cancers or from bone metastases, most often from breast, lung, or protaste cancers.176 Base-of-skull metastases cause specific syndromes characterized by pain or headache associated with neurological deficits.177 Syndrome identification may allow early diagnosis and treatment and in some cases suggest the need for repeated imaging or a different imaging study. In most situations, however, either MRI or axial CT scanning of the base of skull with bone windows readily identifies the lesion. Radiotherapy usually is the treatment of choice.178 Orbital syndrome Patients with orbital metastases present with increasing pain in the retro-orbital and supraorbital regions of the affected eye. Associated problems include blurred vision, diplopia, proptosis, chemosis, external ophthalmoplegia, ipsilateral papilledema, and decreased sensation in the ophthalmic division of the trigeminal nerve. Parasellar syndrome Patients with neoplastic invasion in the parasellar region may develop unilateral supraorbital and frontal headache, as well as diplopia.179 Tumor involvement of the superior orbital fissure can injure the optic (II), oculomotor (III), trochlear (IV), or abducens (VI) nerve, or the ophthalmic

m. koh and r.k. portenoy division of the trigeminal nerve. As a result, headache may be associated with ophthalmoparesis or papilledema and/or a visual field defect. Middle cranial fossa syndrome Facial numbness, paresthesias, and pain with a referral pattern to the cheek or jaw are the presenting signs of middle cranial fossa syndrome.180 The pain typically is described as a dull, continuous ache, but a syndrome mimicking classic trigeminal neuralgia also may occur. Physical examination may reveal sensory loss in the trigeminal nerve distribution and an abducens (VI) nerve palsy.181 Jugular foramen and hypoglossal syndromes The glossopharyngeal (IX), vagus (X), and accessory (XI) nerves exit the jugular foramen. The hypoglossal (XII) nerve exits in the neighboring hypoglossal canal, and the cervical sympathetic chain also lies nearby. Patients with a jugular foramen syndrome may develop hoarseness, dysphagia, deep aching in the ipsilateral mastoid region, and glossopharyngeal neuralgia with or without bradycardia and syncope.176 Additionally, there also may be referred neck and shoulder pain. Neurological signs may include ipsilateral Horner’s syndrome and weakness of the palatal muscles or the sternocleidomastoid or trapezius muscles. With involvement of the hypoglossal canal, the patient may develop dysarthria associated with ipsilateral paresis and atrophy of the tongue. Occipital condyle syndrome The occipital condyle syndrome presents with severe unilateral occipital pain that is worsened with neck flexion.182 There is almost always concomitant involvement of the hypoglossal canal, leading to paresis and atrophy of the ipsilateral tongue.183 Physical examination also may reveal a head tilt, limited movement of the neck, and tenderness to palpation over the occipitonuchal junction. Clivus syndrome Damage to the clivus may lead to a severe headache, maximally experienced at the vertex. The syndrome may be suspected when headache at this location is exacerbated by neck flexion. Lower cranial nerve (VI–XII) dysfunction usually occurs late. Sphenoid sinus syndrome A sphenoid sinus metastasis often presents with bifrontal and retro-orbital pain, which may radiate to the temporal regions.184 Patients may have associated nasal congestion

cancer pain syndromes and diplopia caused by unilateral or bilateral sixth nerve paresis. Other headache syndromes A new, changed, or progressive headache in a patient with a history of cancer (or factors predisposing to cancer) should be evaluated first with a thorough neurological examination, and then with imaging if the diagnosis of an intracranial mass lesion remains suspected. The prevalence of tumor-associated headache in patients with primary brain tumors or metastases is approximately 37%–62%.185 Posterior fossa lesions appear more likely than supratentorial tumors to cause headache. Headache rarely occurs as an isolated symptom (8%); more often, it is accompanied by symptoms or signs of systemic disease.186,187 Suspicion that a headache is the result of intracranial hypertension from a mass lesion is increased when the pain has specific characteristics, including gradual worsening over time, awakening with headache, worsening of headache on exertion or Valsava maneuvers, early-morning vomiting or a stiff neck, or any neurological symptom. The mechanisms underlying the development of tumorassociated headache are presumably multiple. Headache may be related to traction on veins, arteries, or dura of the brain. It also may be a result of direct infiltration of cranial nerves with pain-sensitive afferents in the head and/or neck region.185 Whether headache can be caused by increased intracranial pressure itself, without injury to pain-sensitive structures, remains a topic of debate.185 The presence of cerebral metastases is usually a bad prognostic sign, and treatment is usually palliative. A corticosteroid often provides initial relief by reducing cerebral edema. Whole-brain radiotherapy may control symptoms. The use of stereotactic radiosurgery188 and neurosurgery189 is considered in patients with single lesions. Ear and eye pain syndromes Otalgia, or ear pain, may be primary (orginating from the ear) or secondary (referred from somewhere else). Pain referral patterns involving the ear are complex because of its multiple innervations by four cranial nerves and two cervical nerves.190 Specifically, the posterior and middle pinnae of the ear are supplied by the greater auricular nerve from C2 and C3, and the auriculotemporal branch of the mandibular division of the trigeminal nerve innervates the helix, tragus, and parts of the external auditory canal and tympanic membrane. The facial (VII),

65 glossopharyngeal (IX), and vagus (X) nerves supply the rest of the ear. Primary otalgia in the external ear may be a result of a skin cancer, such as squamous or basal cell carcinoma or melanoma. Schwannomas or glomus tumors originate from the middle ear and also may cause otalgia. Herpes zoster infection of the ear, also known as Ramsay Hunt syndrome, is relatively more common in immunocompromised cancer patients and is another type of primary otalgia. Secondary otalgia, in which pain is referred to the ear from a remote site of injury, may be caused by many types of cancer. Cancers of the tongue, oropharynx, or hypopharynx;191,192 thyroid cancer;193 acoustic neuroma;194 and metastases to the temporal bone or infratemporal fossa195,196 all may present with ear pain. As noted, eye pain may result from a base-of-skull tumor. Primary tumors of the eye or metastases to the choroid also produce a syndrome of eye pain and visual disturbance. Metastases are most common from breast and lung cancers and malignant melanomas.197–199 Small retro-orbital metastases involving rectus muscles or optic nerve also may present in this way.200,201 Muscle and soft tissue pain Sarcomas can arise from muscle, connective tissue, or fat. These may be bulky tumors, and pain at the site of the primary or metastatic tumor is common.202–204 Muscular cramps in cancer patients usually are caused by a neural, muscular, or biochemical abnormality.205 In a study of 50 cancer patients, 22 had a peripheral neuropathy, 17 had root or plexus pathology, two had polymyositis, and one had low serum magnesium levels. Chest wall pain Somatic chest wall pain may occur from direct tumor infiltration of the ribs, intercostal spaces, or parietal pleura. This type of pain is common among those with lung cancer or mesothelioma. A momentary severe breakthrough pain may occur with deep respiration or cough. A malignant intercostal mononeuropathy may accompany this lesion and yield a syndrome with mixed nociceptive and neuropathic features. Paraneoplastic syndromes causing somatic pain Paraneoplastic syndromes are disorders that involve injury to tissues remote from the primary or secondary sites of

66 cancer. This injury may be related to host immune dysfunction or the secretion of a hormone-like substance by the tumor. Some are associated with chronic pain syndromes. Hypertrophic pulmonary osteoarthropathy Hypertrophic pulmonary osteoarthropathy is a paraneoplastic syndrome that includes clubbing of fingers, periostitis of long bones, and occasionally a rheumatoid-like polyarthritis.206 The syndrome has been associated with lung cancer, breast cancer, mesothelioma, and other neoplasms.207 The diagnosis is suggested by the occurrence of pain, tenderness, and swelling in the knees, wrists, and ankles; bone scintigraphy may be positive at the sites of pain. The finding on radiography of osseous thickening consistent with periostitis may be confirmatory.208 The syndrome may precede diagnosis of the underlying malignancy by months and has been associated with elevated growth hormone– releasing hormone levels in patients with non–small cell lung cancer.209 Paraneoplastic gynecomastia Gynecomastia in males occurs in 2%–10% of those with testicular cancers and can complicate other tumors, such as lung, gastric, and renal cell.210–212 The latter cancers may secrete a human chorionic gonadotropin–like substance that promotes breast tissue growth.210 The breast enlargement usually causes pain and may be the presentating sign of the neoplasm. Paraneoplastic pemphigus Pemphigus is a serious autoimmune skin condition that manifests as widespread mucocutaneous lesions involving the lips, conjunctiva, and genitalia. When severe, desquamation can occur, and death may occur from fluid loss or infection or from an associated bronchiolitis obliterans.213 A paraneoplastic pemphigus usually is related to non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, Castleman’s tumor (a rare type of lymphoproliferaitve disease), or thymoma.214 The likely cause is the production of autoantibodies.215 The illness may be monophasic and resolve after a period of weeks or months. Resection of the pimary tumor may be associated with more rapid recovery. Paraneoplastic Raynaud’s phenomenon Rayneud’s phenomenon is characterized by intense vasospasm of digital arterioles, leading to pallor, and then cyanosis and subsequent hyperemia of the fingertips. It often is painful, particularly when episodes are sustained. It has been associated with lung,216 ovarian,217 and testicular tumors.218

m. koh and r.k. portenoy Tumor-related visceral pain syndromes Visceral pain may be caused by obstruction of any hollow viscus or injury to any other visceral structure, such as visceral pleura or peritoneum.6 These syndromes are particularly common in gastrointestinal and gynecologic malignancies. Hepatic distention syndrome Pain-sensitive structures in the region of the liver include the liver capsule, vessels, diaphragm, and biliary tract.219 Nociceptive afferents that innervate these structures travel via the celiac plexus, phrenic nerve, and lower right intercostal nerves. Chronic cancer pain usually occurs as a result of hepatomegaly and subsequent stretching of the hepatic capsule, which may be caused by a primary hepatoma or intrahepatic metastases. Pain related to liver capsule stretching commonly is described as a dull right subcostal pain, which is worsened with positional changes, or associated with a sharp twinge on deep inspiration. Depending on the related involvement of the diaphragm and biliary tract, the pain may be referred to the right shoulder or scapular region, respectively.220 Midline retroperitoneal syndrome Midline rostral retroperitoneal pathology may produce pain by injury to deep somatic structures of the posterior abdominal wall or posterior peritoneum, or by infiltration of the celiac plexus. The most common causes are pancreatic cancer221,222 and retroperitoneal lymphadenopathy.223 Pain is experienced in the epigastrium, across the upper abdomen, or in the low thoracic region of the back; pain may occur in some or all of these sites concurrently, or change over time with progression of the neoplasm. The pain often is described as a dull ache or a “boring” pain, which is worsened by recumbency and partially relieved by sitting up. On examination, the syndrome may be suspected if the patient develops a sharp exacerbation of the pain when asked to slowly recline over a rolled towel placed at the junction of the thoracic and lumbar spine. Pancreatic cancer is usually incurable at presentation,224 and although pain may be an early symptom, it more commonly complicates relatively advanced disease. If pain originates from infiltration of the pancreas itself, it may be related in part to perineural invasion. This pathology may be mediated by tumor-related secretion of nerve growth factor and its receptor (TrkA).225 The pain associated with pancreatic cancer also may be related to obstruction of the biliary tree, which may cause painful ductal hypertension226 or dysmotility of the adjacent

cancer pain syndromes small bowel. Pain also may be related to compression of portal vessels or to nearby metastases to liver or peritoneum. The specific presentation of the midline retroperitoneal syndrome associated with pancreatic cancer may be influenced by the location of the tumor mass. Primary afferent neurons that innervate the head of the pancreas traverse the right splanchnic nerves and right thoracic sympathetic ganglia, typically between the sixth and 12th vertebral levels. This innervation pattern may explain the propensity for tumors in this location to produce pain over the epigastrium and right of midline. The pain that accompanies a tumor in the body of the pancreas may be most prominent across the epigastrium; the innervation of this tissue includes the right splenic nerves and bilateral thoracic sympathetic ganglion. Pain from a tumor in the pancreatic tail is more likely to be experienced in the left epigastrium, presumably because of the innervation of this region through the left splenic and sympathetic ganglia from T6 to L1.227 Chronic intestinal obstruction Diffuse abdominal pain may be related to peritoneal carcinomatosis or chronic intestinal obstruction associated with abdominal neoplasm or scarring.228 The common cancers that cause intestinal obstruction are ovarian (up to 42%) and colorectal (up to 24%).229 Pain may be related to distention, mural ischemia, or mesenteric tension. Pain may be continuous or colicky, and may be referred to the dermatomes represented by the spinal segments supplying the affected viscera. Nausea, vomiting, and constipation are important associated symptoms. Abdominal radiographs taken in the supine and erect positions may demonstrate the presence of air–fluid levels and intestinal distention. CT or MRI scanning of the abdomen may be able to reveal the extent and intra-abdominal neoplasm, information that may strongly influence the decision to pursue medical or surgical management.230 Peritoneal carcinomatosis Peritoneal carcinomatosis causes peritoneal inflammation, mesenteric tethering, malignant adhesions, and ascites, all of which can cause pain. Ovarian, colorectal, and gastric cancers are the common causes of this syndrome.231 Pain and abdominal distention are the most common presenting symptoms. CT scanning may demonstrate evidence of ascites, omental infiltration, and peritoneal nodules.232 Malignant perineal pain Tumors of the colon or rectum, female reproductive tract, and distal genitourinary system are most commonly responsible for perineal pain.233 The pain syndrome usually

67 includes deep pelvic pain that may be focused more posteriorly (rectal pain) or anteriorly (genital pain), or involve the area diffusely. The pain may be increased by sitting or standing, and there may be a component of tenesmus or tenesmoid pain, or intermittent severe pain consistent with bladder spasms.234 Some patients describe a discrete syndrome characterized by deep pelvic discomfort or pain that occurs rapidly after standing and disappears in other positions (a malignant “tension myalgia syndrome”; see later). Adrenal pain syndrome Adrenal metastases commonly originate fom lung cancer235 and can produce unilateral flank and abdominal pain.236 The pain may radiate into the ipsilateral upper and lower quadrants of the abdomen. A superimposed severe acute pain may occur in association with adrenal hemorrhage from metastases.237 Ureteric obstruction Gastrointestinal, genitourinary, and gynecological cancers are the common causes of ureteric obstruction.238 Patients present with unilateral flank pain radiating to the inguinal region. Pain often is colicky – intermittent and wave-like. When severe, it may be associated with nausea and vomiting. Imaging may confirm the nature of the syndrome by demonstrating hydronephrosis ipsilateral to the pain.239 Tumor-related neuropathic pains Neuropathic pain syndromes directly caused by neoplastic invasion may involve the spinal cord, leptomeninges, nerve roots, plexuses, or peripheral nerves. Leptomeningeal metastases Any solid or hematological neoplasm potentially can infiltrate the leptomeninges. The common tumors include lung cancer and breast cancer,240 and both lymphoma and leukemia.241 Overall, leptomeningeal metastases are associated with poor prognosis, with a median survival of 4 months.242 The pain and neurological syndromes associated with leptomeningeal neoplasms are varied.242–245 The pain syndrome may take the form of headache, neck or back pain, or pain in a cranial nerve or radicular distribution; rarely, central pain due to spinal cord or brain injury may occur. The headache may mimic tension-type or migraine headache, or have the characteristics typical of intracranial hypertension – generalized aching or throbbing, worse in the morning and with Valsalva maneuvers, and sometimes associated with vomiting and diplopia on lateral gaze. The neck or back

68 pain typically is aching, but seldom is severe, and is similar to pain associated with benign spine disease. The neurological findings include sensory or motor deficits related to any cranial nerve or nerve root, or any other potential neurological problems, such as seizures, cognitive impairment, hemiparesis, hemisensory syndromes, or spinal cord syndromes. Given the variability of the pain and neurological findings associated with leptomeningeal disease, the insidious onset, and the extent to which the symptoms and signs may mimic benign pathology, the diagnosis often is delayed. The diagnosis of leptomeningeal metastases always should be suspected when imaging studies (performed without contrast enhancement, in the expectation of finding benign structural pathology) are negative even as pain is worsening, or pain or neurological findings begin to involve multiple sites. The diagnosis of leptomeningeal neoplasm is made by the finding of malignant cells on lumbar puncture. Contrastenhanced cranial and spinal cord MRI also may identify the existence of tumor and may be positive even if the cerebrospinal fluid is initially negative.245 Painful cranial neuralgias As described previously, cranial neuralgias may occur from metastases in the base of the skull or leptomeninges.246 Other lesions result from cancer in the soft tissue of the head or neck, or sinuses. Glossopharyngeal neuralgia Neuralgia of cranial nerve IX may result from leptomeningeal metastases or primary or metastatic deposits that involve the jugular foramen.247–249 The findings may be the most prominent component of the jugular foramen syndrome (see earlier). Patients typically experience severe unilateral throat or neck pain, which may radiate to the ear and mastoid region. The pain may be continuous and sharp or aching, or take the form of intense attacks that last minutes or more; these episodes may be triggered by swallowing or head movements.250 The pain may occur in association with hoarseness. Episodic bradycardia and syncope may be related to involvement of afferents from the glossopharyngeal nerve that interact with the tractus solitarius in the midbrain, which in turn influences the dorsal motor nucleus of the vagus nerve, causing asystole.251 Antiepileptic drugs have been used anecdotally to manage the neuralgia and associated phenomena.252,253 Trigeminal neuralgia Tumors of the middle or posterior fossa may mimic classic trigeminal neuralgia, leading to trials of management strategies employed for the latter disorder.254–256 Some patients experience more persistent

m. koh and r.k. portenoy aching or sharp pain in the face or teeth, and in contrast to classic trigeminal neuralgia, there may be neurological deficits identified on cranial nerve examination. When the clinical findings include the latter characteristic, the term middle cranial fossa syndrome may be preferred. Imaging of both the brain and the base of the skull may be necessary to characterize or exclude a mass lesion as the cause of the pain and associated features. Malignant painful radiculopathy Any process that compresses, distorts, or inflames nerve roots may cause radiculopathy or a polyradiculopathy. Painful radiculopathy may occur from leptomeningeal metastases, extension of tumor into the intervertebral foramen from sites in the vertebral body, or tumor deposits in the epidural space or paraspinal gutter. Radicular pain may be continuous or intermittent, aching or sharp, or dysesthetic (e.g., burning or electric-like) in quality. The pain may or may not be associated with neurological signs. When in the thoracic level, radicular pain appears to be more commonly bilateral and experienced as a tight band across the chest or abdomen. The latter presentation may signal a relatively high likelihood of associated epidural disease. Imaging with MRI is usually diagnostic in those suspected of having a malignant radiculopathy; a high index of suspicion should lead to the ordering of a spinal MRI with and without contrast enhancement. Malignant painful plexopathy Tumor arising in tissues adjacent to any of the major plexuses, or occasionally, tumors arising from the neural tissue itself, can produce injury to the plexus. Although the mass lesion may be relatively small, its location may lead to severe pain and dysesthesia associated with devasting neurological complications. Cervical plexopathy The ventral rami of the upper four cervical spinal nerves join to form the cervical plexus between the deep anterior and lateral muscles of the neck. The cutaneous branches emerge from the posterior border of the sternocleidomastoid. A malignant cervical plexopathy may be caused by a primary head and neck tumor in this region or by metastatic deposits, most often from lung or breast cancers that originate in the cervical lymph nodes.257 Pain may be experienced in the periauricular, postauricular, or anterior neck. Additionally, pain may be referred to the lateral aspect of the face, head, or shoulder. Pain may be aching and burning and may worsen by neck movement or swallowing. There may be an associated Horner syndrome if the superior cervical ganglion is involved.

cancer pain syndromes Brachial plexopathy Malignant brachial plexopathy is most common in patients with lung or breast cancer, or lymphoma. Tumor may invade from nodes in the axillary, cervical, or supraclavicular chains, or infiltrate the plexus from nearby tissues.258 Classically, tumor that arises from the superior sulcus of the lung – also known as Pancoast tumor – affects the lower brachial plexus and starts as pain and parasthesia in the medial two fingers, often associated with deep pain in the region of the elbow. This progresses until pain, sensory change, and weakness involve structures in a C7, C8, and T1 root distribution.259 Upper plexus involvement is more common from tumor originating in supraclavicular lymph nodes. It usually presents as pain over the shoulder and/or thumb and index finger. Ultimately, progression of the neoplasm may result in panplexopathy, with pain in the entire forequarter and neurological findings consistent with injury to all divisions of the plexus. Brachial plexopathy also may result from any of a variety of lesions other than the cancer, including postradiation effect, paraneoplastic syndrome, and herpes zoster. If pain is severe and progressive, a malignant cause should be strongly suspected.260 The determination that the neoplasm is directly responsible for the pain may open avenues for treatment with disease-modifying therapy, such as radiation.261 Axial imaging of the plexus itself, preferably with MRI262 but also with CT scanning, may be sufficient to establish the diagnosis of a malignant brachial plexopathy. If tumor is observed and encroaches on the paraspinal gutter, it is important to ensure that the imaging has included the epidural space; tumor may grow proximally through the intervertebral foramen and place the spinal cord at risk. A separate MRI of the spine, a hybrid MRI study that evaluates plexus and spine in one sitting, or a follow-up CT myelogram should be considered. The possibility of proximal extension of tumor into the spine is increased when there is a panplexopathy or Horner’s syndrome. Lumbosacral plexopathy The lumbar plexus is formed by the ventral rami of the L1–4 nerve roots. The sacral plexus forms in the sacroiliac notch from the ventral rami of S1–3 and the lumbosacral trunk (L4–5), which courses caudally over the sacral ala to join the plexus.263 Colorectal, cervical, and breast cancers, sarcoma, and lymphoma are the most common tumors associated with lumbosacral plexopathy. In one study, two thirds of the patients who developed plexopathy did so within 3 years of their primary diagnosis and one third had symptoms within 1 year.264 Like brachial plexopathy, proximal growth of tumor into

69 the spine, with a resultant risk of cauda equina syndrome, may occur. The initial symptom of malignant lumbosacral plexopathy is pain. The pain may be followed by numbness, paresthesias, or weakness weeks to months later. Focal tenderness, leg edema, and positive direct or reverse straight leg–raising signs also may occur. The distribution of the pain of lumbosacral plexopathy is related to the location of the neoplasm and specific structures involved. Upper lumbar plexopathy (L1–4 distribution), which characterizes approximately one third of all malignant lumbosacral plexopathies, usually is caused by an abdominal tumor and produces pain in the anterolateral thigh, knee, and proximal leg. Physical examination demonstrates neurological deficits that localize to an L1–4 nerve root distribution. Lower lumbosacral plexopathy (L4–S1 distribution) accounts for about 50% of affected patients, and typically arises from direct extension of sigmoid or rectal cancer, gynecological tumors, or a pelvic sarcoma onto the lumbosacral trunk. Pain usually is severe and may be in the buttocks and posterior leg and foot. Associated symptoms and signs conform to an L4–S1 distribution. Sacral plexopathy (S1–3), which occurs most often from injury caused by rectal cancer or gynecological tumors, may cause pain in the lower buttocks, perineum, or posterior legs. Pain is often severe while sitting, less severe while standing, and least severe while standing or walking. Occasional patients develop a coccygeal plexopathy (S4– coccygeal nerve), typically from a low rectal or prostate tumor, and this lesion may present as anal pain, numbness, and sphincter dysfunction. Similar to the brachial plexopathies, any of these presenting lesions can progress to a panplexopathy, with symptoms and signs involving L1–S3 distribution, including pain that may occur in the lower abdomen, back, buttocks, perineum, or legs. Leg edema is a common finding with these more severe lesions. Some patients with pain in the inguinal region and thigh have findings that suggest a malignant psoas syndrome. This disorder, which is characterized by malignant infiltration of the psoas muscle, is distinguished by findings consistent with an upper lumbosacral plexopathy, painful fixed flexion of the ipsilateral hip, and radiological or pathological evidence of major ipsilateral psoas involvement by the neoplasm.265 Focal autonomic dysfunction, such as anhydrosis or vasodilation, may occur in association with any of the subtypes of plexopathy.266 At times, focal autonomic neuropathy may occur as a prominent sign without significant

70 symptoms or other neurological signs, and may suggest the localization of the underlying neoplasm.267 Neuropathic pain in association with focal autonomic findings or focal edema may suggest that the malignant lesion has become complicated by a concurrent complex regional pain syndrome (CRPS; also termed causalgia or reflex sympathetic dystrophy). This complication is possible, and could suggest new avenues of pain treatment, but the diagnosis almost always remains tentative because the malignant lesion itself can produce the autonomic findings, and edema may be related to tumor-associated lymphatic or vascular obstruction. In some cases, a trial of sympathetic nerve block is undertaken in the hope that a CRPS is occurring and would be the type that is, at least in part, sympathetically maintained. Cross-sectional MRI or CT is the usual diagnostic procedure to evaluate the structural correlates of a lumbosacral plexopathy. Recent studies have suggested MRI to be superior to CT.268 Like other neuropathic pains potentially related directly to the neoplasm, identification of the causative lesion may be valuable if primary therapy is available to address the need for local control.269 Tumor-related mononeuropathy Injury to a peripheral nerve may result from compression or infiltration by tumor arising in an adjacent bony structure. Patients may experience pain and dysesthesia, and depending on the nature of the nerve, associated deficits of sensory or motor function, or both. The most common scenario is compression of an intercostal nerve from a rib metastasis. Other examples include sciatica associated with tumor invasion of the sciatic notch or the malignant pyriformis syndrome, femoral nerve compression by sarcoma arising in the upper thigh,270 and peroneal palsy associated with primary bone tumors of the proximal fibula. Patients rarely develop common types of nerve entrapment due to compression by tumor,271 but malignant carpal tunnel syndrome and malignant lateral femoral cutaneous neuropathy (known as meralgia paresthetica) occur occasionally.272 Paraneoplastic sensory neuronopathy Rarely, cancer patients develop a neurological syndrome related to paraneoplastic, immune-mediated injury to the dorsal root ganglia.273 It is more common in women and most often associated with small cell lung cancer;274 it also has been reported in patients with breast cancer275 and Hodgkin’s lymphoma.276 Patients present with asymmetrical pain and parasthesias, which may involve the face and body, as well as any extremity. The pain is associated with sensory loss, which may be severe enough to produce a

m. koh and r.k. portenoy sensory ataxia.274 Clinical examination reveals loss of deep tendon reflexes, sensation, and proprioception.277 Electrophysiologic studies show a marked involvement of sensory fibers,278 and the laboratory evaluation may reveal autoantibodies such as anti-Hu,278 anti-Ri,279 and anti-CV2.280 Treatment of the primary tumor may or may not help.281 To date, immunotherapy for this condition has remained disappointing.282 This syndrome also can herald cancer and occur months or years before the neoplasm otherwise declares itself. Paraneoplastic painful peripheral neuropathy Sensorimotor or a predominant sensory peripheral neuropathy is another paraneoplastic syndrome and may be associated with virtually any tumor type, most typically nonHodgkin’s lymphoma283 and the paraproteinemias.284 As many as 13% of patients with multiple myeloma, for example, develop painful peripheral neuropathy,285 which may present as a mild sensorimotor, a pure sensory, or a subacute or relapsing–remitting polyneuropathy.286 Electrophysiologic studies and nerve biopsies show demyelination and axonal degeneration. Chronic pain syndromes associated with cancer therapy Although chronic pain appears to be an uncommon longterm consequence of cancer therapy, it may follow surgery, chemotherapy, or radiotherapy. When it occurs in those with long-term remission or cure, pain may evolve to become “chronic pain as illness” in a manner identical to that in patients with chronic noncancer pain syndromes. Chronic postchemotherapy pain syndromes Diverse types of chemotherapy can eventuate in chronic pain syndromes. These syndromes are diverse and may be neuropathic or nociceptive. Painful peripheral neuropathy Although painful peripheral neuropathy resulting from cytotoxic chemotherapy usually subsides over time, some patients develop persistent pain. Drugs that usually cause acute peripheral neuropathy, such as vincristine, cisplatin, and oxaliplatin,287 also may cause long-term effects in some patients. Although cumulative dose may contribute to this outcome, dose alone does not explain the transition from acute to chronic pain in these patients.288 The syndrome itself usually is a sensorypredominant peripheral neuropathy with pain and dysesthesia most severe in the distal legs and sometimes extending to the hands and distal arms. Concomitant neurological

cancer pain syndromes deficits, such as weakness or clumsiness, loss of reflexes, and ataxia, are variable. A variety of strategies for particular agents have been explored to manage the symptoms or prevent the occurrence of the neuropathy,289,290 but none has been established. Raynaud’s syndrome Chronic Raynaud’s phenomenon may be associated with pain and can complicate the treatment of patients with testicular tumors291 and perhaps other neoplasms. It has been speculated that a possible mechanism involves hyperreactivity of the central sympathetic nervous system.292 Bony complications of steroid therapy Prednisolone is one of the mainstays in chemotherapy regimens for lymphoma.293 Avascular necrosis of the femoral or humeral head294,295 and vertebral compression fractures due to osteoporosis may occur as a complication of this drug or corticosteroid therapy for other conditions.296 Chronic pain and disability may result. Chronic pain associated with hormonal therapy Gynecomastia is a common complication of antiandrogen therapies for prostate cancer, occurring in as many as 70% of patients.297,298 It is relatively less common during treatment with flutamide or cyproterone, and is uncommon during luteinizing hormone–releasing factor agonist therapy.299–303 Some men report persistent discomfort associated with the lesion. Prophylactic tamoxifen304 and radiotherapy298 have been shown to be useful in reducing the incidence and severity of gynecomastia. Antiandrogen therapy for prostate cancer also may lead to osteoporosis. Back pain due to vertebral compression fractures may ensue.305 Chronic postsurgical pain syndromes There are several well-defined pain syndromes that occur after surgical excision of cancer. These neuropathic pain syndromes are presumed to be the result of nerve or plexus injury. Postmastectomy pain syndrome Postmastectomy pain syndrome is common and may occur after any breast procedure; lymph node dissection in the axilla appears to increase the risk.306–308 The syndrome is characterized by a dull, burning, and aching pain in the axilla, anterior chest wall, and medial aspect of the proximal arm. Allodynia may be prominent. Although the pain may begin immediately after surgery, it usually has an onset many months later.309 The etiology of the pain is believed to be related to an injury to the intercostobrachial nerve, a cutaneous sensory branch

71 of T1–2. Phantom breast syndrome is the major differential diagnosis.310–312 Alternatives to axillary node dissection, such as isolated sentinel node removal or radiotherapy without axillary lymph node dissection, probably reduce the severity of the postmastectomy pain syndrome.313–315 Treatments conventionally used for neuropathic pain are typically used in an effort to provide symptomatic relief, and several agents, including prophylactic venlafaxine, have been studied and appear promising.316,317 Drugs that have been tried without much efficacy include intraoperative ibuprofen–arginine and amantadine.318,319 Post–radical neck dissection pain Patients commonly experience neck and shoulder pain weeks to months after surgery to the neck.320 The pain may be neuropathic and described as a burning or lancinating dysesthesia in the neck and shoulder, often encompassing the area of sensory loss. A subtype of this syndrome is presumably related to the trauma to the accessory (XI) nerve during surgery,321 preservation of which has been associated with less neck and shoulder pain, less need for analgesics, and greater range of shoulder function.322,323 Another chronic pain syndrome is musculoskeletal and appears to result from imbalance in the shoulder girdle.324 This syndrome also may be related to injury to the accessory nerve, which weakens the trapezius muscle and leads to drooping of the shoulder. Shoulder drooping also may give rise to a thoracic outlet syndrome and suprascapular nerve entrapment, ultimately yielding a mixed neuropathic and musculoskeletal pain syndrome. Treatment is with analgesics, physical therapy, appropriate bracing, and trigger point injections.6 Post-thoracotomy pain Chronic post-thoracotomy pain is defined as pain in the region of a thoracotomy that persists for months after surgery or presents anew after healing.325 The pain is neuropathic, usually described as aching or burning, and associated with sensory and autonomic changes.326 The likely cause is injury to the intercostal nerves during surgery,326 and the important differential diagnosis is recurrent neoplasm, which is most often in the chest wall or pleura, but may be anywhere in the chest (including the mediastinum). Patients with persistent pain or new-onset pain after healing should be appropriately imaged, usually with chest CT scan repeated at time intervals to exclude recurrent or progressive cancer. Patients with post-thoracotomy pain as a surgical complication may have pain that persists for years.326 Conventional treatments for neuropathic pain usually are employed to provide symptomatic relief.327 Intercostal nerve blocks and

72 improved operative techniques, such as intercostal bundle sparing, which spares the intercostal nerve during surgery, may reduce the incidence of this problem.328 Postoperative frozen shoulder Patients who have undergone mastectomy or other procedures in the region of the shoulder are prone to developing frozen shoulder syndrome.329 The incidence is reduced by more limited surgery.330 The syndrome occurs as a result of immobility and the formation of soft tissue contractures, and patients report limitation and painful movement of the shoulder. Early physical therapy can reduce the severity of the problem.331,332 Postsurgery pelvic floor pain Patients who undergo pelvic surgery may develop a syndrome that mimics the syndrome known as tension myalgia.333 This is believed to be related to injury or spasm affecting pelvic sling muscles. Patients report aching and stretching pain on standing, which disappears promptly when sitting or recumbent. Occasional patients with deep pelvic tumors report similar symptoms, and imaging is needed to exclude persistent or recurrent disease. Stump pain Stump pain may follow the amputation of any body part. It may occur immediately, but usually presents several months or years post surgery.334 The etiology is related to peripheral nerve injury, perhaps with subsequent neuroma formation, and the pain typically is described as burning or otherwise dysesthetic and is located in the stump itself. Anecdotally, stump pain affecting the limbs may be attenuated by careful fitting of a prosthesis; other conventional treatments for neuropathic pain are needed to allow rehabilitation to occur.335,336 Phantom limb pain Phantom limb pain occurs after amputation and is perceived in the area of the missing tissue.337 It is prevalent and typically declines over time.338,339 The quality of the pain is neuropathic, and it is often associated with nonpainful phantom sensations, including the foreshortening or posturing of the absent part. The pathophysiology of phantom pain appears to involve neuroplastic reorganization of the somatosensory cortex;340 a study of upper limb amputees with phantom limb pain revealed a strong correlation between pain and the magnitude of shift in cortical representation of the mouth into the hand area in the motor and somatosensory cortex.341 In cancer patients, phantom pain may be more common among those with amputations for direct tumor injury and those who have had chemotherapy.340,342 Patients who have

m. koh and r.k. portenoy had a relatively long duration of preoperative pain, and those with pain 1 day before surgery, also may be at higher risk.343,344 The risk may be reduced by regional anesthesia at the time of surgery;345,346 epidural anesthesia was found to be superior to general anesthesia in terms of longterm pain relief in patients undergoing limb amputations.347 Once established, the pain may be difficult to treat, and conventional drugs for neuropathic pain are used.348,349 Phantom pain Phantom pain also may appear after amputation of other body parts. Phantom breast complicates 1%–3% of mastectomies,350,351 phantom pelvic pain may occur after hemipelvectomy,352 phantom rectal pain has been described after rectal cancer surgery,353 and phantom eye pain has been reported in 26% of patients undergoing eye enucleations.354 In these and other phantom pains, worsening after a period of stability should prompt a search for recurrent malignancy. A study of late-onset pain in rectal cancer patients confirmed that it may be an early sign of tumor recurrence.355 Chronic postradiation pain syndromes Chronic pain complicating radiation therapy tends to occur late in the course of a patient’s illness. As late-onset pain also may be a presenting symptom of tumor recurrence, however, this differential diagnosis usually requires evaluation before attributing the pain to radiation injury. Radiation-induced brachial plexopathy Radiationinduced plexopathy can complicate radiation for breast and lung cancer.356 The incidence is low (about 1.3%) in women who have radiation for breast cancer, and risk factors include high-dose radiation and concurrent chemotherapy.357,358 Early-onset transient plexopathy may occur anywhere from a few weeks to 6 months after radiation, and delayed-onset progressive plexopathy may occur 6 months to 20 years after a course of radiotherapy that included the plexus in the radiation field.307 The presenting signs are weakness and sensory changes that may affect the whole plexus but tends to predominate in C5–6 root distribution.358,359 Severe pain is uncommon and occurs in 18% of patients at time of presentation.6 Radiation changes in the skin and lymphedema are commonly associated. The pathophysiology is still poorly understood but is believed to involve progressive fibrosis and vascular changes, which together produce entrapment and ischemia of nerves.360 Electrophysiologic testing may be helpful in evaluating patients with progressive plexopathy after radiation. The finding of myokymia (spontaneous discharges accompanied by wave-like muscle quivering) is pathognomonic for radiation injury.361 Imaging also is essential, and MRI in

cancer pain syndromes radiation injury typically reveals diffusely thickened plexus with signal intensity that is similar to skeletal muscle on both T1- and T2-weighted images.362,363 The finding of a discrete mass on imaging, or signal consistent with tumor on a positron emission study, should lead to consideration of biopsy to exclude recurrent disease or the development of a new primary tumor. The natural history of radiation-induced plexopathy may involve slow progression with loss of neurological function.364 Symptomatic treatments typically are offered,356 but efforts to prevent worsening, such as surgical neurolysis, have been disappointing.364,365 Overall, the incidence of this syndrome has declined over the years with lower radiation dose regimens and better radiation techniques.366 Radiation-induced lumbosacral plexopathy Radiation fibrosis of the lumbosacral plexus also is rare and may occur from 1 to 30 years after radiation treatment. It has been reported in ≤0.1% of patients treated for endometrial and cervical cancer.367 The use of intracavitary brachytherapy appears to be a risk factor.368 The syndrome is characterized as numbness, parasthesia, and weakness, often beginning in an L5–S1 root distribution. Severe pain is uncommon and occurs in only 10% of patients.6 Similar to brachial plexus lesions, the differential diagnosis is recurrent or new cancer. The investigations are similar to those of radiation-induced brachial plexopathy, with CT scans showing a nonspecific diffuse infiltration of the tissues and electromyography showing myokymic discharges.369 Chronic radiation myelopathy Chronic radiation myelopathy is a late complication of spinal cord irradiation. It may develop from 1 to many years after radiation. Sensory symptoms, including pain, typically precede the development of progressive motor and autonomic dysfunction. The pain usually is characterized as a burning dysesthesia and is localized to the area of spinal cord damage or below. It often presents as a transverse myelopathy at the cervicothoracic level, sometimes in a Brown-S´equard pattern.370 The pathophysiology appears to be a combination of glial cell damage and vascular injury leading to white matter necrosis.371 MRI allows the clinician to exclude an epidural lesion and demonstrates the nature and extent of intrinsic cord pathology. The course may be steady progression over months followed by a subsequent phase of slow progression or stabilization. Chronic radiation enteritis and proctitis Chronic enteritis and proctitis may result from irradiation to the abdomen and pelvis.142 The incidence is about 6% (ranging from 0.5% to 17%).372 The syndrome usually occurs 1–2

73 years post radiation but has been reported as late as 20 years later.373 Risk factors for this condition include malnutrition, diabetes mellitus, hypertension, vasculitis, and total radiation dose greater than 50 cGy.374 Colicky abdominal pain as a result of partial or complete small bowel obstruction may be prominent, and small bowel obstruction, pseudoobstruction (impaired gastrointestinal motility without any anatomical obstruction), fistula formation, perforation, and bleeding are all potential manifestations.142,375 The pathophysiology of radiation-induced enteritis is not well understood but likely involves direct cytotoxicity of radiation to intestinal cells, leading to occlusive vasculitis and subsequent fibrosis.376 Characteristic endoscopic biopsy features include atypical fibroblast and collagen proliferation and occlusive vasculitis.377 The diagnosis of chronic radiationinduced enteritis is made clinically, and tumor recurrence must be excluded before this diagnosis is entertained. Surgical interventions undertaken in an effort to manage radiation-induced enteritis may be followed by new problems, such as anastomotic breakdown.378 When necessary, resection may be preferred to bypass, which has higher complication rates.379 Symptomatic relief may be pursued using analgesic drugs, dietary approaches,380 and even parenteral nutrition.381 Prevention may be promoted by the use of lower radiation dosages and methods to keep the small intestines out of the radiation field, such as “bowel protection devices”382 and synthetic mesh slings.383 Radioprotectants such as amifostine, which selectively enters nonmalignant cells and protects them from the ionizing effect of radiotherapy, also have been used to protect against radiation-induced enteritis in colorectal and gynecological cancers.384 Lymphedema pain Adjuvant radiotherapy to breast cancer patients who had axillary lymph node dissection increases the risk of developing lymphedema.385 Lowerextremity lymphedema may follow pelvic radiation. The pathophysiology of this condition is believed to be related to fibrosis and subsequent constriction of the lymphatic channels.386 One third of patients with lymphedema of the arm experience pain and tightness.387 The pain may be musculoskeletal and related to the increased weight of the limb and associated joint dysfunction, or neuropathic and related to an entrapment syndrome involving the median nerve in the carpal tunnel or the brachial plexus.388 New onset of severe or progressive pain in the lymphedematous arm is suggestive of tumor recurrence or infection, and requires reevaluation. Prevention and treatment of lymphedema have been pursued using measures such as decongestive physiotherapy,

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74 compression therapy, therapeutic exercises, and pharmacotherapy.389 Drugs that have been used to reduce lymphedema include coumarin, diuretics, and selenium. Coumarin, which acts to reduce vascular permeability, has been the most extensively used drug, but its role remains controversial.390 There is no evidence to support the use of diuretics.391 Selenium was shown to reduce arm edema in a small study of 12 patients, and larger trials are needed to validate this.392 Burning perineum syndrome Chronic perineal discomfort is a rare delayed complication of pelvic radiotherapy.393 It may develop approximately 6–18 months after radiation therapy. A similar syndrome may be experienced by patients who undergo brachytherapy for prostate cancer.394 Osteoradionecrosis Endarteritis obliterans culminating in osteoradionecrosis is a late complication of radiotherapy to bone. Although any bone is susceptible, the syndrome is most common in the mandible after radiation for head and neck cancer. The accompanying pain may be severe. Poor dentition may predispose to mandibular osteoradionecrosis and justifies a dental consultation before head and neck radiotherapy to remove unhealthy or infected teeth.395 Higher doses of radiation (⬎50 cGy) and trauma also appear to be risk factors.395,396 Treatment with hyperbaric oxygen has been proposed as a means to limit bone damage, but its efficacy is uncertain.397,398

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397. Topazian RG, Goldberg MH. Oral and maxillofacial infections. Philadelphia: W. B. Saunders, 1994, pp 280–3. 398. D’Souza J, Goru J, Goru S. The influence of hyperbaric oxygen on the outcome of patients treated for osteoradionecrosis: 8 year study. Int J Oral Maxillofac Surg 36:783–7, 2007.

SECTION

III

ASSESSMENT

5

The assessment of cancer pain: measurement strategy karen o. anderson

The University of Texas M. D. Anderson Cancer Center

Regular pain assessment and pain management should have the highest priority in the routine care of the patient with cancer. Between 60% and 80% of patients with advanced cancer will need pain treatment. Pain is also a problem for many patients early and intermittently during the course of their disease. In addition, cancer survivors who are cured of their cancer may have persistent chronic pain as a result of the disease or its treatment. When pain is present, the quality of life (QOL) of patients and their family members is adversely affected. However, the majority of patients with cancer-related pain can obtain pain relief if the pain is adequately assessed and appropriate treatment is provided. Numerous guidelines for the management of cancer pain have been endorsed by governmental organizations, professional associations, and the World Health Organization (WHO). Research studies evaluating the WHO guidelines (1986, 1996) for cancer pain relief indicate that 70%–90% of patients obtain good pain relief when this protocol for oral analgesic medications is followed.1–4 Other pain management therapies can provide pain control when oral analgesics are not effective. In spite of the availability of effective pain treatments, multiple studies document undertreatment of pain.5–9 A study completed by the Eastern Cooperative Oncology Group (ECOG) surveyed more than 1300 outpatients with recurrent or metastatic cancer.5 Sixty-seven percent of the patients had pain or were being treated for pain with daily analgesics. Among the patients with pain, 42% were prescribed analgesics that were less potent than those recommended by the WHO guidelines. One of the most important predictors of undertreatment of pain was the discrepancy between the patient and physician in their estimates of pain intensity. Inadequate pain assessment is a major barrier to good pain control for the patient with cancer. Pain must be identified to be treated, and pain whose severity is underestimated

will not be treated aggressively enough. More than 800 ECOG-affiliated physicians completed a survey designed to assess their knowledge and practice of cancer pain management.10 The physicians ranked a list of potential barriers to pain management to indicate barriers that hindered pain treatment in their practice settings. The most frequently identified barrier was inadequate pain assessment; 76% of the physicians rated poor assessment as one of the top four barriers to good pain management. Patient reluctance to report pain, closely related to inadequate assessment, was the next most frequently cited barrier. Similarly, recent surveys of physicians in the Radiation Therapy Oncology Group and health care providers treating minority cancer patients found that poor pain assessment and patient reluctance to report pain were identified as top barriers to optimal pain management.11,12 Why is pain assessment so often inadequate in many cancer care settings? Most health care providers do not have the training and skills necessary to adequately assess pain and its impact. Accurate appraisal of pain may be even more difficult when the providers are not of the same gender or ethnic background as the patients.12,13 Moreover, pain assessment is not a standard part of patient appointments, and it is often up to patients to volunteer that they have pain, or that their current pain treatment is not working. Unfortunately, several studies have shown that patients are reluctant to be assertive in reporting their pain.11,14 When physicians and nurses do ask about pain, they often fail to document pain severity, characteristics, or etiology. Also, health care providers usually do not assess the impact of pain on the daily lives of the patient and the family. This chapter reviews the methodological and clinical issues involved in the assessment of cancer pain. Fig. 5.1 provides an overview of the pain assessment process and indicates areas that need to be evaluated in a patient with cancer-related pain. The chapter discusses the role of the 89

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Cancer Pain Assessment

Medical Evaluation

Pain Severity

Pain Characteristics

Pain Impact

Physical exam

Verbal descriptor scales

Location

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Visual analog scales

Temporal pattern

Quality of life

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Numerical rating scales

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Social support Concurrent symptoms

Fig. 5.1. Overview of cancer pain assessment.

medical evaluation and how pain assessment provides the information needed for pain treatment planning and evaluation. It also discusses the importance of determining pain severity and the relation of severity to treatment. The chapter describes standardized pain scales and questionnaires that can facilitate the assessment process and presents strategies for determining pain characteristics and the impact of pain on patients’ lives. It also examines the use of pain assessment procedures in special populations, quality assurance, and innovative technologies.

Medical and neurological evaluation The assessment of cancer-related pain calls for a careful medical evaluation, including a thorough medical history, physical and neurological examination, and appropriate diagnostic procedures. A retrospective survey of cancer patients referred for pain assessment found that two thirds of the patients had new and often treatable pathology diagnosed as a result of a neurological evaluation.15 Appropriate laboratory and imaging studies also may be necessary to evaluate the etiology of the patient’s pain. Establishing the physical cause of the pain is an important goal of assessment and will influence the choice of treatment. Pain in cancer patients can be a result of the cancer itself or cancer therapies, or may be related to noncancer illnesses or conditions.16,17 A prospective study of more than 2000 patients referred to a pain service found that 70% of the patients had pain due to multiple sources.18 The most frequent sources of pain were soft tissue invasion, bone pain, nerve damage or infiltration, and visceral pain. Other studies found that bone pain and visceral pain were the most common etiologies of cancer pain.16,19 Cancer therapies such as surgery, chemotherapy, radiation therapy, and immunotherapy also produce significant pain in many patients.20 Pain

related to cancer therapy may have a short duration, or a chronic pain syndrome such as peripheral neuropathy may develop.

Assessment of pain severity Pain severity is the dominant factor determining the effects of pain on the patient and the urgency of the treatment process. Many adults with mild cancer-related pain function quite effectively with pain that does not seriously impair their activities of daily living. As pain severity increases, however, it typically disrupts many areas of the patient’s life.21 Guidelines for cancer pain treatment from the Agency for Health Care Policy and Research, the American Pain Society, the National Comprehensive Cancer Network, and the WHO all use a determination of pain severity as the primary item of information in specifying treatment.22–25 Thus, it is crucial to assess accurately the patient’s pain severity. Several reliable and valid methods for scaling the severity or intensity of pain have been developed. Verbal descriptor scales (VDS) have a long history in pain research.26 Patients are asked to pick a category, such as “none,” “mild,” “moderate,” “severe,” or “excruciating,” that best describes their pain intensity. Pain relief can be rated in a similar way, using categories such as “none,” “slight,” “moderate,” and “complete.” Although VDS have proven useful in research and clinical settings, these scales assume that patients comprehend the meaning of the descriptors and define them in the same way. This assumption is questionable when patients have diverse educational, cultural, or linguistic backgrounds.27 Visual analogue scales (VAS) are often used in clinical and research settings.28 The patient is asked to determine how much of the VAS, usually a straight line, is equivalent

the assessment of cancer pain: measurement strategy to or analogous with the severity of the pain. One end of the line represents “no pain,” and the other end represents a concept such as “pain as bad as you can imagine.” The VAS have proven useful in studies comparing the effectiveness of analgesic drugs and other pain treatments. However, the VAS concept may be difficult for some patients to comprehend.29 Numerical rating scales (NRS) measure pain intensity by asking the patient to select a number to represent his or her pain severity. The most commonly used NRS uses an 11-point scale of 0–10. The numbers are typically arrayed along a horizontal line, with 0 on the left labeled as “no pain” and 10 on the right labeled with a phrase such as “pain as bad as you can imagine.” As pain intensity due to cancer often is variable, patients can be asked to rate their pain at the time of responding to the scale, and also at its “worst,” “least,” and “average” over the past 24 hours. Numerical scales are often more easily understood by patients than VAS or VDS. The use of numbers may remove some sources of cultural and linguistic variation.30 In addition, the use of NRS is recommended in many pain treatment guidelines.23 Ratings of pain intensity obtained using the NRS, VDS, and VAS are highly intercorrelated, with the NRS and VAS most highly correlated with one another.31,32 The NRS have been found to be more reliable than the VAS in clinical trials, especially with less-educated patients.29 Oral versions of the NRS can be administered to very sick patients who are unable to write. Pain questionnaires Pain is a multidimensional construct with sensory and affective qualities in addition to intensity. Many standardized pain questionnaires assess pain severity and other dimensions of pain. A few multidimensional pain questionnaires are short enough to be considered for repeated clinical or research administration to cancer patients. A short form of the McGill Pain Questionnaire (SF-MPQ) uses verbal descriptor scales to assess the sensory and affective components of pain.33 The SF-MPQ includes 15 descriptors that are rated on a four-point severity scale. Three pain scores are derived from the sum of the intensity ratings of the sensory, affective, and total descriptors. The SF-MPQ also includes the Present Pain Intensity index of the standard MPQ and a VAS. A study of patients with lung cancer supported the reliability and validity of the SF-MPQ.34 The Memorial Pain Assessment Card (MPAC) includes VAS that have been adapted for regular clinical

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use.35 The MPAC consists of one verbal descriptor scale and three VAS measuring pain intensity, pain relief, and mood. The SF-MPQ and the MPAC provide valuable information, but the descriptor scale and VAS may be difficult for some patients to comprehend. The Brief Pain Inventory (BPI) was designed to assess pain in cancer patients.36 Using a 0–10 NRS, the BPI asks patients to rate the severity of their pain at its “worst,” “least,” “average,” and “now,” the time the rating is made. Using an 11-point NRS with anchors of “no interference” and “interferes completely,” the BPI also assesses how much pain interferes with mood, walking, general activity, work, relations with others, sleep, and enjoyment of life. The BPI asks patients to mark the location of their pain on a pain drawing, and includes other questions about pain treatment and the extent of pain relief. The BPI also provides a list of descriptors to help the patient describe pain quality. A short form of the BPI frequently is used for regular pain assessment in clinical and research settings (see Fig. 5.2). Using pain questionnaires minimizes many patientreporting biases and assists health care professionals in obtaining complete information. Using pain scales that assign a metric to pain intensity and interference makes pain an “objective” symptom, similar to other signs and symptoms, such as blood pressure and heart rate. Standard questions allow patients to feel free to report the presence and severity of pain, and also to report treatment efficacy. There is a possibility of error when completing questionnaires, however, and a need for health care providers to routinely check the way patients have answered questions and to confirm their understanding of the instructions.37 For example, patients need to be aware of the time frame for rating their pain (e.g., past 24 hours, past week) and to understand the pain variable being measured (e.g., “average” pain). Simple pain scales or questionnaires make it possible to assess pain on each outpatient contact with the patient and at least once every 24 hours for a patient in the hospital, or more frequently if pain is identified as a problem. Because pain in cancer is variable and often progressive, pain assessment must be repeated regularly to achieve and maintain optimal pain control. Levels of pain intensity Categorizing a pain severity rating as “mild,” “moderate,” or “severe” is a crucial step in the assessment process and determines the urgency of the treatment process. The guidelines for cancer pain treatment from the WHO,

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STUDY ID #:_ _ _ _ _ _ _ _ _ _

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Please rate your pain by circling the one number that best describes your pain at its worst in the last 24 hours. 0 1 2 3 4 5 6 7 8 9 10 No Pain as bad as Pain you can imagine Please rate your pain by circling the one number that best describes your pain at its least in the last 24 hours. 0 1 2 3 4 5 6 7 8 9 10 No Pain as bad as Pain you can imagine Please rate your pain by circling the one number that best describes your pain on the average. 0 1 2 3 4 5 6 7 8 9 10 No Pain as bad as Pain you can imagine Please rate your pain by circling the one number that tells how much pain you have right now. 0 No Pain

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Fig. 5.2. The Brief Pain Inventory (Short Form). Copyright 1991, Charles S. Cleeland.

the assessment of cancer pain: measurement strategy

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Time: _ _ _ _ _ _ _ _ ___________________ ______________

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0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% No Complete Relief Relief Circle the one number that describes how, during the past 24 hours, pain has interfered with your: A. General Activity 0 1 2 3 Does not Interfere B. Mood 0 1 2 Does not Interfere

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Fig. 5.2 (continued)

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94 American Pain Society, Agency for Health Care Policy and Research, and National Comprehensive Cancer Network (NCCN) all recommend varying treatment approaches for these three categories of pain severity. For example, the three-step analgesic ladder in the WHO guidelines recommends a family of analgesic drugs based on the three categories of pain intensity.25 The NCCN guidelines include a treatment algorithm that also is based on the categorization of pain as mild, moderate, or severe.23 For example, severe pain is considered a pain emergency that mandates rapid titration of a short-acting opioid, prevention of common side effects of opioids, and psychosocial support. The recommended treatment of moderate pain includes an opioid medication, prevention of side effects, patient education, and psychosocial support (if indicated). Thus, the implementation of cancer pain treatment guidelines necessitates the categorization of pain intensity. Mild, moderate, and severe pain can be defined as ranges of patient responses to a numerical rating of pain at its “worst” on an 11-point scale. The ranges for each category of pain severity are based on the degree of interference with function associated with each category.21 Serlin and colleagues21 identified 1–4, 5–6, and 7–10 as the optimal ranges for classifying pain as mild, moderate, or severe, respectively. A subsequent study of cancer patients with pain from bone metastases also found a nonlinear relation between pain intensity and interference. The Serlin category for mild pain (1–4) was confirmed, but the categories for moderate (5–7) and severe (8–10) were slightly different from those identified by Serlin. Mild pain most often calls for a “mild” analgesic (acetaminophen or a nonsteroidal anti-inflammatory drug) or a “moderate” analgesic such as hydrocodone.23 Mild pain typically causes the least interference with function. However, patients with mild pain may benefit from education about the need to report pain when it occurs, when it gets worse, or if it is not relieved by current treatment. Moderate pain calls for a more aggressive analgesic program and thorough assessment of the impact of the pain on the patient’s life. Because pain at this level impairs multiple areas of a patient’s function, a follow-up contact should be made within 24 to 72 hours to assess the efficacy of the pain treatment provided. Severe pain mandates very aggressive analgesic treatment with a “strong” opioid such as morphine. Follow-up contact for reassessment should occur within 24 hours after the initial assessment. A comprehensive assessment of the impact of the pain is necessary to determine whether the patient needs psychosocial support or other behavioral treatments.

Assessing pain characteristics In addition to measuring pain severity, the assessment of cancer pain should include the determination of other pain characteristics that will help guide treatment choices. Much of this information can be obtained through the use of standardized questionnaires that assess the patient’s subjective reports of pain characteristics. A clinical interview may be used to collect additional information.

Spatial characteristics of the pain Information on spatial characteristics of the pain (e.g., location, perceived depth) is helpful in determining the etiology of the pain.39 For example, patients may draw the pain in the distribution of a particular nerve, suggesting that the pain is neuropathic in origin. The location of the pain can be assessed by asking the patient to provide a graphic representation of the pain location or to complete a pain site checklist. Some pain questionnaires, including the BPI, contain a human figure drawing for the patient to use. Pain location and perceived depth (e.g., deep, surface) also may help to determine why pain is exacerbated by particular movements or positions.

Temporal pattern of the pain Cancer pain does not always remain at the same intensity over a 24-hour period, and it is important to capture the temporal pattern of pain. Is it constant, or episodically more severe? Are the episodes spontaneous or do they occur with specific movements or in response to other aggravating factors? The temporal pattern of pain often is clearly described by the patient in the initial interview. It may be necessary, however, to have patients rate their pain and analgesic use in a home diary to determine its pattern. A home diary also may be used to determine the patient’s response to analgesics by recording variables such as time to onset of pain relief and duration of relief. Assessment of the temporal pattern will help determine whether the patient experiences significant incident pain, exacerbation of pain with movement. Incident pain is common when the pathologic process responsible for the pain is influenced by movement or position. Some types of pain (e.g., neuropathic pain) may have periods when pain spontaneously becomes more severe. These periodic increases in pain are often referred to as “breakthrough pain,” defined as a transitory increase in pain occurring in the context of stable baseline pain.40 The frequency of breakthrough pain

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is an important temporal variable that may be used as an outcome measure in clinical trials.41 Cancer pain treatment guidelines recommend additional analgesics for the patient to take during breakthrough or incident episodes, or before episodes if it is possible to anticipate when they will occur. For some patients, however, the presence of breakthrough pain may indicate that the dose or potency of the routine analgesic prescribed for pain management is inadequate.40

studies of minority patients with cancer experiencing pain found that many patients use nontraditional treatment approaches (e.g., herbal teas, prayer) for their pain.13,45 Assessment of the patient’s pain treatment history should include the evaluation of alternative treatment approaches and whether these approaches interfere with or supplement the prescribed analgesics. If possible and medically indicated, the patient’s alternative approaches may be incorporated into the pain management program.

Pain quality

Assessment of barriers to pain control

The patient’s subjective report of the quality of the pain may reflect the pain’s etiology.42 For example, neuropathic pain often is described as “numb,” “pins and needles,” or “burning.” Pain from tumor destruction of soft tissue or bone often is described as “aching.” People may find it difficult to spontaneously describe their pain in a clinical interview. Word lists of potential descriptors help the patient to report pain quality. Some questionnaires, including the BPI, the SF-MPQ, and the Neuropathic Pain Scale,43 include lists of descriptors for the patient to select. Evaluating the quality of the pain is an important part of pain assessment and will help determine the etiology of the pain and the recommended treatments.

Patients with cancer frequently underreport pain and pain severity. A number of patient-related barriers to the assessment of cancer pain have been identified.47–49 Patients with cancer often do not want to be labeled as complainers, do not want to distract their health care provider from treating the cancer, or are afraid that their pain means that their cancer is progressing. Some patients are fatalistic and believe that pain is an inevitable part of having cancer and must be accepted. Often, patients are concerned about having to take potent opioids because they fear they will become addicts or will have unmanageable side effects. Other frequently reported barriers are forgetting to take pain medications and the belief that one should be able to tolerate pain without medication.47 Some patients also are concerned that if they take pain medication, they will become tolerant to the effects of analgesics when their disease progresses.14 Assessment of the barriers to pain control may be done in a clinical interview or by using a standardized measure such as the Barriers Questionnaire48 or Adolescent Barriers Questionnaire.50 After the barriers for a patient have been identified, appropriate education should be initiated. Many patients prefer to be active partners in their pain assessment and treatment. They can be reassured that, in most instances, pain relief can be obtained and that it is part of the health care professional’s role to provide that relief. Education about cancer pain and pain treatments can improve the outcome of pain treatment for many patients. Several randomized clinical trials with cancer patients experiencing pain found that education on pain management produced significant reductions in pain intensity ratings.51,52 A study of underserved minority patients, however, found that education on pain management did not provide significant improvement in pain intensity ratings.53 In addition to patient-related barriers, system barriers that may interfere with optimal pain treatment should be assessed. System barriers may include lack of institutional support for pain management, inadequate supportive care

Response to prior treatment The patient’s history of pain therapies and their outcomes are additional variables that need to be assessed. When determining response to prior analgesics, the patient’s adherence to his or her prescribed medications must be determined. A study of outpatients with cancer-related pain found that patients adhered to their opioid therapy only 62%–72% of the time.44 Nonadherence was a significant predictor of symptom distress and impaired QOL. The most frequent reasons for nonadherence were side effects of the medications and concerns about addiction. In a study of minority patients with cancer, the inability to understand instructions was associated with nonadherence to analgesic medications.45 Thus, it is important to assess adherence to analgesic regimens and the reasons for any nonadherence. Careful assessment can identify possible targets for patient education and/or the need to treat side effects of analgesics or change medication regimens. The results of recent studies indicate that a majority of cancer patients use some type of nontraditional or alternative approach (e.g., spiritual practices, nutritional supplements) to treat their disease or its symptoms.46 Similarly,

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96 services (e.g., social work, physical therapy), limited availability of opioids in local pharmacies,54 and socioeconomic issues that interfere with the provision of pain treatments. The assessment of system barriers is particularly important for low-income, underserved, and racial or ethnic minority patients, who often face multiple barriers to optimal medical care.

Assessing pain impact Comprehensive assessment of cancer pain should include the measurement of pain interference with areas of the patient’s life and functioning. Information on the impact of pain will contribute to specific treatment recommendations. An optimal treatment plan for pain control is based on evaluation of more than pain severity and pain etiology. The assessment of pain impact includes the measurement of QOL, mood, and social support systems. Quality of life Health-related QOL is a concept defined as the perceived value of life as modified by impairments, functional states, perceptions, and social opportunities influenced by disease, injury, and treatment.55 Measures of QOL typically include evaluation of physical functioning, psychological status, social relationships, and symptoms.56–58 It is beyond the scope of this chapter to review the many instruments available to measure QOL. Some of the QOL instruments that have been used successfully with cancer patients include the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire,59 the Functional Living Index – Cancer,60 the Functional Assessment of Cancer Therapy measurement system,61 and the Medical Outcomes Study SF-36 and SF-12 Health Surveys.62–64 All these QOL questionnaires have demonstrated adequate reliability and validity in clinical research. One drawback to the repeated use of QOL measures is the time required for patients to complete the questionnaires and for clinicians to score and interpret the results. The BPI provides a synopsis of areas of pain interference with functioning. For patients with cancer-related pain, this synopsis is a useful alternative to more lengthy QOL measures. A study of Chinese cancer patients found that pain interference ratings on the BPI were significantly correlated with ratings on a standardized QOL questionnaire.65 Moreover, pain intensity ratings were a significant predictor of QOL, even after controlling for disease severity. The BPI interference items provide valuable information related to QOL and may be adequate in many cases. However, the

BPI does not indicate the extent to which functioning or QOL is impaired by nonpain factors. Mood The majority of cancer patients adjust to the stress of the disease and its treatment without developing clinical depression, anxiety disorders, or any other psychiatric condition.66,67 However, patients with pain are more likely to report feelings of depression, anxiety, or distress than those without pain.68–70 The NCCN recommends screening for emotional distress in all patients with cancer.71 A simple 11-point NRS to measure distress or single items assessing anxiety or depression may be used to screen for distress.72,73 If significant distress is suggested, then additional assessment may be performed using a standardized mood questionnaire or a clinical interview. Mood disorders among cancer patients are difficult to identify because of the similarity of some mood symptoms to common disease-related symptoms, such as fatigue, weight loss, sleep disturbance, and impaired concentration. The Profile of Mood States is one of the more commonly used measures of mood in cancer patients.74 The scale is relatively easy for patients to understand and complete. In addition, the scale is sensitive to change over a brief period of time, making it ideal for studying responsiveness to treatment. However, the 65-item standard version, and even the 30-item “short form,” is lengthy for very ill patients to complete. Consequently, a shorter 11-item version has been developed for cancer patients.75 The well-validated State–Trait Anxiety Inventory has been used to measure anxiety in cancer patients.76 The State version that assesses present levels of anxiety is usually most appropriate for patients with cancer. The Beck Depression Inventory is a reliable, valid, and frequently used measure of clinical depression.77 The clinician or researcher needs to look closely at the content of the items endorsed by the patient in addition to the overall score.78 Examination of responses to the somatic, cognitive, and affective items may help differentiate symptoms that may be related to cancer (e.g., weight loss) from those that may be related to depression (e.g., sadness). Social support Social support makes an important contribution to the functioning and well-being of patients with cancer but is difficult to measure.79 Relationships and activities with family members and friends may affect how an individual copes with cancer-related pain. For an abbreviated evaluation of

the assessment of cancer pain: measurement strategy social interactions, the BPI and the QOL measures include items on the impact of pain, illness, or general health on social relationships. If the BPI or a QOL measure suggests difficulty with social support, then further assessment is warranted. The Multidimensional Pain Inventory (MPI) includes subscales assessing social support and the perceived responses (negative, solicitous, distracting) to pain of the spouse or significant other.80 A study comparing the MPI responses of cancer and noncancer pain patients found that cancer patients reported more support and solicitous behavior from spouses or significant others than did noncancer patients.81 Concurrent symptoms Cancer patients with pain usually have symptoms other than pain that need to be assessed and treated. The disease itself often produces fatigue, weakness, cachexia, and cognitive deficits. Cancer treatments frequently cause nausea, vomiting, fatigue, and other physical, cognitive, or affective symptoms. The negative side effects of analgesic medications may include constipation, nausea, fatigue, and sedation. Common symptoms of cancer and cancer treatment significantly impair the daily function and QOL of patients. Thus, it is important to assess symptoms routinely and develop appropriate treatment plans. A checklist of potential concurrent symptoms, such as the M. D. Anderson Symptom Inventory (MDASI) or the Edmonton Symptom Assessment System (ESAS), may be used to assess the presence and intensity of symptoms.82,83 The core MDASI consists of 13 symptoms that are common across all cancer diagnoses and treatments: pain, fatigue, nausea, sleep disturbance, emotional distress, shortness of breath, lack of appetite, drowsiness, dry mouth, sadness, vomiting, difficulty remembering, and numbness or tingling (see Fig. 5.3). Each symptom is rated on an 11-point scale, with 0 being “not present” and 10 being “as bad as you can imagine.” The MDASI also contains six items that describe how much the symptoms have interfered with areas of the patient’s life during the past 24 hours: general activity, mood, walking ability, normal work (including work outside the home and housework), relations with other people, and enjoyment of life. The core symptom items on the MDASI can be used to monitor patients’ symptoms in routine clinical care. Modules of additional symptom items may be added to the basic MDASI for patients who are receiving aggressive treatments (e.g., stem cell transplantation) or who have cancer diagnoses associated with specific symptoms (e.g, lung cancer and coughing). As with pain, it is important to evaluate

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these symptoms over time to monitor changes in severity and response to treatment. The ESAS is designed to assess nine common symptoms in cancer patients: pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, and feelings of well-being. The severity at the time of assessment of each symptom is rated on a 0–10 numerical scale. The reliability and validity of the ESAS have been supported in multiple studies.73,84

Pain assessment in children with cancer Pain assessment in children with cancer has received less attention than in adults.85,86 However, adequate care of children with cancer must include a plan for the assessment and management of any cancer-related pain. The WHO, the American Pain Society, and the American Academy of Pediatrics have developed guidelines for the assessment and treatment of pain in children.87,88 The guidelines recommend regular assessment and documentation of the child’s pain level as an essential vital sign that guides treatment recommendations. Developmentally appropriate pain intensity measures should be used with all children. The assessment of pain in infants often relies on physiological measures and observer reports of behaviors that indicate probable pain.89,90 A variety of pain intensity measures are available for toddlers and preschool children, including pain thermometers,91 color scales,92,93 and faces scales.94 Most children over the age of 5 usually are able to complete standard NRS and VAS.95 The child’s self-report of pain should be considered the gold standard of pediatric pain assessment and used whenever possible. However, behavioral observations by health care providers or parents are necessary for pain assessment in very young children and in children who do not have the ability to report their pain because of disability or disease. A number of reliable, valid behavioral observation methods have been developed for the assessment of pediatric behaviors related to pain, such as crying, clinging, reduction in normal activity, and social withdrawal.96–98 Two standardized interviews for school-age children and adolescents may provide valuable information regarding the impact of cancer pain on the child’s daily life: the Children’s Comprehensive Pain Questionnaire95 and the VarniThompson Pediatric Pain Questionnaire.99 In addition, a special panel of the American Academy of Pediatrics has suggested that a Pain Problem List be included in the medical record of every child with cancer.100 The goal of this list is to identify pain problems and appropriate pain management strategies.

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Date: _________________________

Institution:_________________________

Subject Initials: ________________

Hospital Chart #:____________________

Study Subject #: _______________

M. D. Anderson Symptom Inventory (MDASI) Core Items Part I. How severe are your symptoms?

People with cancer frequently have symptoms that are caused by their disease or by their treatment. We ask you to rate how severe the following symptoms have been in the last 24 hours. Please fill in the circle below from 0 (symptom has not been present) to 10 (the symptom was as bad as you can imagine it could be) for each item. Not Present

0

As Bad As You Can Imagine

1

2

3

4

5

6

7

8

9

10

1. Your pain at its WORST?

2. Your fatigue (tiredness) at its WORST?

3. Your nausea at its WORST?

4. Your disturbed sleep at its WORST? 5. Your feelings of being distressed (upset) at its WORST? 6. Your shortness of breath at its WORST?

7. Your problem with remembering things at its WORST? 8. Your problem with lack of appetite at its WORST?

9. Your feeling drowsy (sleepy) at its WORST? 10. Your having a dry mouth at its WORST?

Fig. 5.3. The MDASI. The core MDASI consists of 13 symptoms and six interference items.

Pain assessment in elderly patients with cancer Sixty percent of all cancers occur in persons aged 65 years and older.101 Several studies found that elderly patients with cancer are at risk for undertreatment of cancer-related pain. In a survey of outpatients with metastatic cancer who were experiencing pain, Cleeland and colleagues5 found that

patients 70 years of age and older were more likely than younger patients to receive inadequate analgesics. Similarly, a survey of more than 13,000 nursing home residents with cancer found that 26% of the patients experiencing daily pain received no analgesics.102 Only about half the patients in pain received opioids, and only 13% of patients over 85 received strong analgesics.

the assessment of cancer pain: measurement strategy

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Date: _________________________

Institution:_________________________

Subject Initials: ________________

Hospital Chart #:____________________

Study Subject #: _______________

Not Present

0

As Bad As You Can Imagine

1

2

3

4

5

6

7

8

9

10

11. Your feeling sad at its WORST?

12. Your vomiting at its WORST?

13. Your numbness or tingling at its WORST?

Part II. How have your symptoms interfered with your life? Symptoms frequently interfere with how we feel and function. How much have your symptoms interfered with the following items in the last 24 hours: Did Not Interfere

0

Interfered Completely

1

2

3

4

5

6

7

8

9

10

14. General activity?

15. Mood?

16. Work (including work around the house)?

17. Relations with other people?

18. Walking?

19. Enjoyment of life?

Fig. 5.3 (continued)

Lack of pain assessment or inadequate assessment contributes to the undertreatment of cancer pain in the elderly.103 In the nursing home study by Bernabei and colleagues,102 regular pain assessments were not included in most patient charts. However, 86% of the patients, including cognitively impaired individuals, were able to verbally report pain to the research staff. Similarly, Ferrell and colleagues104 found that 83% of elderly patients in a nursing

home setting could complete at least one of the four pain intensity scales administered. Other studies have documented that elderly patients with mild to moderate cognitive impairment can complete simple pain rating scales when given careful instruction.105–107 Before pain assessment, all elderly patients should be screened to identify any sensory, motor, or cognitive deficits that affect their ability to report pain. Pain scales

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100 may be printed with large letters and scales for patients with limited visual abilities. The Faces Pain Scale for the elderly may be used for individuals who have difficulty understanding numerical or VAS formats.108 Pain assessment instruments also can be administered in an interview format for patients who have visual or motor impairments that prevent completion of paper-and-pencil measures. Clinicians and researchers should be aware of possible hearing impairments and assess whether elderly patients can comprehend oral instructions.109 When cognitive deficits are severe and prevent self-report of pain, observation of pain-related behaviors is an alternative strategy.110–112

Pain measurement for quality assurance The development of specific practice guidelines for pain management has led to quality assurance standards for pain treatment.22,24,111 In addition, the Joint Committee on Accreditation of Healthcare Organizations has developed standards for the assessment and management of pain in health care organizations. Hospitals and other health care facilities are expected to demonstrate compliance with these standards when they are reviewed for accreditation. The standards include the regular assessment and recording of patients’ pain levels. Pain assessment tools provide a method for routine monitoring and charting of pain in the hospital or clinic setting. Numerical scales seem best suited for easy tracking of pain for this purpose. Innovative educational programs have been developed to improve pain assessment and treatment in health care institutions.111,113,114 A model pain management program to implement quality assurance guidelines for the treatment of cancer pain was evaluated at a tertiary care cancer center.115 The program included the formation of a quality improvement team, staff education on pain assessment and management, pain rounds, and focus groups to discuss issues related to cancer pain. Following implementation of the model program, improvements were found in patients’ satisfaction with pain treatment and nurses’ knowledge of and attitudes toward pain management. The Cancer Pain Role Model Program, developed by the Wisconsin Cancer Pain Initiative in 1990, has trained more than 1000 health care professionals in the United States.116–118 Health professionals who participate in the program receive intensive education in cancer pain assessment and treatment. Then the professionals are asked to develop an action plan to facilitate improved pain assessment and treatment in their own institutions.

Innovative trends in pain assessment Recent developments in computer and communications technology offer new opportunities for the assessment of patients’ pain and other symptoms. Handheld computers and other electronic recording devices have been used for the assessment of pain in patients’ home and work environments.119 Given that memory for pain and other symptoms often is poor, the “real-time” assessment of symptoms can provide accurate data regarding symptom patterns and changes over time. Electronic pain diaries have been used successfully to monitor pain and related symptoms in patients’ daily lives using sampling strategies such as ecological momentary assessment.120,121 For patients who are not comfortable using handheld computers, the development of telephone interactive voice response (IVR) technology provides an exciting option for two-way communication with the provider. Telephone systems have been used widely in outpatient health care settings for communicating with patients. However, traditional telephone communication requires considerable staff time and is not feasible for assessing symptoms on a regular basis. Using IVR technology that combines touch-tone telephones with computers and the Internet may be an effective way to follow patients who have symptoms like pain that need to be monitored closely while away from the clinic or hospital. A patient can respond to spoken instructions by using the keypad of a touch-tone phone. For example, a patient might be asked to rate his/her pain at its worst in the past day from 0 (no pain) to 10 (pain as bad as you can imagine). Information obtained in this way can be used to update a patient file on an Internet or intranet site. The system also may be configured to alert health care providers and to provide patient education on pain management. Several recent studies have evaluated the use of IVR systems to track the symptoms of patients with lung cancer122 and to improve the symptom management of patients with solid tumors.123

Conclusions Inadequate pain assessment is the most common reason for undertreatment of cancer-related pain. Oncology health professionals often lack training in pain assessment and are focused on treating the cancer. Patients may hesitate to report their pain for a variety of reasons, including concerns about the meaning of pain, their hesitancy to complain, a reluctance to distract their physician from treating the cancer, and concerns about pain medications. Accurate

the assessment of cancer pain: measurement strategy and regular assessment of patients’ pain is essential for effective treatment planning and evaluation. Pain assessment measures designed for the patient with cancer can facilitate the assessment process. Pain severity and interference in daily activities caused by pain are important targets for pain assessment. Assessment based on questionnaires needs to be supplemented by a patient interview and medical–neurological examination. When deficits in QOL, mood, or social support are indicated by patients’ questionnaire or interview responses, additional evaluation is suggested. Pain is typically associated with other cancer-related symptoms that require regular assessment. Pain assessment should be repeated frequently to monitor treatment efficacy and to identify any changes in patients’ pain related to treatments or disease progression. Patients may benefit from education regarding cancer pain and effective pain management treatments. The pain assessment of pediatric and geriatric patients requires special consideration. Quality assurance standards require the regular use of pain assessment measures in oncology treatment settings. Recent innovations in computer and communications technology provide new approaches to pain assessment in patients’ daily environments.

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Multidimensional assessment: pain and palliative care norma o’leary, a carol stone, b and c peter g. lawlor b,c a b Marie Curie Cancer Centre, Our Lady’s Hospice, and University of Alberta

Pain occurs in the majority of patients with advanced cancer1,2 and is associated with multiple other symptoms,3–5 which in combination are manifested with increasing frequency toward the last days of life.6 Although the pursuit of World Health Organization (WHO) guidelines can achieve adequate pain relief for 80%–90% of patients with cancer,7–9 there is evidence to suggest that this is not achieved in clinical practice.10,11 Although there are many potential explanations, the failure to conduct a multidimensional assessment likely plays a significant role in this undertreatment.10,12–15 A multidimensional approach incorporates the assessment of pain in the context of other variables, including other symptoms, therapeutic interventions, and the domains of physical, psychosocial, and spiritual functioning.16–18 This approach contrasts with the unidimensional approach, which attributes all aspects of the pain experience (including use of analgesics and psychological distress) to the patient’s reported pain intensity. More than 30 years ago, Melzack and Casey19 conceptualized pain as being composed of three major dimensions: sensory–discriminative, motivational–affective, and cognitive–evaluative. However, there are relatively few literature references to the multidimensional nature of cancer pain before the publication of a study by Ahles et al.20 in 1983. This study demonstrated that pain occurring in association with cancer consisted of the following general components: sensory (including characteristics such as site, radiation, intensity, and quality); affective (including mood disturbance and anxiety); cognitive (including the influence of pain on thought processes, and the meaning of pain); and behavioral (including use of analgesic medication, and relationship of pain to activities of daily living). The International Association for the Study of Pain has defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”21 There is therefore evidence to

support the concept, and a high level of consensus regarding the multidimensional nature of pain. In the past two decades, the educational efforts of WHO have sought to promote multidimensional assessment by broadening the organization’s original cancer pain program into cancer care and palliative care.1

Major steps in the pain experience The basic components of the pain construct are represented in Fig. 6.1, using nociceptive pain as an example. First, the productive or nociceptive input stage involves activation of peripheral nociceptors and the arrival of impulses in the dorsal horn of the spinal cord. Neuropathic pain is associated with nerve injury or damage and may occur without peripheral nociceptor activation. Second, the actual perception of pain occurs at the brain level. The extent to which the message is relayed from the spinal cord to higher brain centers comes under the influence of descending modulatory circuits, in addition to the action of endogenous and exogenous opioids in the dorsal horn. Third, the stage of expression is the measurable component of the pain experience. This expression is derived from multiple inputs. Ultimately, pain is not only a sensory nociceptive phenomenon, it also is an emotional experience, owing to input from various cognitive and affective factors,20,22,23 grouped under the headings of “psychosocial milieu” and “emotional distress” in the model described in Fig. 6.1.

Pain and palliative care: a quality-of-life issue In the biomedical model of care that operates in most cancer centers, the concept of health-related quality of life (HRQOL) is at risk of being neglected by oncologists.24,25 The interaction of pain and other domains contributing to the global quality-of-life (QOL) construct is represented 105

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in the matrix in Fig. 6.2. In most of these interactions, there is potential for bidirectional influence. The degree of concomitant disturbance in the physical, psychological, and social functioning domains; the impact of pain and other symptoms; the role of spiritual and existential distress; the subtle contribution of cultural influences; and the relative interplay of all these factors are complex and unique for each individual. For cancer patients without effective disease-modifying treatments, the illness trajectory usually entails an inexorable disease progression. The interrelationships and the relative roles of pain, other symptoms, and the various other domains in Fig. 6.2 therefore are subject to potential change over time. This temporal dynamic may be associated with varying levels of suffering, coping, and adjustment, which in turn influence the overall QOL. At this stage, the palliative focus of care assumes primary importance. In the case of patients with cancer pain that is difficult to control using conventional strategies, such as that

Expression of pain experience Pain behaviors and pain visual analog score

Brain level

Psychosocial milieu

Cognitive appraisal

Emotional distress

Modulation due to descending systems*

Spinal cord level

Tissue injury

Nociceptive input

Nociceptor activation

* Inhibitory and facilitatory

Fig. 6.1. Production, perception, and expression components of the pain construct.

Optimal quality-of-life

Coping and adjustment

Suffering

Physical function

Spiritual / existential issues Palliative Care

Social function

Psychological function

Cancer Opioid therapy

Other therapies pain

Other symptoms or problems

Fig. 6.2. Multidimensional matrix incorporating pain in the context of palliative care.

multidimensional assessment: pain and palliative care proposed by WHO1 or other agencies,26 the need for a multidimensional assessment assumes even greater importance. These patients and others with varying care needs often are referred to pain specialists and practitioners in palliative care. Palliative care is concerned with the provision of care to patients with progressive incurable illness, and to their families.27 The goal of palliative care is to achieve optimal QOL, with emphasis on providing comfort toward the end of life, as opposed to pursuing primarily curative strategies. The provision of comfort entails pain relief in addition to alleviation of distress in relation to various social, psychological, existential, and spiritual issues, as well as the many other symptoms that emerge with advanced disease. The recognition and relief of distress in the many domains contributing to the multidimensional QOL construct serve to enhance adjustment and adaptive coping and reduce the global distress and potential suffering associated with terminal illness. Not surprisingly, therefore, the palliative care model in its usual capacity incorporates a multidisciplinary team approach.

Pivotal role of cognitive status The presence of cognitive impairment, whether as a result of delirium or dementia, presents a major impediment in the assessment of pain and other symptoms in patients with advanced cancer.28–30 The chapter on cancer pain in the elderly (Chapter 24) addresses the challenges of pain assessment in patients with dementia. Although dementia occurs predominantly in the elderly, delirium occurs in all age groups with cancer.31 The frequency of delirium in advanced cancer patients varies from 28% to 40% on admission,31,32 and the vast majority have delirium in the hours to days before death.31 The diagnosis of delirium is made on the basis of cognitive impairment, particularly disordered attention, along with other features, such as altered awareness, perceptual disturbance, acute onset, and fluctuation in course.33 The Mini Mental State Examination (MMSE)34 has been used widely to screen for cognitive impairment as a component of delirium. Normal population-based scores have been established for this instrument in relation to age and educational level.35 The diagnosis of delirium frequently is missed, particularly if no objective cognitive testing is carried out.36–38 Regular cognitive screening with an instrument such as the MMSE therefore aids the detection of delirium, and in turn provides useful information regarding the reliability of patient-rated pain assessment scores.39 Although the MMSE has acquired gold standard status as a cognitive assessment tool, there are many other validated instruments for this purpose: The Blessed or Short

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Orientation Memory Concentration Test has psychometric properties that match the MMSE, yet it is more user friendly in the advanced cancer population.40,41 Based on the level of psychomotor activity, hyperactive, hypoactive, and mixed subtypes of delirium have been identified.42–44 The emotional lability, disinhibition, and psychomotor agitation components of the delirium syndrome frequently are interpreted as worsening pain by relatives and sometimes by medical and nursing staff, especially in the absence of any objective cognitive testing.45 Family members with the best of intentions advocate for more analgesia for their relative, whom they see as being in excruciating pain. Fainsinger and colleagues46 refer to the “destructive triangle” created as a result of the family’s misinterpretation of the patient’s delirium symptoms as pain and their consequent advocacy for nursing and, in turn, physician efforts to “do something.” In an effort to relieve the patient’s distress in this crisis situation, the physician often increases the opioid dose without taking the time to conduct a disciplined multidimensional assessment. The increase in opioid, in turn, tends to aggravate the agitation further, particularly when the opioid is already implicated as a precipitant.46,47 A multidimensional assessment in this setting would embody cognitive testing, the recognition of delirium, and institution of more appropriate interventions, such as an opioid switch or dose reduction, in addition to prescribing a neuroleptic for the symptomatic treatment of delirium.48 A study by Gagnon et al.30 suggests that the circadian distribution of opioid analgesic breakthrough use in advanced cancer patients with delirium differs from that of cancer patients without delirium. Patients with delirium used more breakthrough doses in the evening and at night compared with nondelirious patients, who used more breakthrough doses during the day. One potential explanation offered by the authors is that delirium-associated psychomotor agitation occurring in the “sundown” period could be misinterpreted by family and staff as worsening of pain, resulting in the administration of a greater number of breakthrough doses.

Assessing other symptoms: relevance to the pain presentation A comprehensive prospective analysis of symptoms in 1000 patients referred to a palliative medicine program found a median of 11 (range, 1–27) symptoms per patient.4 Symptom prevalence differed in relation to age, gender, and performance status. The symptom priority level ascribed by the patient in terms of distress may vary over time, and pain

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108 is not always associated with the highest level of distress. The presence of multiple other symptoms and problems besides pain therefore warrants serial assessment and monitoring of these symptoms or problems as part of the multidimensional assessment of pain and other symptoms.5,49 Clinical example The interrelationships of pain, constipation, and associated symptoms and problems represent a typical example from clinical practice that highlights the need to evaluate the patient’s whole symptom profile (see Fig. 6.3). Although there usually are multiple factors associated with constipation, asthenia (with reduced physical activity), opioids, and hypercalcemia are among the most common causes. Constipation can produce nausea, which may lead to decreased fluid intake; consequently, dehydration may occur. Dehydration then may contribute to or aggravate problems such as asthenia, opioid toxicity, and hypercalcemia. Similarly, constipation can produce abdominal pain or aggravate incidental pain, leading to a possible increase in opioid consumption, which perpetuates this cycle.

Constipation is a frequent, distressing, underestimated, yet highly treatable and preventable complication in advanced cancer patients.50 Plain abdominal radiography, which allows for the assessment of stool in the colonic quadrants and the generation of a constipation score, has been suggested as a useful and reliable method for assessing this problem.51 Optimal use of symptom assessment tools Failure of adequate pain control may be a reflection of inadequate pain assessment or failure to recognize pain’s multidimensional nature. It is clearly challenging to find the ideal instrument that will fully and adequately assess the different dimensions of cancer pain together with its intensity.52 However, assessment instruments may increase awareness of symptom-related distress, improve outcome associated with careful monitoring, be useful as a communication tool within the multidisciplinary team, and be mandatory for research.15 A pain assessment tool should be valid, reliable, sensitive to treatment effects, and easily administered. The choice of

Impaired physical functioning

Anorexia

Asthenia-cachexia

Hypercalcemia

Opioids

Pain

Constipation

Opioid

Nausea

toxicity

Dehydration

Fig. 6.3. Interrelationships of pain, constipation, and other symptoms in advanced cancer.

multidimensional assessment: pain and palliative care

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Fig. 6.4A. Edmonton Symptom Assessment System.

tool should be determined by the outcome to be measured, such as pain intensity, interference, relief, site, temporal aspects, and qualitative aspects. Pain assessment tools can be classified as unidimensional, multidimensional, and part of HRQOL measures. Unidimensional tools include visual analogue scales, numerical rating scales, and categorical rating scales. Whereas unidimensional tools are valid, reliable, and easy to use, multidimensional tools are more challenging for patients to complete yet provide a more comprehensive assessment of the pain and its impact. The Memorial Symptom Assessment Scale (MSAS), the Symptom Distress Scale (SDS), and the Edmonton Symptom Assessment System (ESAS) are examples of

instruments that have been developed to monitor multiple symptoms in the setting of advanced cancer. The MSAS is a validated patient-rated instrument that assesses the frequency, intensity, and distress level associated with 32 physical and psychological symptoms.53 It contains specific subscales that capture physical, psychological, and global symptom distress. The SDS is a patient-rated instrument that assesses the frequency, intensity, and distress level of nine physical and two psychological symptoms.54 The most recent version of the ESAS consists of a series of nine numerical rating scales that evaluate a mix of psychological and physical symptoms in addition to a global sense of well-being (Fig. 6.4A).55,56 The numerical rating

110 scales are rated by patients who are cognitively intact, and the resulting scores are then transferred to a graphical representation in the patient’s chart (Fig. 6.4B). In the case of patients with mild cognitive impairment, the ratings are conducted in association with family or staff. For patients with moderate or severe cognitive impairment, especially toward the last days of life,56,57 the family or staff provide the ratings. The graphical representation of the patient’s ESAS symptom profile can visually portray different score patterns depending on the varying predominance of physical or psychosocial symptom complexes. Discordance may occur between pain intensity levels recorded on the ESAS and the patient’s verbal pain descriptions, the patient’s use of opioid, or other pain behaviors manifested by the patient. This discordance, which may be associated with apparent under- or overreporting of pain, may be explored with the patient and family, thereby facilitating the identification of other dimensions associated with the pain experience, such as opioid phobia or somatization of psychological distress.58 Although clear differences likely exist between patient and proxy raters of the ESAS,59 a study assessing the reliability of patient, nurse, and family caregiver ESAS ratings suggests that an integrated approach incorporating proxy and patient ratings led to increased reliability.58 Although the patient’s self-report traditionally has been regarded as the gold standard, discordance arising between the patient and proxy ratings could potentially serve as a useful marker for further exploration of the meaning, for example, of unexpectedly high or low patient-reported pain scores. A study examining the clinical utility of the ESAS showed that although 84% of patients were able to rate the ESAS items on admission to a palliative care unit, 83% of the assessments before death were rated by either a nurse or relative.57 In addition to having high levels of interrater reliability, the ESAS items (excluding activity level) show a high level of correlation with the Support Team Assessment Schedule, a validated multidimensional clinician-assessment instrument.60 A validation study by Chang et al.61 suggests that the ESAS has a satisfactory level of internal consistency, criterion, and concurrent validity. The ESAS has been used widely in palliative care audit and research.62–67 In a prospective study of delirium in patients with advanced cancer, those who were able to rate their own ESAS scores had higher pain scores and total ESAS scores during delirium than when delirium was absent. Here, the ESAS scoring appeared to capture the “crescendo pain” previously reported in association with the presence of delirium.68

n. o’leary, c. stone, and p.g. lawlor As pain rarely occurs in isolation in patients with cancer, multisymptom assessment tools may be useful. A recent systematic review of multisymptom assessment instruments in cancer patients found 21 instruments to be appropriate for clinical use. The instruments varied in symptom content and extent of psychometric validation.69 Assessment of pain as part of an HRQOL measure will provide information on the patients’ pain in the context of their functioning in several domains – physical, psychological, social, and others. The Schedule for Evaluation of Individual Quality of Life (SEIQoL) is an individualized QOL measure that allows patients to define domains that contribute to their QOL.70 Pain can be nominated as one of those domains, and patients can rate the pain experience in relation to the other domains that affect their QOL. SEIQoL has an advantage over other HRQOL measures in that patients nominate the areas they feel affect QOL rather than those being predefined by the tool.

Predictors of difficulty in cancer pain management Even when WHO guidelines1 are followed, failure to achieve satisfactory pain relief occurs in 10%–20% of patients.7–9 For these instances, some authors have proposed descriptors such as “opioid–poorly responsive pain” or “opioid-irrelevant pain.”71 Therefore, there is a need both in clinical practice and in the standardized comparison of research findings for a systematic approach to identify and categorize factors associated with a poor prognosis. Cancer pain classification: speaking a common language The development of staging systems for the extent of cancer disease has helped provide a basis for differential prognoses.72,73 It also has allowed a systematic and standardized approach to comparing research findings, thereby facilitating the development of evidence-based clinical management protocols. Using a somewhat analogous rationale, the Edmonton Staging System was developed for cancer pain. This physician-rated tool generated different prognoses for the achievement of satisfactory analgesia, based on the presence or absence of specific prognostic factors.74,75 The tool has undergone further modification based on recent validation studies.76,77 The most recent version has been renamed the Edmonton Classification System for Cancer Pain (ECS-CP) (see Table 6.1). Largely because of difficulty in clearly demonstrating true pharmacodynamic

multidimensional assessment: pain and palliative care

Fig. 6.4B. Edmonton Sypmtom Assessment System (graph).

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112 Table 6.1. Features of the Edmonton Classification System for Cancer Pain (ECS-CP) Mechanism of pain No Nc Ne Nx Incident pain Io Ii Ix Psychological distress Po Pp Px Addictive behavior Ao Aa Ax Cognitive function Co Ci Cu Cx

No pain syndrome Any nociceptive combination of visceral and/or bone or soft tissue pain Neuropathic pain syndrome with or without any combination of nociceptive pain Insufficient information to classify No incident pain Incident pain present Insufficient information to classify No psychological distress Psychological distress present Insufficient information to classify No psychological distress Psychological distress present Insufficient information to classify No impairment Partial impairment Total impairment Insufficient information to classify

tolerance in clinical practice, this revised version has omitted the opioid tolerance status as one of the factors to be assessed.78 The ECS-CP acknowledges the multidimensional nature of pain in advanced cancer and represents an attempt to establish a common language among researchers for use in study design as well as interpretation of research findings. As further developments in our knowledge of these and possibly other prognostic variables emerge, this system will need further modification and validation. These prognostic factors, along with other influences, are discussed in the following sections.

Pain mechanisms and specific characteristics Various pain mechanisms and characteristics have been studied in an attempt to better classify cancer pain and to determine the association between these factors and the challenges in achieving stable pain relief (see Table 6.1).76

Neuropathic pain Neuropathic pain is associated with neural dysfunction or pathological change in the peripheral or central nervous

system. It is characterized by dysesthetic or lancinating components and sometimes with the presence of hyperalgesia or allodynia. Studies have suggested that neuropathic pain is either not responsive to opioids79 or, more likely, less responsive to opioids.76,80–83 However, a survey study by Grond et al.84 suggested that in 593 cancer patients, the categorization of pain as neuropathic (n = 32), nociceptive (n = 380), or mixed (n = 181) failed to predict the outcome of pain treatment. Incident pain Incident pains are characterized by paroxysmal and transient pain exacerbations typically but not exclusively related to movement.85 Other precipitants of incident pain include coughing, swallowing, urination, and defecation. Attempts to increase opioid doses to treat these incidental pain episodes may result in toxicity, such as undue sedation between episodes, when the pain is not present. Also, clinical experience suggests that some of these incident pains often subside by themselves, through either cessation of movement or a decrease in other precipitating stimuli. This often occurs before an effective dose of opioid can be administered orally and absorbed, perhaps with the exception of oral transmucosal fentanyl.86,87 The presence of pain that is predominantly incidental in occurrence has been shown to have an independent positive association with time to achieve stable pain control.76 Breakthrough pain Incident pain is considered to be a type of “breakthrough” pain, a transitory flare of pain that occurs against a background of tolerable pain.88 A survey of breakthrough pain characteristics suggested that breakthrough pain occurred in approximately 50% of cancer patients (most of whom had metastatic disease), and although 61% of these patients could identify a precipitant, almost 50% reported that they were never able to predict its occurrence.89 The presence of breakthrough pain also was associated with a higher intensity and greater frequency of background pain. The impact of breakthrough pain was reflected by a greater degree of pain-related functional impairment, worse mood, and greater anxiety levels in patients with breakthrough pain. Furthermore, multivariate analysis suggested that breakthrough pain was independently associated with impaired physical functioning and psychological distress. International surveys also have identified breakthrough pain as an independent predictor of intense pain.90,91 However, these study reports also highlighted the large differences in the

multidimensional assessment: pain and palliative care Table 6.2. Pharmacotherapeutic issues requiring assessment in cancer pain Appropriate opioid dosing Compliance Choice of administrative route and opioid absorption Opioid toxicity and metabolite accumulation Opioid tolerance Responsiveness to individual opioids Opioid cross-tolerance Dose calculation for opioid switches Appropriate use of adjuvants

diagnoses of breakthrough pain around the world, perhaps indicating some ambiguity regarding definition.

Issues in the use of opioid and adjuvant analgesics The salient pharmacotherapeutic issues needing to be addressed in multidimensional assessment are summarized in Table 6.2. Myths and misconceptions Misconceptions regarding opioid side effects, addiction, and other problems are held by some physicians and may be reflected in failure to prescribe as well as inadequate dosing.92,93 Similar fears are held by some patients, who may underreport their pain, possibly because they fear the associated implication of disease progression or because they want to be a “good” patient and not complain.94–97 Clinical experience suggests that these factors may result in poor compliance with the opioid administration schedule or in the failure to appropriately use breakthrough doses of opioid.94 Together these patient and physician factors ultimately may contribute to poor pain control. Absorption and change of route A change in the route of opioid administration is necessary in approximately 80% of patients before death.98 Although generally the oral route is preferred, a change in route often must be made in response to concerns regarding absorption, as in the case of nausea, or because of dysphagia, delirium, or dyspnea. Occasionally, miscalculation of opioid doses occurs during a change in the route of administration, leading to incorrect dosing and, consequently, either inadequate pain control or opioid toxicity.99 Opioid toxicity In the past two decades, there has been increasing concern regarding the neurotoxic side effects of opioids.100–103

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These side effects include delirium, myoclonus, hyperalgesia, allodynia, and seizures. Many of the literature reports concerning opioid neurotoxicity relate to patients on highdose opioids.47,102,103 Often opioid neurotoxicity occurs in the presence of impaired renal function in association with either high102,104 or standard opioid doses.105 Elevation of the morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) has been noted in association with renal impairment105,106 and advancing age.107 M6G binds to opioid receptors and is recognized as a potent analgesic,108 whereas M3G has poor affinity for opioid receptors and is devoid of analgesic activity.109 Although laboratory animal studies have demonstrated neuroexcitatory signs in association with the administration of 3-glucuronide metabolites of morphine and hydromorphone,110,111 studies in humans, with the exception of those with renal impairment,105,112 have not demonstrated elevated metabolite levels in association with features of opioid toxicity.113 Agitation often occurs in association with opioid neurotoxicity.47,102,114 Recognition of this syndrome is essential to avoid further inappropriate escalation of opioid doses, which may aggravate the presentation. Fluid deficit states often accompany opioid toxicity, and accumulation of opioid metabolites in association with dehydration or hypovolemia has been postulated as the basis of some of this toxicity.115 Although the precise role of opioid metabolites in the generation of opioid toxicity remains to be established, assessment of symptoms and signs of both opioid toxicity and dehydration, often in addition to laboratory investigation of renal biochemistry, is an integral part of the multidimensional assessment of cancer pain. Opioid tolerance and responsiveness to individual opioids Tolerance is defined as the decrease in a drug effect, such as analgesia, or an adverse effect as a result of prior exposure to the drug. In clinical practice, tolerance is postulated to account for increasing opioid dose requirements over time to maintain the same level of analgesia.116 The occurrence of tolerance in humans is often controversial117 because disease progression could give rise to similar findings.118 In addition, potentially complex interplay may exist between various pharmacokinetic and pharmacodynamic factors.116 Furthermore, study design issues and assessment tools may fail to identify opioid tolerance. A recent prospective study found no association between the role of opioid dose escalation, as defined by the opioid escalation index, and the time required to reach stable pain control.78

114 Recent advances in molecular biology and receptor pharmacology have helped elucidate some of the underlying mechanisms of opioid tolerance in animal or laboratory models. A shared mechanism for the generation of opioid tolerance and hyperalgesia has been proposed, based on the central role of the N-methyl-d-aspartate (NMDA) receptor.119,120 Targeting the NMDA receptor with opioid or nonopioid NMDA antagonists raises the possibility of improving pain control. Methadone is a competitive antagonist of the NMDA receptor.121 This property has been postulated to explain its greater-than-expected potency in relation to morphine, when morphine has been used on a chronic basis before switching to methadone.122 Furthermore, some authors use it as a potential explanation for their clinical experience of obtaining superior results when using methadone to treat neuropathic pain.123 Although many case reports and retrospective surveys suggest a special role for methadone in the case of tolerance or neuropathic pain,124–131 there is no evidence from randomized trials to support this.132 Nevertheless, among the stronger opioids, methadone often is a useful second-line choice when other options are limited. Therefore, a multidimensional assessment can assist in the process of opioid selection and help determine the appropriateness of an opioid switch to methadone, especially in these more challenging situations. Opioid-induced hyperalgesia Hyperalgesia refers to a heightened sensibility to pain. Opioid-induced hyperalgesia (OIH) has received increased attention in the literature recently.120,133–136 OIH may 1) be part of the opioid-induced neurotoxicity as previously described, 2) occur in the absence of other opioid neurotoxicity symptoms, or 3) occur when the diagnosis of opioid hyperalgesia is missed and escalation of opioid doses results in neurotoxicity.135,136 Whereas opioid tolerance results in a right-sided shift in the dose–response curve, OIH results in a downward shift in this curve, reflecting a decrease in analgesia with an increase in opioid dose. Differentiating OIH from tolerance may be difficult in clinical practice.

n. o’leary, c. stone, and p.g. lawlor toxicity undergoes a favorable shift on the newly substituted opioid.137–139 This often occurs at an equianalgesic dose that is considerably less than that predicted by the standard reference tables, which were derived largely from singledose studies.116 As part of a comprehensive assessment, the physician needs to assess the appropriateness of dose calculations used in any recent or proposed opioid switches. To account for incomplete cross-tolerance, clinical experience suggests that a dose reduction of 25%–50% be made in the equianalgesic dose derived from current tables.140,141 In the case of methadone, the ratio has been shown to vary in relation to the dose of the previous opioid, and the use of different dose ratios for different dose ranges of the previous opioid would appear to offer the safest approach.129 Prior use and potential role of adjuvant analgesics The use of adjuvant analgesics is of particular importance in neuropathic pain, in which the response to opioid alone is likely to be less favorable than in the case of other pain syndromes. There is good literature evidence to support the efficacy of some adjuvants in the treatment of neuropathic pain, such as antidepressants, anticonvulsants, and corticosteroids, although some of this evidence is derived from studies of chronic nonmalignant pain.83,142,143 Similarly, pain due to metastatic bone disease can be treated effectively with bisphosphonates.144–147 A careful assessment will establish the levels of success, dosing, and side effects associated with previously tried adjuvants.

Assessing the prior use, role, and impact of other therapies Although pain in patients with advanced cancer most commonly is a result of the disease process, it must be remembered that pain has been attributed to antineoplastic treatment in 17%–35% of cases.89,90,148 This includes pain associated with chemotherapy, such as peripheral neuropathy,149–153 or postsurgical pains such as post–neck dissection or postmastectomy pain.154,155

Switching opioids: dose calculation

Palliative chemotherapy and radiation therapy

The phenomenon of incomplete cross-tolerance is often apparent when switching or rotating opioids.116 Opioid rotation is used in the event of opioid toxicity, which is usually accompanied by inadequate pain control. The rationale of opioid rotation is that the balance between analgesia and

The potential therapeutic role of other therapies in palliation, such as palliative chemotherapy and the newer targeted therapies, must always be borne in mind.156–159 Unfortunately, the HRQOL dimension often is inadequately evaluated in palliative chemotherapy trials, and the

multidimensional assessment: pain and palliative care burden–benefit ratio must always be considered in making clinical decisions regarding these therapies.24,25,160,161 The role of palliative radiation therapy should also be considered, for example, in patients with bony metastases or plexopathies.162–164 There is a time lag of many weeks for pain relief following completion of radiation treatment, although 50% of patients with bone metastases experience relief within 2 weeks.165 A radiation oncology referral should be considered to assess the feasibility of palliative radiation therapy, and within limits, retreatment of painful bony metastases can achieve success.166 Assessments by other members of the multidisciplinary palliative care team, such as physiotherapists and occupational therapists, also can help identify potential areas for their involvement in optimizing control of pain and other symptoms. Complementary therapies Despite very limited evidence from controlled trials to attest to their efficacy, the increasing use of alternative or complementary medicine in palliative care warrants recognition.167,168 A systematic review of the use of complementary or alternative therapies in cancer patients yielded an average prevalence of 31.4%.169 Patients tend not to disclose this information to conventional practitioners in many cases, and have a lower level of satisfaction with conventional treatment.170 There is some evidence to suggest that patients with the highest level of symptom distress respond best to acupuncture and massage.171 A study of alternative medicine use by women with early-stage breast cancer, who had prior conventional treatment, suggested that use of alternative medicine could be a marker for greater psychosocial distress and worse QOL.172 However, a more recent study found no association between complementary therapy use and psychopathology.168 Communication regarding use of alternative or complementary therapies warrants inclusion in the patient’s multidimensional assessment, not only from a drug safety perspective but also in relation to the patient’s coping and QOL.

Pain, physical function, and activity level Physical activity is recognized as a common precipitant of pain in cancer patients.85,89 The presence of pain in turn tends to curtail physical activity. Studies examining the circadian use of breakthrough doses of opioid analgesics have found that in the absence of delirium, most breakthrough doses are used in the daytime, possibly because this is the time of greatest physical activity.30,173

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The Brief Pain Inventory is an instrument designed to measure not only the intensity of pain, but also the degree to which it interferes with patient functioning, including physical activity.174 Using this instrument, Serlin et al.175 found a nonlinear correlation between pain severity and its interference with functioning, including physical activity. Although there was a difference between “mild” (0–4) and either “moderate” (5–6) or “severe” (7–10) pain, the nonlinear correlation was reflected by the lack of difference in the level of impairment in physical activity between moderate and severe pain levels. These findings were replicated in a study by Wang et al.176 The pain-related curtailment of physical activity may be amplified further by the fatigue and cachexia that accompany progression of the cancer disease process. In combination, pain and other symptom severity in addition to preexisting impairment contribute in varying degrees to the impairment in functional status in patients with progressive cancer disease.177 Assessment of physical function In the assessment of physical function in cancer patients, the Karnofsky Performance Scale and the Eastern Cooperative Oncology Group scale have been used widely.178,179 However, in patients with advanced cancer in the palliative care setting, assessments with these instruments tend to generate clustering of scores at the extreme end of impairment. Consequently, newer instruments such as the Edmonton Functional Assessment Tool (EFAT)180 and the Palliative Performance Scale (PPS)181 have been developed. The EFAT includes domains such as pain, mental alertness, sensory function, communication, and respiratory function, in addition to domains that more directly reflect physical function, such as balance, mobility, wheelchair mobility, activity, activities of daily living, and dependence in performance status. An initial validation study demonstrated good reliability and validity for the EFAT. The PPS is essentially a modification of the Karnofsky scale and assesses ambulation, activity, self-care, intake, and conscious level. Two validation studies of the PPS have been published; the relative simplicity of its administration in the palliative care population is appealing.182,183 An objective assessment of physical functioning constitutes an important part of the multidimensional assessment of pain in palliative care. Discrepancies between functional status performance and visual analogue scores for pain warrant further exploration, as these might reflect somatization of distress in some patients. Impairment in physical functioning and distressing physical symptoms such

116 as pain have the potential to adversely affect psychosocial function.20,89,184–186

Pain and the multiple facets of psychosocial distress Given the ever-increasing technological focus of the biomedical model of care, it is perhaps not surprising that medical staff often fail to recognize and address issues arising in the psychosocial and spiritual domains. Studies suggest that psychosocial187–189 and spiritual distress190 is underrecognized in oncology centers. In a multicenter study of advanced cancer patients, Kaasa et al.191 found that 70% screened positive for psychological distress, which was associated with the presence of pain and impaired functional performance status. Portenoy et al.192 found that 40%–80% of patients across a variety of cancers reported symptoms particularly suggestive of psychological distress, and greater symptom prevalence was associated with poorer Karnofsky performance status. Cella et al.193 examined associations between extent of disease, performance status, and psychological distress in patients with lung cancer. Poorer performance status and more advanced disease together were associated with greater levels of psychological distress. Other studies have suggested a positive correlation between negative affect and various pain and general symptom factors, including pain severity,194–197 pain duration,194 the presence of breakthrough pain,89 pain and sleep disturbance,198 and overall symptom severity.199,200 A study of existential distress in cancer patients suggested an association between pain intensity and other factors, including anxiety and fears concerning both the future in general and pain progression; fear of future pain was also associated with younger age and the duration of pain.201 Collectively, these data support the idea that in cancer patients, features such as the chronicity, severity, attributable psychosocial distress, impairment in physical function, and meaning of pain are particularly associated with impairment in QOL.202 Pain traditionally has been viewed from a dichotomous perspective as being either somatogenic or psychogenic. This view simply related pain intensity to the level of tissue damage, and in the absence of tissue damage, pain was deemed to be psychogenic in origin. Failure to explain the pain experience on the basis of tissue damage–related nociception alone led to the development of the gate theory of pain, which advanced the idea that nociceptive input can be modulated.203 Brain areas involved in cognition or the regulation of mood may have an impact on this modulatory process (Fig. 6.1). Thus, the patient’s subjective

n. o’leary, c. stone, and p.g. lawlor pain experience has multiple facets. The currently recommended assessment of a patient’s report of pain therefore involves an integrated perspective that recognizes not only physical pathology and reported pain intensity, but also the specific constitution of an individual patient’s psychosocial and spiritual milieu.204,205 In cancer patients, the interaction between the predominantly somatic symptom distress and distress in the psychosocial and spiritual domains is extremely complex, especially regarding the relative contributions of these two major sources of distress to each other and, in turn, to the negative impact on overall QOL. Negative affect may occur as an enduring trait with or without clinical depression, and as a transient or “state” form of mood disturbance. Negative affect is a frequent accompaniment of somatic distress such as pain.206,207 Various psychological models have been described to explain the relationship of negative affect and somatic symptoms.207 These include the psychosomatic model, which emphasizes the psychological origin of physical symptoms; a disability model proposing the reverse; and a symptom perception model, which emphasizes the importance of the cognitive appraisal of somatic symptoms in relation to level of negative affect. In the symptom perception model, features of negative affect, such as introspection and hypervigilance, are considered to contribute to an exaggerated cognitive appraisal of somatic sensations. The level of reporting of somatic symptoms in cancer patients has been shown to have a highly positive association with negative affect208 and experienced social stigma,209 and a moderately negative association with social desirability.210 Fear of appearing weak might therefore contribute to the underreporting of pain in an attempt to maintain social desirability. Conversely, in some situations, displaying pain behavior may be used to engender a response from others or achieve gains in some other ways, a process referred to as secondary gain. A recent study examined caregiver and patient ambivalence over emotional expression in patients with gastrointestinal cancer. In the case of caregivers or patients with a high level of ambivalence over emotional expression, patients engaged in more catastrophizing, had higher levels of pain, and reported lower levels of emotional well-being.211 In Zaza and Baine’s186 systematic review of cancer pain association with psychosocial factors, 14 of the 19 included studies found a significant association between pain and psychological distress, seven of the eight included studies found a significant association between higher levels of pain and lower levels of social support and social activity, and three of the four included studies found a

multidimensional assessment: pain and palliative care Table 6.3. Sources of distress in the patient’s existential, spiritual, and social milieu Existential issues Change in body image and function Dependency and loss of both autonomy and role Retrospective review of life losses Guilt: previous negligence, current care burden Fears: death and dying, future pain Anger: cancer diagnosis, treatment failures Concern for family or loved ones Spiritual issues Perception of illness as punishment Search for meaning Social issues Financial distress and insurance issues Occupational arrangements Conflict within the family Provision of care: fears, costs, conflict

significantly positive association between catastrophizing and more intense pain. A constellation of concerns and emotions relating to issues in the existential, spiritual, and social domains has the potential to contribute to psychological distress (see Table 6.3). These issues include the future, dying, finances, occupational matters, altered body image, the meaning of the illness, illness as a punishment, retrospective life analysis, impaired physical function and associated loss of independence, provision of health care, guilt concerning the burden of care, anger concerning diagnosis, concern regarding the family, and family conflict.184,201,212–217 The relevance of distress arising in the psychosocial and spiritual domains to the pain presentation is discussed further, mainly in relation to the concepts of coping and suffering. Other maladaptive coping patterns and psychopathology are discussed separately.

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as physicians, our failure to recognize suffering relates to our preoccupation with objective findings and focusing our attention on the body without recognizing the personalized impact or meaning of pain and other symptoms for the person. A recent survey found that 25% of cancer patients had mild and 25% had moderate to severe degrees of suffering.219 Although cancer pain is a recognized source of suffering, it is rarely the sole cause. It is important to appreciate that in addition to physical symptom distress, suffering may arise in relation to any of the existential, spiritual, or social issues, as outlined in Table 6.3. How does cancer pain result in suffering? An explanatory coping model derived from a stress coping model223,224 and adapted to the context of advanced cancer is proposed in Fig. 6.5. This model outlines the processes of effective coping versus suffering in relation to pain, other symptoms, and multiple other stressors, captured under the heading of global distress. This model is based on the core features of primary appraisal, which results in a perceived threat to self, and secondary appraisal, which refers to the perceived ability to cope with this threat in light of available resources or strategies. Studies have suggested that the meaning of Pain

Other symptoms

Global distress

PRIMARY APPRAISAL

The concepts of coping and suffering To a varying extent, the phenomenon of suffering may constitute part of both the “normal” burden and some of the psychopathological conditions arising toward the end of life, such as depression. Yet suffering differs from depression in that it represents a broader and more inclusive concept.206 Suffering is also distinct from pain,216,218 yet it is invariably closely related to it in the context of advanced disease.219 It has been described as “an impending destruction of the person” or “a threat to personal integrity” by Cassell,213,220 whereas Chapman and Gavrin206 define it as “perceived damage to the integrity of the self.” Suffering also has been referred to as “total pain”221 and “soul pain.”222 Despite these emotive terms and compelling definitions, suffering often is not recognized in advanced disease, “even when it stares physicians in the face.”220 Cassell proposes that

Meaning of pain and other symptoms Fear of disease progression Fear of the future / uncertainty

SECONDARY APPRAISAL Ability to cope / Available resources

Low self-efficacy Suffering

High self-efficacy Effective coping

Fig. 6.5. Pain, coping, and suffering in advanced cancer.

118 cancer pain for the patient – for example, the threat of disease progression, the fear of disability, or the potential loss of social role – plays a substantive role in the genesis of psychological distress.184,225–227 Conversely, ascribing a transcendent or spiritual meaning to the threat associated with pain or any other source of distress can facilitate coping and adaptation.213,228,229 The concept of self-efficacy also is included in the model represented in Fig. 6.5. Self-efficacy is defined as the perceived sense of personal control or the ability to enact coping strategies in the face of threat.230 The perception of low self-efficacy is associated with less effective coping,231 poorer pain control,232 and poorer QOL.230,233 The patient with low self-efficacy is therefore more likely to become overwhelmed by a sense of vulnerability and suffering. Such patients are more likely to hold dysfunctional painrelated attitudes, such as catastrophizing, and to underestimate the availability and value of their coping resources.234 What impact does suffering have on the cancer pain presentation? A complex relationship may exist involving suffering due to existential concerns, the pain experience, and the pain expression. However, negative affect and anxiety often exist as common denominators in association with both pain and existential distress.235,236 Chapman and Gavrin206 highlight the role of the stress response in the generation of suffering as a result of pain or any other stressors. They propose that neuroendocrine changes occurring in response to an acute stressor often confer an adaptive advantage in the short term and help maintain homeostasis. However, chronicity or persistence of the stressor may result in these neuroendocrine changes becoming maladaptive. An accompanying state of exhaustion, dysphoria, hypervigilance, and suffering may develop in the face of a chronic or persistent threat. Somatization, broadly defined as the somatic manifestation (such as pain) of psychological distress, could conceivably occur under these circumstances. This concept is discussed further in the section on other maladaptive coping patterns and psychopathology. Assessment of psychosocial and spiritual distress Recognition of suffering and other levels of psychosocial and spiritual distress in association with pain is essential to the conduct of good palliative care. This helps to identify the need for cognitive behavioral and other psychotherapeutic interventions to address these components of the pain experience. This in turn complements the judicious use of opioids to alleviate the sensory or nociceptive component of pain. Hence, inadequate assessment and failure to recognize these psychosocial and spiritual dimensions may

n. o’leary, c. stone, and p.g. lawlor result in inappropriate opioid use, compound patient and family distress, and staff frustration, especially when such a unidimensional management approach results in opioid toxicity.47 One of the difficulties in assessing the level of psychological distress in cancer patients is the degree of reluctance on the part of the patient to disclose information relating to distress in this domain.237 The failure to disclose this information may reflect failure on the part of the patient to appreciate the significance of such concerns, or possibly reflect a repressive coping style.238 Alternatively, poor interviewing skills on the part of the health professional also may inhibit the disclosure of such information.239 There is evidence to suggest that interview skills that facilitate disclosure of information can be taught and learned.240,241 The general interview approach involves an assessment of the patient’s attitudes, beliefs, concerns, and behaviors. Given the intimacy of much of this information, an empathic approach is essential to establish a sense of rapport and trust.220 Patients and family often are interviewed together, but also separately to facilitate disclosure of their respective concerns. Numerical ratings on an instrument such as the ESAS – for example, those for depression, anxiety, fatigue, and well-being – warrant clarification from the patient’s perspective. Maguire et al.239 have demonstrated that patient disclosure of information pertaining to psychological distress was enhanced by the use of open directive questions that focused on psychological aspects, in addition to educated guesses and empathic statements, aiming to clarify and summarize the information from the patient’s perspective. Meanwhile, the use of leading questions that focused on physical aspects and premature offering of advice and reassurance served to inhibit patient disclosure. Various scales and questionnaires exist to screen for psychosocial and spiritual distress.242–245 Although these scales allow the researcher to systematically collect data, their actual role in the clinical practice of palliative care is less clear. Screening for distress using a visual “distress thermometer” scale detected clinically significant distress in approximately 60% of patients attending a multidisciplinary lung cancer clinic.245 One study found that the screening question “Are you depressed?” had diagnostic potential similar to the use of a structured clinical interview for depression.246 Time constraints, a lack of confidence in effectiveness, and some uncertainty regarding their role are major reasons given by physicians for their failure to more comprehensively address psychological and spiritual issues in cancer patients.190 The multidisciplinary team approach

multidimensional assessment: pain and palliative care constitutes an important part of the management strategy in the palliative care model. In the assessment of psychosocial distress, utilization of skills and input from social workers, psychologists, pastoral advisors, physiotherapists, and occupational therapists is of vital importance and complements that from more traditional players such as nurses and physicians. Team conferencing allows the sharing of information across these disciplines and, in turn, facilitates a consistent team approach with the patient and family. Family conferences also allow further exploration of distressing psychosocial issues.

Recognizing other maladaptive coping patterns and psychopathology Psychiatric disorders occur in about 50% of patients with cancer.32,247 In the Psychosocial Collaborative Oncology Group study, the 47% prevalence rate of psychiatric disorder included adjustment disorder in 68%, major affective disorder in 13%, organic mental disorder in 8%, personality disorder in 7%, and anxiety disorders in 4%. These percentages depend on the stage of disease – for example, delirium has a very high prevalence in the last days of life. The significance of these disorders relates to their associated distress, their impact on the pain presentation, and the potential to apply effective treatments in many cases. Maladaptive coping patterns such as chemical coping and somatization of suffering potentially increase the risk of opioid toxicity.47 The common psychiatric disorders, along with maladaptive coping patterns, are summarized in Table 6.4. Somatization It is important to distinguish between somatization in a general sense, as previously defined, and the definitive psychiatric condition, referred to as “somatization disorder” in the somatoform disorders section of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition.248 The somatoform disorders section also includes “pain disorder,” which like somatization disorder and the other somatoform Table 6.4. Psychopathological factors in advanced cancer Anxiety Adjustment disorder Somatization Depression Chemical coping Cognitive dysfunction and delirium Personality disorder

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disorders, has a restrictive set of criteria. Although the somatoform disorders, including pain disorder, occur in cancer patients, these rather specific disorders likely are far less common than somatization in the broader sense. In a large international primary care study, somatization disorder in the restrictive sense was an uncommon finding generally, whereas the less restrictively defined somatization process was more common.249 Psychological distress with potential for somatization has been identified in the ECS-CP as a predictor of greater duration in achieving stable analgesia in the treatment of cancer pain.76 The general process of somatization or the somatic manifestation of psychological distress occurs commonly across a variety of medical conditions250 and cultures251 and exhibits a wide spectrum of severity,252,253 ranging from a transient association with stressful life events to a severe persistent disorder. Despite the recognition of its generally high frequency (albeit at varying levels of severity), its protean manifestations,254 and its frequent association with depression,255,256 there is a dearth of literature data regarding the phenomenology of somatization in relation to pain and other somatic symptoms specifically in the advanced cancer population. In cancer patients, studies suggest that somatization is associated with both depressive and anxiety disorder, in addition to a past history of atypical somatoform disorder.256,257 Given both the unique nature of the psychological distress and the concurrent presence of reported pain in the cancer population, caution must be exercised in attempting to extrapolate the findings of studies that examined characteristics of the somatization process in populations other than cancer patients. Lipowski253 suggests that there are three essential components to the somatization process. First, there is the experiential or perceptual component, which may refer to any distressing bodily sensation. Second, the cognitive component refers to the appraisal of the distressing perception and the attribution of meaning to it. Third, the behavioral manifestation includes communication of the patient’s appraisal of the distressing perception in verbal and nonverbal modes, which, in the estimate of medical staff, is likely to be inconsistent with the degree of physical disease or dysfunction. When the somatization process involves pain, the patient might report a visual analogue score of 9/10 for pain, yet the observed distress level or functional incapacity might appear to medical staff to be inconsistent with this score. Hence, the management approach in this situation would emphasize functional achievement, rather than the aggressive administration of opioids to treat pain that is largely opioid insensitive.

120 Table 6.5. Questions asked in the CAGE questionnaire

r Have you ever felt you ought to cut down on your drinking? r Have people annoyed you by criticizing your drinking? r Have you ever felt bad or guilty about your drinking? r Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye opener)?

Ethnocultural influences on the pain experience are complex. Although studies largely have demonstrated consistency across cultures in the reporting of certain aspects of cancer pain,175,258 studies of somatization levels in different cultures suggest that differences exist.251,259,260 Cultural differences exist regarding the degree of disclosure of the cancer diagnosis.261,262 A study from Taiwan suggested that nondisclosure of the cancer diagnosis was associated with higher levels of pain and pain interference and lower levels of satisfaction with the level of pain management provided by physicians.261 The authors suggest that lower levels of anxiety and distress in patients who are made aware of their diagnosis could account for the lower levels of pain and pain interference in this group. In the clinical practice of palliative care, patients with suspected somatization often present physicians with a dilemma. On one hand, the physician does not wish to precipitate opioid toxicity by inappropriately treating the somatization or opioid-insensitive pain component with opioids, but on the other hand, the physician does not wish to misdiagnose the nociceptive component of pain as somatization, inadvertently underprescribe opioids, and thereby expose the patient to unnecessary pain. Making an error in either direction therefore may result in patient distress and have a negative effect on QOL. To avoid making such an error in the resolution of this dilemma, a comprehensive and multidimensional assessment is essential. This assessment should place particular emphasis on the identification of psychosocial distress, particularly anxiety, suffering, and depression, and also the recognition of a mismatch between reported pain intensity and impairment levels of physical and functional activity. Chemical coping A history of chemical coping, which refers to a history of drug or alcohol abuse, has been associated with the consumption of higher opioid doses.76 The CAGE (cut down, annoy, guilt, eye opener) alcohol questionnaire is used frequently as a brief screening tool for the detection of alcohol abuse (Table 6.5).263 Bruera et al.264 reported a positive CAGE score of 2/4 or more in 27 of 100 cancer patients (27%) admitted to a Canadian palliative care unit. Patients

n. o’leary, c. stone, and p.g. lawlor with a positive CAGE score had a higher mean morphine equivalent daily dose of opioid on day 2 of admission and also during their entire admission period. Physicians’ detection rate of alcohol abuse without conducting a screening test such as the CAGE varies from 25% to 50%, depending on the physician’s specialty. In a retrospective study of 3380 cancer patients, we reported a positive CAGE score of 2 or more in 640 (18.9%).265 Given the frequent occurrence of positive screening for alcohol abuse in the cancer population, and the associated difficulties in achieving good pain control and dealing with the consequences of a maladaptive chemical coping style, the identification of patients with a history of alcohol abuse assumes great importance. Once identified, these patients can be monitored more carefully for their coping style and targeted for more intensive counseling. Furthermore, most psychiatric disorders are more common in patients with a history of alcohol abuse.266,267 The brevity and associated low burden of the CAGE make it a particularly useful instrument in the advanced cancer population. Anxiety, adjustment disorder, and depression In patients with advanced cancer, it often is difficult to make a distinction between the “normal” psychological burden that exists in relation to physical and psychosocial distress and certain aspects of psychopathology, such as anxiety, adjustment disorder, and depression. Consequently, varying degrees of anxiety, adjustment difficulty, and depressed mood may exist, which might not meet the psychiatric criteria for anxiety disorder, adjustment disorder, or major depression. Therefore, there may be a wide spectrum of psychological distress. Adjustment disorder is the most common psychiatric disorder occurring in cancer patients.247 Depressed mood or anxiety symptoms (not meeting the criteria for major depression or anxiety disorder) may occur in association with adjustment disorder.268 The relationship of pain to major depression, anxiety, and adjustment disorder largely was addressed in sections on suffering, coping, and somatization, using the broad term psychological distress. Maladaptive coping is associated with depression occurring later in the cancer trajectory.226 The specific association of cancer pain with anxiety,201,269 depression,194,270 or a combination of both271 is well recognized. There is some evidence to suggest that the presence of cancer pain is a risk factor for the development of depression.270 However, the temporal or causal relationship between pain and depression is complex, owing to the likelihood of a considerable degree of bidirectional impact. Given the potential for depression to respond to

multidimensional assessment: pain and palliative care psychostimulants or other antidepressants, it is important that the physician search for and treat depression in the patient with cancer pain. Personality disorder Coping with the remarkable combination of physical and psychosocial stressors that accompany advanced cancer is invariably an enormous task for those who are psychologically well. Patients with a personality disorder obviously are less well equipped to address this task. Recognition or suspicion of personality disorder, especially the borderline type, is therefore important in the palliative care management of these patients.272 The unique challenges in assessment and management often require specialist palliative and psychological or psychiatric consultation. Personality disorders are broadly categorized into clusters A, B, and C.273 Borderline personality disorder is included in cluster B, which as its name suggests, is borderline between the psychotic-like group in cluster A and the neurotic-like group in cluster C. Borderline personality is characterized by a number of features: desperate efforts to avoid abandonment, manipulative and impulsive behavior, recurrent suicidal threats and behavior, a pattern of unstable interpersonal relationships, unstable self-image, intense mood swings, and difficulty controlling anger. A detailed account of its features is beyond the scope of this chapter. In the palliative care setting, and in the face of terminal illness, borderline features may become more pronounced. From a pain assessment and management perspective, it is important to recognize the potential of these patients to split staff members, leading to disagreement over levels of pain control. There is a need for consistency in addressing this problem, possibly by limiting the prescribing of analgesics to one physician.274

Conclusion The traditional unidimensional model of pain views the expression of pain, whether in the form of pain behaviors or patient ratings on a visual analogue scale, as exclusively nociceptive or sensory in origin and therefore responsive to opioid pharmacotherapy. This approach therefore fails to appreciate the multiple other dimensions of the pain experience: the impact of other symptoms, the positive and negative aspects of therapeutic interventions, and input from the psychosocial milieu such as depression, somatization, and distress relating to financial, spiritual, and existential issues. This input is particularly important to recognize in the case of suffering or total pain, maladaptive coping, and other

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psychopathology. Hence, a multidimensional approach to pain assessment is essential to assess the interaction between pain and these factors. Problems associated with a unidimensional approach include the potential for excessive reliance on pharmacological agents, especially opioids, and underutilization of nonpharmacological treatments. These problems potentially increase the risk of opioid neurotoxicity and toxicities associated with other pharmacological agents. Recognition and relief of psychosocial and spiritual distress in the terminally ill patient is one of the fundamental tenets of the multidisciplinary palliative care model, whose ultimate objective is the relief of pain and global patient distress, thereby helping to provide an optimal QOL. Future research studies should enable us to better characterize the phenomena of coping, suffering, somatization, and depression in the palliative care setting. References 1. World Health Organization. Cancer pain relief and palliative care. WHO Expert Committee. World Health OrganizationTechnical Report Series, 804. Geneva: World Health Organization, 1990, pp 1–75. 2. Vainio A, Auvinen A. Prevalence of symptoms among patients with advanced cancer: an international collaborative study. Symptom Prevalence Group. J Pain Symptom Manage 12:3– 10, 1996. 3. Grond S, Zech D, Diefenbach C, Bischoff A. Prevalence and pattern of symptoms in patients with cancer pain: a prospective evaluation of 1635 cancer patients referred to a pain clinic. J Pain Symptom Manage 9:372–82, 1994. 4. Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer 8:175–9, 2000. 5. Potter J, Hami F, Bryan T, Quigley C. Symptoms in 400 patients referred to palliative care services: prevalence and patterns. Palliat Med 17:310–14, 2003. 6. Fainsinger R, Miller MJ, Bruera E, et al. Symptom control during the last week of life on a palliative care unit. J Palliat Care 7:5–11, 1991. 7. Zech DF, Grond S, Lynch J, et al. Validation of World Health Organization Guidelines for cancer pain relief: a 10-year prospective study. Pain 63:65–76, 1995. 8. Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management. Stepping up the quality of its evaluation. JAMA 274:1870–3, 1995. 9. Meuser T, Pietruck C, Radbruch L, et al. Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93:247–57, 2001. 10. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 330:592–6, 1994.

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7

Evaluating pain for children with cancer patricia a. m C grath a,b and eric j. crawford a a b The Hospital for Sick Children and The University of Toronto

Introduction

Factors that modify a child’s cancer pain

All children with cancer undoubtedly will experience some pain during the course of their treatment. Children may experience many different types of pain from invasive procedures, the cumulative effects of toxic therapies, progressive disease, or psychological factors.1–5 The pain often is complex, with multiple sources comprising nociceptive and neuropathic components. In addition, several situational factors usually contribute to children’s pain, distress, and disability. Thus, pain assessment is an integral component of diagnosis and pain management for all children with cancer. At diagnosis, we need a reliable evaluation of the sensory features of a child’s pain and an understanding of the relevant psychosocial factors that can exacerbate pain and distress. Subsequent assessments of pain intensity enable us to determine when treatments are effective and to identify the children for whom they are most effective. Pain assessment is a dynamic process that begins with a diagnostic examination and culminates with a clinical decision that a child’s pain has improved sufficiently. The assessment tools or specific measures we use differ depending on our clinical objectives – to capture pertinent diagnostic information, to routinely monitor pain intensity during treatment, to document pain features and symptoms related to different types of cancer and different treatment protocols, and to assess whether psychosocial factors are exacerbating pain and distress. In this chapter, we recommend a practical approach to achieve these varied clinical objectives. We describe a child-centered framework for understanding the relevant factors that can influence their cancer pain, the key components of a thorough pain assessment, and the psychometric properties of pain intensity scales for children. We conclude with suggestions on how to incorporate pain assessment more easily into routine clinical practice.

As with adults, children’s pain is plastic in that the eventual pain evoked by a noxious stimulus (whether an acute injury, invasive procedure, active disease, or toxic therapy) may be different depending on their expectations, their perceived control, or the significance they attach to the pain.6,7 A child’s perception of pain also is shaped by age, cognitive level, gender, and the type of pains already experienced and managed. “How much it hurts” depends in part on psychological factors such as the meaning or the relevance of the pain, expectations for obtaining eventual recovery and pain relief, and children’s coping abilities. Psychologically mediated modulation of pain occurs at the earliest levels of pain processing, as well as at the highest levels. Recent positron emission tomography (PET) and functional MRI (fMRI) studies have demonstrated that painful stimulation activates different cortical regions, depending on an individual’s expectations and attention.8 In addition, much compelling evidence about the powerful mediating role of psychological factors in children’s pain is derived from clinical studies of acute, recurrent, and chronic pain.9,10 Attention, perceived control, expectations, and the relevance of the pain influence the ultimate perception of any pain. Moreover, our beliefs guide our behaviors and shape our emotional responses to pain. Thus, although the causal relationship between an injury and a consequent pain seems direct and obvious, what children understand, what they do, and how they feel all affect their pain. To optimally control children’s pain, we should assess the psychological and situational factors that mediate their pain. The cognitive, behavioral, and emotional factors (listed in Fig. 7.1) represent a unique interaction between the child and the situation in which the pain is experienced. These situational factors may vary dynamically throughout the course of a child’s illness, depending on the specific

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evaluating pain for children with cancer

COGNITIVE • Inaccurate understanding (treatment, disease, prognosis) • Little active control (choices or pain-reducing strategies) • Uncertainty re. effective therapies (drug and non-drug) • Negative expectations (obtaining pain relief, prognosis) • Aversive relevance (disease and treatments)

BEHAVIORAL • Family or staff responses that increase children’s distress or lessen their control • Inconsistent use of pain control therapies • Little use of child initiated paincontrol methods • Withdrawal from normal activities (school, sports, social) • Altered parental responses to child re. typical parenting relationships

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EMOTIONAL • High anticipatory anxiety (procedures) • Frustration regarding disruption to life • Fear, anxiety, sadness, depression (re. prognosis and impact on life) • Anger • Fear of being sick • Underlying anxiety or depression (co-morbid condition)

Neuromodulatory Mechanisms

Nociceptive or Neuropathic Stimulation

Child Age, Cognitive level Gender Prior pain experience Temperament Coping abilities Family learning Culture

Pain and Distress

Fig. 7.1. Situational factors mediating children’s pain.

circumstances in which he or she experiences pain. For example, a child receiving treatment for cancer will have repeated injections, central port access, and lumbar punctures – all of which may cause some pain (depending on the analgesics, anesthetics, sedatives, and nondrug therapies that are used). Even though the tissue damage from these procedures may be the same each time, the particular set of situational factors for each treatment is unique for each child – depending on the child’s (and parents’) expectations, the child’s (and parents’ and staff’s) behaviors, and the child’s (and family’s) emotional state. Certain factors can intensify pain, exacerbate suffering, or adversely affect a child’s quality of life.7 Interdisciplinary cancer teams, who treat children from a comprehensive biopsychosocial perspective, typically evaluate the impact of these factors throughout the course of a child’s treatment. Building on their knowledge of the patient and family history, they are uniquely poised to evaluate the extent to which these situational factors might contribute to children’s pain, distress, and disability. Cognitive

factors encompass children’s beliefs about what is happening and will happen, their understanding of cancer and treatments, their expectations for pain control and recovery, and their knowledge of pain control strategies. In general, children’s pain can be lessened by providing accurate ageappropriate information about pain – for example, emphasizing the specific sensations that children will experience (such as the stinging quality of an injection, rather than the general hurting aspects) – by increasing their control and choices, by explaining the rationale for what can be done to reduce pain, and by teaching them some independent painreducing strategies. For children receiving palliative care, key cognitive factors also include the relevance or meaning of their illness, particularly its life-threatening potential; their beliefs about death; and their understanding of the significance of their lives.2 Behavioral factors refer to the specific behaviors of children, parents, and staff when children experience pain (e.g., displaying frustration, calmly providing encouragement for children to use pain control strategies, engaging them in

132 distracting conversation and activities) and also encompass parents’ and children’s wider behaviors in response to prolonged pain or progressive disease (e.g., maintaining as normal a life as possible, increasing physical restrictions and social withdrawal). When children’s behaviors are restricted, when they are physically restrained during medical procedures, or when their usual daily activities and social interactions are disrupted, their emotional distress and pain may intensify. Emotional factors include parents’ and children’s feelings in response to painful procedures, to the daily effects of the underlying cancer and therapies, and to the subsequent impact of the cancer diagnosis on the family. Children’s emotions affect their ability to understand what is happening, their ability to cope positively, their behaviors, and ultimately their pain. Children’s immediate emotional reactions to a painful procedure may vary from a relatively neutral acceptance to annoyance, anxiety, fear, frustration, anger, or sadness. In general, the more emotionally distressed children are, the stronger or more unpleasant their pain. Young children may not understand what they are feeling or may be unable to verbalize their fears and anxieties. Yet, almost all children are aware of differences in how their parents and families behave toward them when they have cancer. If they progress from receiving active curative treatments to receiving only palliative therapies, even very subtle behavioral cues can still evoke fear, uncertainty, apprehension, or depression, depending on children’s ages and what they understand about death and separation. Thus, an essential component of pain control should be evaluating whether these emotions are exacerbating children’s pain and distress and impairing the quality of their lives. Developmental considerations Children’s understanding and descriptions of pain naturally depend on their age, cognitive level, and previous pain experience.11–15 As they mature, children experience a wider range of injuries, illnesses, and trauma. Their frame of reference for evaluating a new pain sensation broadens as children experience pains of varying quality, location, and strength. In response to “What is your least and most pain?,” young children usually report similar childhood injuries for both extremes, such as “falling down or falling off a bike,” but add comments like “with a big scab, lots of blood” to differentiate them.6 In contrast, older children typically report mild injuries such as “scratch, paper cut” as their least pain experiences and major injuries such

p.a. m C grath and e.j. crawford as “got glass pieces in my foot and had 10 stitches” and “breaking my elbow really badly” as examples of their most painful ones. Children’s answers reveal the frame of reference against which they evaluate the strength of any new pain they experience. Young children, with more limited pain experience, may experience stronger pain from moderate injuries or invasive procedures in comparison with older children. Children learn how to describe the quality, location, and intensity of pain in the same manner that they learn specific words to describe the different sounds, tastes, smells, and colors they experience. Most children can communicate meaningful information about their pain. However, their ability to describe specific pain features – the quality (aching, burning, pounding, sharp), intensity (mild to severe), duration (a few seconds to years), location (diffuse location on surface of the skin to more precise localization internally), and unpleasantness (mild annoyance to an intolerable discomfort) – develops as they mature. Children’s pain language develops gradually from the diversity of pains they experience in their daily activities and is shaped by the words used within their families, peers, and community. Thus, children naturally differ in the specific words they use to describe their pains because of differences in their backgrounds, previous pain experiences, and learning. Despite such language differences, children learn very quickly to communicate to their parents when they are emotionally distressed and when they are physically hurt. Most toddlers (approximately 2 years of age) use simple words taught by their parents to describe being hurt and to show where they are hurting. Gradually, children learn to differentiate and describe three levels of pain intensity – basically “a little,” “some or medium,” and “a lot.” By the age of 5, most children can differentiate a wider range of pain intensities and use simple quantitative scales to rate their pain intensity. In our clinical experience, young children with cancer are more sophisticated in their pain vocabularies and more mature in their ability to use pain scales compared with similarly aged healthy children. Children with cancer typically have experienced more and more diverse pain experiences throughout the course of their treatment and have had more somatic-focused conversations with adults. Although health care providers often use children’s age as a proxy for their cognitive level, children with cancer are unique given their disease and its impact on them and their families. Pain assessment should be truly child centered. Health care providers should not communicate

evaluating pain for children with cancer only with parents, bypassing young children because they assume they cannot provide accurate information. Our program of decreasing procedural pain for children with cancer began with a series of interviews with children to enable us to understand the child’s perspective of the aversive and painful components of each procedure.6 Children as young as 2.5 years communicated their feelings, enabling us to confirm that control, accurate information, predictability, and simple relaxation techniques could significantly decrease the pain caused by lumbar punctures, bone marrow aspirations, injections, and portacatheter access. Even very young children with cancer were able to provide quantitative pain ratings for procedures, which allowed us to refine a treatment program of psychological and drug therapies to minimize their pain and distress.

Key components of pain assessment for children with cancer The effective management of cancer pain begins with an accurate assessment of pain to develop an appropriate treatment plan and continues with ongoing assessments of pain and any side effects, with appropriate adjustments to the treatment regimen as necessary.1,2 Because children with cancer may experience different types of pain from procedures, therapies, disease, and psychological factors, health care providers must carefully evaluate the varied causes and contributing factors to select the most effective treatments for each child’s pain. Clinical interview A comprehensive clinical interview is the first step in diagnosing the cause(s) of a child’s cancer pain and selecting the appropriate therapies to prevent pain. A detailed pain history should include (when possible) the child’s own descriptions of his/her pain characteristics. Location, intensity, quality, duration (or frequency, if recurring), spatial extent, temporal pattern, and accompanying physical symptoms are the key pain characteristics for a diagnostic assessment (Fig. 7.2). All these characteristics should be evaluated as part of the initial clinical examination, and pain intensity and any other characteristics that are clinically relevant for children should be monitored regularly. Children’s descriptions about the nature of their pain (when self-report is available) complete the information obtained through radiological and laboratory investigations. Building on their knowledge of the child’s and family’s previous experiences throughout the child’s illness, health care

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providers should evaluate the extent to which the situational factors (shown in Fig. 7.1) contribute to children’s pain, distress, and disability. Within evidence-based practices, children’s interviews should follow a similar structure to enable health care providers to better document the association between different types of cancer and pain experiences. We can obtain the same pain information for all children and objectively document the nature of their pain experiences in relation to different types of cancer and different treatments simply by asking children a few age-appropriate questions in a consistent manner. For example, the words children use to describe their pains are important for understanding the etiology of their pains and guiding treatment decisions. Children describe neuropathic cancer pains as “shooting, stinging, or burning.” In contrast, they describe nociceptive bone pain as an aching sensation and visceral pain as a more squeezing sensation. Open-ended questions such as “Show me exactly where it hurts,” “What does it feel like?,” and “How often does it hurt?” can be combined with some simple checklists (as in Fig. 7.2) to capture a child’s unique verbatim answers and to document data that can be compared more easily among different children. When possible, health care providers should also ask children directly about the broader aspects of their pain in addition to its sensory characteristics: “What helps your pain, what makes it worse, and how does the pain interfere with your daily activities?” or “How has cancer changed your life?” After obtaining as much information about the pain from children directly, health care providers should speak with parents to ensure that they obtain a full pain history – the pain features, temporal pattern, aggravating factors, accompanying symptoms, and medication use, along with its related side effects and effectiveness. Quantitative pain scales Quantitative pain scales complement the subjective information captured in clinical interviews. These scales provide a numerical value that denotes a child’s position along some pain continuum, such as pain strength on a 0–10 scale. The numbers derived from pain scales should provide an objective indicator of the child’s status (relative to all children) and enable health care providers to more accurately evaluate treatment efficacy. More than 60 pain measures have been developed and validated for use with infants, children, and adolescents.16–21 Although all scales provide a quantitative pain score, the scales assess different components of a child’s pain – overt behaviors, physical changes, or subjective experience.

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Pain History

• • • • •

Location(s)

Onset Investigations conducted Radiological and laboratory results Consult results Analgesic and adjuvant medications (type, dose, frequency, route)


single or
multiple sites
head
oral facial
neck or shoulder


arm or hand
back
abdomen


pelvis
genital, perineal, anal
leg or foot

Intensity*

Current ______ ; Usual ______ ; Range: Min ______ to Max ______

Temporal Pattern


Constant or
episodic If episodic, how frequent:
daily
1–2×/month


1×/week
other


2–3× /week


few minutes
several hours (4–6)


1/2 hour
all day (12)


couple hours (2–3)
other

Quality


aching
burning
cold
cutting
dull


hot
pounding
sharp
shooting
squeezing


stabbing
stinging
throbbing
tingling
other

Accompanying Symptoms

•

Episode length:

• •

Aggravating Factors

• • •

Fatigue Sleep distribution Nausea, loss of appetite Individual (stress, mood, emotions) Environmental (location: home, school, hospital; people: family, friends) Temporal (time of day, week, year)

* See Quantitative Pain Scales section for pain intensity measurement Fig. 7.2. Clinical interview: pain characteristics.

Behavioral scales were developed to provide some objective measure of pain for children who cannot communicate directly about what they are feeling because of their immaturity or impaired cognitive level. Parents or health care providers monitor children to document how many distress behaviors (e.g., crying, protective guarding) they exhibit during a particular time period (e.g., during a lumbar puncture or after surgery). The vast majority of behavioral scales were developed for acute procedural pain or

postoperative pain (for review, see references 18, 22, 23). More recently, behavioral scales were developed in consultation with parents and caregivers for special populations, such as children who are cognitively or physically impaired.24–26 Physiological pain measures such as heart rate, respiratory rate, blood pressure, palmar sweating, cortisol and cortisone levels, oxygen levels, vagal tone, and endorphin concentrations have been studied as potential pain measures.

evaluating pain for children with cancer However, they reflect a complex and generalized stress response rather than correlating with a particular pain level. As such, they may have more relevance as distress indices within a broader behavioral pain scale. Increasing attention has focused on examining pain-related activity in human brains using techniques such as PET and fMRI. These techniques provide indirect indices of neural activity, showing brain regions that are clearly involved in pain processing, such as the insular and cingulate cortices, as well as the sensory-processing areas. They are not pain measures per se, but methods to study pain processing in normal and pathological pain states (for review, see reference 27). Physiological and behavioral measures provide indirect estimates of pain because the presence or strength of pain is inferred solely from the type and magnitude of responses to a noxious stimulus. In contrast, psychological or selfreport measures are designed to directly capture the subjective experience of a child’s pain. Measures include a broad spectrum of projective techniques, interviews, questionnaires, qualitative descriptive scales, and quantitative rating scales.18,19 Interviews are the cornerstone of assessment for children with recurring or persistent pain, enabling clinicians to identify relevant child, family, and situational factors that contribute to children’s pain and distress.28–30 Yet, quantitative pain scales are needed to enable clinicians to monitor children’s pain intensity over time. Many pain scales have excellent psychometric properties, are convenient to administer, are easy for children to understand, are adaptable to many clinical situations, and help parents monitor their children’s pain at home. Health care providers should choose the best measure to satisfy their clinical objectives.

Validity and psychometric considerations Like any measurement instrument, a pain measure should provide valid and reliable information about a specific feature of the pain. Validity means that a pain intensity scale unequivocally measures how much pain a child experiences, so changes in children’s pain ratings reflect meaningful differences in the strength of their pain. Reliability means that a pain intensity scale provides consistent and trustworthy pain ratings regardless of the time of testing, the clinical setting, or who is administering the measure. Pain scales should be relatively free from bias in that children should use them accurately, irrespective of whether they are trying to please adults. Pain scales should be practical and versatile for assessing different types of pain (e.g., disease-related, procedural pain) with many different children (according to age, cognitive level, cultural

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background) and for use in diverse clinical and home settings.

What does a child’s pain score mean? The precise meaning of a child’s pain score depends on the general psychometric properties of the particular pain measure used. For example, when a child’s pain rating decreases from 8 to 4 on a 0–10 visual analogue scale (VAS), we can interpret that their pain decrease of 4 units represents a 50% reduction in their pain intensity (based on the properties of VAS for adults and children). However, on some scales, numbers are assigned to represent different pain intensities (e.g., no pain equals 0, mild pain equals 1, moderate pain equals 2, strong pain equals 3, and intense pain equals 4). In this instance, we cannot interpret that the real difference between a pain score of 4 and 2 represents a 50% reduction in a child’s pain intensity because we do not know whether the amount of pain described as “moderate” is half the amount of pain a child feels when he or she rates it as “intense.” Instead, we know only that larger numbers mean stronger pains, but not specifically how much stronger. Nevertheless, most pain scores are interpreted as if the differences between any two numbers (e.g., 1–2, 6–7, 9– 10) are equivalent and that the ratios between numbers are equivalent. The four types of measurement scales are 1) nominal – as the numbers designating players on a sports team, 2) ordinal – as the rank ordering of children according to height, 3) interval – as in the Fahrenheit temperature scale, and 4) ratio – as in a yardstick. They describe four different relationships between the properties of an event or perception (e.g., pain intensity score) and the number or metric system. Ratio scales have all the properties of the three other scales; they represent a set position or order between numbers and the magnitude of the difference between numbers, and the numbers reflect actual ratios of magnitude. Because each scale has a certain number of permissible mathematical calculations that are valid, it is important to know the specific scale type when measuring a child’s pain or evaluating analgesic efficacy. Conclusions about how much more intense one type of pain is compared with another or how much pain is reduced are valid only when ratio scales are used.31 The most common methods for validating pain intensity scales for children are to compare pain scores on the proposed new measure with an accepted scale (concurrent validity) or to verify that pain scores on the proposed scale decrease after analgesic administration (construct validity). Some studies have compared several rating scales to

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136 determine the correlations among different measures and to explore whether one measure may represent a more valid index of pain.32–37 The results of most studies show good correlations among tools with no unequivocal demonstration of one particular scale’s superiority. Thus, the choice of scale can be based on the type of pain, age of the child, and the specific clinical or research objectives.

Recommendations for clinical practice No single pain measure is appropriate for all children and for all circumstances. The choice of a pain measure depends on our clinical objectives, the type of pain to be assessed, and the child’s age and cognitive abilities. Many simple, easy-to-use pain scales provide meaningful values that reflect a child’s pain intensity and are ideal measures for evaluating treatment effectiveness throughout a child’s treatment. However, they are not adequate for evaluating

situational factors that affect their pain and distress. Health care providers who treat children with cancer need a flexible repertoire comprising a few pain intensity scales for assessing procedural, postoperative, treatment-related, and disease pain, as well as a broader assessment interview or questionnaire to assess psychosocial factors that affect pain and monitor children’s QOL. We have already referred readers to detailed reviews on the varied behavioral, physiological, and self-report pain measures for infants and children. In this section, we describe a few of these pain measures that should satisfy our key clinical objectives and could be incorporated easily into routine clinical practice. (Note: These are not the only measures that are appropriate for children with cancer.) Table 7.1 provides a snapshot of several measures that may be used throughout a child’s cancer management; checkmarks denote whether measures are best suited for use at diagnosis, during procedures, or for routine monitoring. We

Table 7.1. Pain measures

Diagnosis Interviews Structured clinical interview (described in text) Varni–Thompson Pediatric Pain Questionnaire (Varni et al., 1987)28 APPT (Savedra & Tesler, 1989)38 Children’s Comprehensive Pain Questionnaire (McGrath, 1990)6 Behavioral measures Premature Infant Pain Profile (Stevens et al., 1996)39 COMFORT Scale (Ambuel et al., 1992)40 Toddler/Preschool Postoperative Pain Tool (Tarbell et al., 1992)41 Procedure Behavior Checklist (LeBaron & Zeltzer, 1984)42 Pain Observation Scale for Young Children (Bolen-van der Loo et al., 1999)43 Douleur de l’enfant Gustave-Roussy (Gauvain-Piquard et al., 1987)44 Postoperative Pain Measure for Parents (Chambers et al., 1996)45 Self-report pain measures NRS (described in text) Word rating scale (described in text) Poker Chip Tool (Hester, 1979)46 Multiple Size Poker Chip Tool (St. Laurent-Gagnon et al., 1999)47 Word-Graphic Rating Scale (Tesler et al., 1991)48 VAS (Abu-Saad, 1984)49 Color Analogue Scale (McGrath et al., 1996)50 The Oucher (Beyer, 1984)51 FACES Pain Scale (Bieri et al., 1990)52 Faces Pain Rating Scale (Wong & Baker, 1988)53

Procedural

Disease, treatment related, postsurgical

√ √

√ √

√ √

√ √ √

√ √

√ √ √

√

√ √ √ √ √ √ √ √ √ √ √

√ √ √ √ √ √ √ √ √ √

√ √ √ √ √ √ √ √ √ √

evaluating pain for children with cancer

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Table 7.2. Properties of questionnaires Name

Pain type

Method

Pain characteristic

Scale type/pain score

Comments

Varni–Thompson Pediatric Pain Questionnaire (Varni et al., 1987)28

Chronic pain (arthritis)

Questionnaire with VAS, color-coded rating scales, and word descriptors

Sensory, affective, and evaluative dimensions

Children and adolescents ages 4–19 years

APPT (Savedra et al., 1993)29,38,48

Postoperative

Questionnaire with body outline, analogue scale, and adjective pain descriptor scale

Pain location, intensity, and quality

Children’s Comprehensive Pain Questionnaire (McGrath, 1990)6

Recurrent pain syndromes, chronic pain

Semi-structured interview with VAS, rating scales, and word descriptors

Sensory, affective, and evaluative dimensions; situational factors that intensify pain

Descriptive information on multiple aspects, with some pain features scored on interval and ratio scales Descriptive information on multiple aspects, with some pain features scored on interval and ratio scales Descriptive information on multiple aspects, with some pain features scored on interval and ratio scales

have selected measures that encompass a wide age range for children. Interviews and pain questionnaires Children’s interviews are ideally suited to the assessment of children’s understanding of their pain, as well as the factors that influence it. Previously, we described how to incorporate basic pain questions into a standardized format and include them as part of the initial diagnostic appointment for a child with cancer. We believe that the pain characteristics and situational factors outlined in Figs. 7.1 and 7.2 should be obtained at children’s initial consultation and monitored throughout their cancer treatment. We recommend a semi-structured interview format adapted to the clinic’s regular intake process. In addition, we list three interview questionnaires that may be used to elicit more information about the different dimensions of a child’s pain and contributing psychosocial factors. Table 7.2 summarizes relevant information about each pain questionnaire, listing the formal scale name, its acronym, the type of pain measured to validate the scale, the behaviors monitored or the pain characteristics measured, the type of pain score obtained, and the recommended age range of children. The Varni–Thompson Pediatric Pain Questionnaire includes VAS, color-coded rating scales, and verbal descriptors to provide information about a child’s pain history, socioenvironmental factors that may influence the pain, and

Children and adolescents ages 8–17 years

Children and adolescents ages 5–19 years

the sensory, affective, and evaluative dimensions of children’s chronic pain.28 The Adolescent Pediatric Pain Tool (APPT) includes a body outline, which children color to denote the location of their pain; a combined analogue and Likert scale, on which children mark a line to denote pain intensity; and a verbal descriptor scale of 56 words, from which children select those that best describe the qualitative, affective, evaluative, and temporal components of their pain.29 The Children’s Comprehensive Pain Questionnaire is a semi-structured interview used for assessing children with recurrent or chronic pain.6 This global interview was revised to more efficiently capture information about pain characteristics and about the typical situational factors that modify children’s pain and distress.7 Behavioral pain scales When different health care providers use behavioral scales to monitor children’s pain during clinic treatments or while children are hospitalized, they typically need a relatively simple and straightforward scale (a few distress behaviors to note, a brief time period for observation, and an easy calculation of a pain score). The resulting pain score should be sufficiently sensitive to enable staff to treat children’s pain and document reductions in children’s pain intensity. However, when the clinical objective is to more rigorously evaluate the efficacy of particular therapies, staff may need a more sophisticated scale with more subtle distress behaviors and

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138 Table 7.3. Properties of behavioral pain measures Name

Pain type

Method/time

Pain behaviors

Pain score

Comments

Premature Infant Pain Profile (Stevens et al., 1996)39

Procedural and postoperative

Time sampling (15–30 seconds)

Behaviors rated 0–4 in intensity

Premature infants

COMFORT Scale (Ambuel et al., 1992)40

Distress in Pediatric Intensive Care Unit patients

Time sampling (2 minutes)

Behaviors rated 0–5 in intensity, max. 40

Infants to adolescents

Toddler/Preschool Postoperative Pain Tool (Tarbell et al., 1992)41

Postoperative pain

Time sampling (5-minute period)

Each behavior scored as 0 (absent) or 1 (present), max. 7

Children 1–5 years

Procedure Behavior Checklist (LeBaron & Zeltzer, 1984)42

Procedural (lumbar puncture, bone marrow aspiration)

Phase sampling (three periods in procedure)

Behaviors rated 1–5 in intensity, subscores for each period, max. 40

Children and adolescents, 6–18 years

Pain Observation Scale for Young Children (Bolen-van der Loo et al., 1999)43

Postoperative

Time sampling (2-minute periods)

Behaviors scored when present, max. 9

Children 1–4

Douleur de l’enfant Gustave-Roussy (Gauvain-Piquard et al., 1987)44

Cancer pain

Time sampling (4-hour period)

Behaviors rated 0–4 in intensity

Children 2–6 years

Postoperative Pain Measure for Parents (Chambers et al., 1996)45

Postoperative

Period sampling (morning, afternoon, evening)

Seven: gestational age, behavioral state, heart rate, O2 saturation, brow bulge, eye squeeze, nasolabial furrow Eight: arterial blood pressure, heart rate, muscle tone, facial tension, alertness, calmness/agitation, respiratory behavior, physical movement Seven: verbal pain, scream, groan, facial expression (open mouth, squint, furrow forehead), restless motor behavior, rubbing or touching painful area Eight: muscle tension, screaming, crying, restraint used, pain verbalized, anxiety verbalized, verbal stalling, physical resistance Nine: facial, cry, breath, movement of torso, movement of arms/fingers, movement of legs/toes, state of arousal, child’s verbal response, touching the painful spot Seven: pain (e.g., somatic complaint) Six: depression (e.g., lack of expressiveness) Four: anxiety (e.g., moodiness) 29-item checklist, reduced to 15 based on correlations with child-rated pain

Behaviors scored when present, max. 15

Children 7–12 years

physiological parameters so as to potentially provide more sensitivity and enable staff to compare treatments among children. Seven behavioral scales are listed in Table 7.3. These scales have been developed to measure children’s acute pain during invasive procedures, postoperative pain, and disease-related cancer pain. The observation period during

which children’s distress behaviors are monitored vary from short periods at distinct phases of an invasive procedure, as with the Procedure Behavior Checklist developed to assess pain during lumbar punctures and bone marrow aspirations, to a more prolonged 4-hour observation period for children with cancer pain, which is used in the Douleur de l’enfant Gustave-Roussy pain scale.

evaluating pain for children with cancer As shown in the pain behaviors column in Table 7.3, some behaviors may reflect children’s fear, anxiety, and overall distress as well as their pain. In essence, these scales provide a reliable, valid, and quantitative index of children’s overt distress. They enable health care providers to evaluate children’s distress objectively, with minimal response bias. Some behavioral scales provide well-defined descriptions of different types of distress behavior as a foundation so that health care providers can more easily use uniform criteria (rather than only their interpretation of the children’s distress) when they observe children and rate their pain. Regardless of the specific behavioral scale used, children’s disease or health condition, concomitant drug therapy, and other distress sources in the health care environment may limit their responsivity and affect the validity of the pain score as a meaningful index of their pain. It is essential that health care providers use their content expertise to carefully consider the type of distress behaviors in a selected pain scale to ensure that they are likely to be unaffected by the context and thus are sensitive primarily to changes in a child’s pain experience. Self-report pain scales Quantitative rating scales provide health care providers with practical tools for regularly assessing pain intensity to ensure that children receive adequate pain control. A diverse array of analogue, facial, object, and verbal rating scales have been developed for toddlers, children, and adolescents.18,19 Children choose a level on the scale that best matches the strength of their own pain (i.e., a level on a number or thermometer scale, a number of objects, a mark on a VAS, a face from a series of faces varying in emotional expression, a particular word from lists describing different intensities). These scales are easy to administer, requiring only a few minutes for children to rate their pain intensity. The majority of pain intensity scales have been validated by comparing children’s pain scores on the new measure with an accepted scale (concurrent validity) or by demonstrating that children’s pain scores on the new scale decrease after analgesic administration (construct validity). The 0–10 numerical rating scale (NRS) is used extensively in clinical practice. Research in adults has shown that NRS are sensitive pain measures for adults (although they may not have ratio properties) and that NRS are less subject to error when used by patients, in comparison with analogue scales.54,55 Although no studies have yet been published comparing NRS and analogue scales for children, data accruing from studies in our center (in progress) show that these simple scales are valid for children too.

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Health care providers can easily ask children “How much does it hurt now? 0 means no pain and 10 means strongest possible pain.” In our practice, children with cancer have used these scales easily for all types of pain throughout their treatment. Eight pain intensity scales are listed in Table 7.4. Various object scales (poker chips,46 red balls,56 partially filled glasses57 ) have been developed for use with young children and for children who are visually impaired.47,56 The concrete physical features of object scales and the limited range (e.g., four chips in the poker chip task) should appeal to young children,46,47 whereas the wider range of nine differently sized balls on the tactile scale might be equally suited to young and older children56 who would probably use the entire range of intensity levels. Many analogue scales are variants of the traditional VAS – a black 100-mm line with end points designated as “no pain” and “strongest pain imaginable.” Children mark the line to show their pain level; the length of the line from the left end point to a child’s mark represents the strength of his/her pain. These scales were initially developed for adults and children to enable us to understand how changes in perception (e.g., brightness, loudness, pain) correspond to changes in physical stimuli (e.g., light intensity, sound level, noxious stimulation). Generally, children older than 5 years are able to use these scales in a valid and reliable manner to rate their pain intensity.6,49,65 The Color Analogue Scale is the pain intensity scale we generally use for children older than 5 years in our specialized clinic and research program. In addition to its psychometric properties and construct validity, the scale is convenient to administer, easy for children to understand, versatile for many clinical settings, and beneficial for parents to monitor children’s pain at home. Hospitals and providers would need to stock these scales and ensure that staff administered them consistently. When properly used, they are more sensitive measures of a child’s pain, and the resulting pain scores have the properties of a ratio scale. Although children provide essential information about their pain in their own words, verbal scales of pain intensity are not widely used. Two scales were evaluated and shown to yield pain scores on an interval scale.48,53 The revised Word-Graphic Rating Scale includes “no pain,” “little pain,” “medium pain,” “large pain,” and “worst possible pain.” In our clinic and research program, we have always used word scales, choosing the common adjectives that children report clinically to describe their pain. Our intensity scale includes “no pain,” “a little/mild,” “medium/moderate,” “a lot/strong,” and “a real lot/intense”

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140 Table 7.4. Properties of self-report pain measures

Pain characteristics

Name

Pain type

Method

Scale type/pain score

Comments

Poker Chip Tool (Hester, 1979)46

Acute pain (immunization)

Intensity

Multiple Size Poker Chip Tool (St. Laurent-Gagnon et al., 1999)47

Procedural (immunization)

Word-Graphic Rating Scale, a component of the AAPT (Tesler et al., 1991; Sinkin-Feldman et al., 1997)48,58 VAS (Abu-Saad, 1984; McGrath et al., 1985; McGrath, 1987)49,59,60

Postoperative pain; pain in hospitalized children

Object scale comprising four poker chips Object scale comprising four poker chips, varying in size (2–3.8 cm) Analogue and word scale

Quantitative, interval scale; pain scores 0–4 Quantitative, interval scale; pain scores 0–4

Children ages 4–7 years

Intensity

Interval scale, may have ratio properties

Children and adolescents ages 8–18

Analogue scale; vertical, with end points designated as “no pain” and “strongest pain” (100 and 150 cm) Analogue scale, varying in length, hue, and area

Intensity, affect, and emotions caused by pain

Quantitative, ratio scale properties; pain scores 0–100

Children ages 5 and older

Color Analogue Scale (McGrath, et al., 1996)50

Acute trauma, postoperative, recurrent, chronic pain

Intensity

Quantitative, ratio scale properties; pain scores 0–10.0

Postoperative pain

Number and pictorial scales; children’s pictures positioned at regular intervals along number scale

Intensity

Numbers: interval scale; pain scores 0–100. Pictures: ordinal or interval scale; pain scores 0–5

Psychometric properties demonstratedChildren ages 5 years and older; versatility demonstrated for clinical and home use Two scales should not be combined; numbers are for older children, whereas pictures are for younger children

The Oucher (Beyer, 1984; Beyer & Aradine, 1986)51,61 ; African American and Hispanic versions available (Beyer et al., 1992; Villarruel & Denyes, 1991)62,63 FACES Pain Scale (Bieri et al., 1990; Goodenough et al., 1997)33,52

Hypothetical levels; procedural

Discrete pictorial scale comprising seven adult faces varying in emotional expression

Intensity, affect

Interval scale, pain scores 0–7

Faces Pain Rating Scale (Wong & Baker, 1988; Wong & Whaley 1999)53,64

Procedural

Discrete pictorial scale consisting of six faces varying in emotional expression

Intensity

May be ordinal or interval scale; pain scores 0–6

Acute, recurrent, and chronic pain

Intensity

Children ages 4–6 years

Children and adolescents ages 3–15 years; Initially developed to measure pain intensity, subsequently studied as measure of pain affect Children and adolescents ages 3–18 years; instructions link each face to a different amount of hurt

evaluating pain for children with cancer for young/older children. The scales have face validity; we are now obtaining children’s numerical ratings for each of the levels. Several facial scales have been developed as measures of pain intensity, pain effect, or anxiety for children.18 Although these scales are similar in that they comprise six or seven faces varying in emotional expression, each has different properties, and the resulting numbers are not equivalent. Three scales are listed in Table 7.4. The FACES Pain Scale displays seven faces,52 whereas the Faces Pain Rating Scale displays six faces, but the instructions to children link a specific face with a particular amount of hurt.53,64 In contrast, the Oucher Scale depicts six photographs of a child expressing increasing levels of distress; the photographs are positioned at equal intervals along a 0–100 scale.62 The author carefully stipulates that the number and facial scales are distinct, with the numbers representing an interval scale and the faces representing only an ordinal scale. Subsequent versions of the scale have been developed for African American62 and Hispanic children.63 The Facial Affective Scale was designed to capture the affective dimension of pain. It is not a measure of pain intensity, but a broader measure of pain unpleasantness or negative affect. The scale includes nine faces representing different levels of distress and joy; children rated the unpleasantness depicted by each face to determine its number or affective value.6,59 We use this scale in our clinic to assess children’s pain affect. Quality of life Health-related quality of life refers to the perceived value of life as it has been affected by impairments, functional states, perceptions, and social opportunities influenced by disease, injury, treatment, or policy.66 Numerous instruments have been developed for adults with cancer.67,68 Most instruments capture information on physical functioning, social interactions, occupational ability, emotional wellbeing, and family relationships. Like pain, QOL should be assessed directly from the patient when possible.69 Health care providers typically monitor children’s QOL routinely throughout their cancer treatment, appraising the broader psychosocial factors that affect children’s well-being and ascertaining the adverse impact of the disease and its treatment for children. Although research on developing QOL instruments for children is still in an early stage, a few instruments have been validated.70–75 For example, the Pediatric Quality of Life Inventory – Cancer Module captures information on several health dimensions, such as pain, nausea, anxiety, and perceived physical appearance. It may be administered

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to children 5–7 years of age in an interview format, and is a self-administered questionnaire for children 8–18 years of age. QOL instruments can provide a more objective assessment of children’s well-being and thus provide a framework for evaluating treatment options at different stages in children’s cancer management.

Summary Optimal pain control for children with cancer requires an integrated treatment plan comprising both drug and nondrug therapies. The specific interventions should be selected after determining the pain’s physical etiology and severity, in accordance with any contributing situational, psychological, and familial factors. Cancer pain must be treated from a multidimensional perspective because multiple sensory, environmental, and emotional factors are responsible for the pain – no matter how seemingly clear cut an etiology. Treatment begins with a thorough assessment of these multiple factors, using structured clinical interviews and standardized pain measures. Pain assessment is a dynamic process that guides our clinical management, because the disease state and factors that influence children’s pain are not static. We should select specific therapies to target the responsible central and peripheral mechanisms and to mitigate the painexacerbating impact of situational factors, recognizing that the multiple causes and contributing factors will vary over time. Different combinations of drug and nondrug therapies will be required at different times. Drug therapies – analgesics, analgesic adjuvants, and anesthetics – are essential for pain control, but nondrug therapies – cognitive, physical, and behavioral – also are essential. Health care providers should assume as much responsibility for monitoring and relieving children’s pain as for medically managing their cancer. Pain assessment is a dynamic process that begins with a diagnostic examination and culminates with a clinical decision that a child’s pain has improved sufficiently. As described in this chapter, the assessment tools or specific measures we use differ depending on our clinical objectives – to capture pertinent diagnostic information, to routinely monitor pain intensity during treatment, to document pain features and symptoms related to different types of cancer and different treatment protocols, and to assess whether psychosocial factors are exacerbating pain and distress. Evaluating a child’s pain is not an onerous process. A few standardized questions about pain characteristics may be incorporated easily into diagnostic interviews. Children can easily complete many simple pain intensity scales to

142 ensure that they are receiving optimal pain control throughout their cancer treatment. With the ease of administration of these scales, health care providers should consistently monitor children’s pain, and they can choose from a variety of number, word, and analogue scales. However, when conducting clinical trials to compare therapies, analogue scales should be used because they provide potentially the most sensitive pain value and a pain score that can be interpreted on a ratio scale. Ordinary clinical care is a form of research or evidenceaccruing practice. Health care providers are determining causes of pain, selecting an intervention from various alternatives, evaluating the effectiveness of the intervention and any side effects, and adjusting treatments as required to manage the cancer and maintain a proper balance between effectiveness and side effects. All health care providers consistently evaluate the effectiveness of their treatments. Yet, the increasing emphasis on evidence-based practice requires that we simply keep more objective and more consistent records as part of ordinary clinical care. We now have the knowledge to evaluate children’s cancer pain with practical, time-effective, and cost-effective methods. The benefits will be a vastly improved understanding of children’s cancer pain and an enhanced ability to select the best treatment for each child. References 1. World Health Organization. Cancer pain relief and palliative care in children. Geneva: World Health Organization, 1998, pp ix, 76. 2. Brown SC, McGrath PA. Evaluation and control of cancer pain in the pediatric patient. In: De Leon-Casasola OA, ed. Cancer pain: pharmacological, interventional and palliative care approaches. Philadelphia: W. B. Saunders, 2006, pp 33– 52. 3. Collins JJ, Weisman SJ. Management of pain in childhood cancer. In: Schechter NL, Berde CB, Yaster M, eds. Pain in infants, children, and adolescents. Philadelphia: Lippincott Williams & Wilkins, 2003, pp 517–38. 4. Liossi C. Procedure-related cancer pain in children. Oxon, U.K.: Radcliffe Medical Press Ltd., 2002, p 210. 5. Miaskowski C, et al. Guidelines for the management of cancer pain in adults and children. APS clinical practice guidelines series, no. 3. Glenview, IL: American Pain Society, 2005, pp xiii, 166. 6. McGrath PA. Pain in children: nature, assessment, treatment. New York: Guilford Press, 1990, pp xii, 466. 7. McGrath PA, Hillier LM. Recurrent headache: triggers, causes, and contributing factors. In: McGrath PA, Hillier LM, eds. The child with headache: diagnosis and treatment. Seattle: IASP Press, 2001, pp 77–107. 8. Casey K, Bushnell M. Pain imaging. Seattle: IASP Press, 2000.

p.a. m C grath and e.j. crawford 9. Schechter NL, Berde CB, Yaster M. Pain in infants, children, and adolescents, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2003, pp xx, 892. 10. McGrath PA, Dade LA. Strategies to decrease pain and minimize disability. In: Price DD, Bushnell MC, eds. Psychological methods of pain control: basic science and clinical perspectives. Seattle: IASP Press, 2004, pp 73–96. 11. Gaffney A. Cognitive developmental aspects of pain in schoolage children. In: Schecter NL, Berde CB, Yaster M, eds. Pain in infants, children and adolecents, Baltimore: Williams & Wilkins, 1993, pp 75–85. 12. Gaffney A. How children describe pain: a study of words and analogies used by 5-14 year olds. In: Dubner R, Gebhart G, Bond M, eds. Pain research and clinical management, vol. 3. Elsevier: Amsterdam, 1988. 13. Harbeck C, Peterson L. Elephants dancing in my head: a developmental approach to children’s concepts of specific pains. Child Dev 63:138–49, 1992. 14. Ross DM, Ross SA. Childhood pain: the school-aged child’s viewpoint. Pain 20:179–91, 1984. 15. Peterson L, et al. Developmental contributions to the assessment of children’s pain: conceptual and methodological implications. In: Bush J, Harkins S, eds. Children in pain: clinical and research issues from a developmental perspective New York: Springer-Verlag, 1991, pp 33–58. 16. Royal College of Nursing Institute. Clinical guideline for the recognition and assessment of acute pain in children: recommendations. London: Royal College of Nursing Institute, 1999. 17. Champion GD, et al. Measurement of pain by self-report. In: Finley GA, McGrath PJ, eds. Measurement of pain in infants and children. Seattle: IASP Press, 1998, pp 123–60. 18. McGrath PA, Gillespie J. Pain assessment in children and adolescents. In: Turk DC, Melzack R, eds. The handbook of pain assessment. New York: Guilford Press, 2001, pp 97–118. 19. Stinson JN, et al. Systematic review of the psychometric properties, interpretability and feasibility of self-report pain intensity measures for use in clinical trials in children and adolescents. Pain 125:143–57, 2006. 20. Finley GA, McGrath PJ. Measurement of pain in infants and children. Progress in pain research and management, vol. 10. Seattle: IASP Press, 1998, pp ix, 210. 21. Stevens BJ, Franck LS. Assessment and management of pain in neonates. Paediatr Drugs 3:539–58, 2001. 22. McGrath PJ. Behavioral measures of pain. In: Finley GA, McGrath PJ, eds. Measurement of pain in infants and children. Seattle: IASP Press, 1998, pp 83–102. 23. von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of pain for children and adolescents aged 3 to 18 years. Pain 127:140–50, 2007. 24. Breau LM, et al. Psychometric properties of the noncommunicating children’s pain checklist – revised. Pain 99: 349–57, 2002. 25. Terstegen C, et al. Measuring pain in children with cognitive impairment: pain response to surgical procedures. Pain 103:187–98, 2003.

evaluating pain for children with cancer 26. Hunt A, et al. Development of the paediatric pain profile: role of video analysis and saliva cortisol in validating a tool to assess pain in children with severe neurological disability. J Pain Symptom Manage 33:276–89, 2007. 27. Bushnell MC. Brain imaging of pain: a thirty-year perspective. In: Merskey H, Loser JD, Dubner R, eds. The paths of pain 1975–2005. Seattle: IASP Press, 2005, pp 285–97. 28. Varni JW, Thompson KL, Hanson V. The Varni/Thompson Pediatric Pain Questionnaire. I. Chronic musculoskeletal pain in juvenile rheumatoid arthritis. Pain 28:27–38, 1987. 29. Savedra MC, et al. Assessment of postoperation pain in children and adolescents using the adolescent pediatric pain tool. Nurs Res 42:5–9, 1993. 30. McGrath PA, Hillier LM. Modifying the psychological factors that intensify children’s pain and prolong disability. In: Schechter NL, Berde CB, Yaster M, eds. Pain in infants, children, and adolescents, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2003, pp 85–104. 31. Price DD. Psychological mechanisms of pain and analgesia. Seattle: IASP Press, 1999, pp xiii, 248. 32. Abu-Saad HH, Pool H, Tulkens B. Further validity testing of the Abu-Saad Paediatric Pain Assessment Tool. J Adv Nurs 19:1063–71, 1994. 33. Goodenough B, et al. Pain in 4- to 6-year-old children receiving intramuscular injections: a comparison of the Faces Pain Scale with other self-report and behavioral measures. Clin J Pain 13:60–73, 1997. 34. Stein P. Indices of pain intensity: construct validity among preschoolers. Pediatr Nurs 21:119–23, 1995. 35. Van Cleve L, Johnson L, Pothier P. Pain responses of hospitalized infants and children to venipuncture and intravenous cannulation. J Pediatr Nurs 11:161–8, 1996. 36. Vessey JA, Carlson KL, McGill J. Use of distraction with children during an acute pain experience. Nurs Res 43:369–72, 1994. 37. Fogel-Keck J, et al. Reliability and validity of the Faces and Word Descriptor scales to measure procedural pain. J Pediatr Nurs 11:368–74, 1996. 38. Savedra MC, Tesler MD. Assessing children’s and adolescents’ pain. Pediatrician 16:24–9, 1989. 39. Stevens B, et al. Premature Infant Pain Profile: development and initial validation. Clin J Pain 12:13–22, 1996. 40. Ambuel B, et al. Assessing distress in pediatric intensive care environments: the COMFORT scale. J Pediatr Psychol 17:95– 109, 1992. 41. Tarbell SE, Cohen IT, Marsh JL. The Toddler-Preschooler Postoperative Pain Scale: an observational scale for measuring postoperative pain in children aged 1-5. Preliminary report. Pain 50:273–80, 1992. 42. LeBaron S, Zeltzer L. Assessment of acute pain and anxiety in children and adolescents by self-reports, observer reports, and a behavior checklist. J Consult Clin Psychol 52:729–38, 1984. 43. Boelen-van der Loo WJ, et al. Clinimetric evaluation of the pain observation scale for young children in children aged between 1 and 4 years after ear, nose, and throat surgery. J Dev Behav Pediatr 20:222–7, 1999.

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44. Gauvain-Piquard A, et al. Pain in children aged 2-6 years: a new observational rating scale elaborated in a pediatric oncology unit – preliminary report. Pain 31:177–88, 1987. 45. Chambers CT, et al. Development and preliminary validation of a postoperative pain measure for parents. Pain 68:307–13, 1996. 46. Hester NK. The preoperational child’s reaction to immunization. Nurs Res 28:250–5, 1979. 47. St-Laurent-Gagnon T, Bernard-Bonnin AC, Villeneuve E. Pain evaluation in preschool children and by their parents. Acta Paediatr 88:422–7, 1999. 48. Tesler MD, et al. The word-graphic rating scale as a measure of children’s and adolescents’ pain intensity. Res Nurs Health 14:361–71, 1991. 49. Abu-Saad H. Assessing children’s responses to pain. Pain 19:163–71, 1984. 50. McGrath PA, et al. A new analogue scale for assessing children’s pain: an initial validation study. Pain 64:435–43, 1996. 51. Beyer JE. The Oucher: a user’s manual and technical report. Evanston, IL: Judson, 1984. 52. Bieri D, et al. The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties. Pain 41:139–50, 1990. 53. Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs 14:9–17, 1988. 54. Jensen MP, Karoly P. Self-report scales and procedures for assessing pain in adults. In: Turk DC, Melzack R, eds. Handbook of pain assessment. New York: Guilford Press, 2001, pp 15–34. 55. Jensen MP. The validity and reliability of pain measures in adults with cancer. J Pain 4:2–21, 2003. 56. Westerling D. Postoperative recovery evaluated with a new, tactile scale (TaS) in children undergoing ophthalmic surgery. Pain 83:297–301, 1999. 57. Whaley L, Wong DL. Nursing care of infants and children. St. Louis: Mosby, 1987. 58. Sinkin-Feldman L, Tesler M, Savedra M. Word placement on the Word-Graphic Rating Scale by pediatric patients. Pediatr Nurs 23:31–4, 1997. 59. McGrath PA, deVeber LL, Hearn MT. Multidimensional pain assessment in children. In: Fields HL, Dubner R, Cervero F, eds. Advances in pain research and therapy. New York: Raven Press, 1985, pp 387–93. 60. McGrath PA. The multidimensional assessment and management of recurrent pain syndromes in children. Behav Res Ther 25:251–62, 1987. 61. Beyer JE, Aradine CR. Content validity of an instrument to measure young children’s perceptions of the intensity of their pain. J Pediatr Nurs 1:386–95, 1986. 62. Beyer JE, Denyes MJ, Villarruel AM. The creation, validation and continuing development of the Oucher: a measure of pain intensity in children. J Pediatr Nurs 7:335–46, 1992. 63. Villarruel AM, Denyes MJ. Pain assessment in children: theoretical and empirical validity. ADV Adv Nurs Sci 14:32–41, 1991.

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64. Wong DL, Whaley L. Whaley and Wong’s nursing care of infants and children, 6th ed. St. Louis: Mosby/Year Book, 1999. 65. Zeltzer L, Anderson CM, Schechter NL. Pediatric pain: current status and future directions. Curr Issues Pediatr 20:415–86, 1990. 66. Patrick DL, Erickson P. Assessing health-related quality of life for clinical decision making. In: Walker SR, Rosser RM, eds. Quality of life assessment: key issues for the 1990s. London: Kluwer, 1993, pp 11–64. 67. Anderson KO, Syrjala KL, Cleeland CS. How to assess cancer pain. In: Turk DC, Melzack R, eds. Handbook of pain assessment. New York: Guilford Press, 2001, pp 579–600. 68. Skeel RT. Measurement of outcomes in supportive care: quality of life. In: Berger AM, Portenoy RK, Weissman DE, eds. Principles and practice of palliative care and supportive oncology. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 1107–22. 69. Lesage P. Cancer pain, goals of a comprehensive assessment. In: Schmidt RF, Willis WD, eds. Encyclopedic reference of pain. New York: Springer-Verlag, 2006, pp 217–20.

p.a. m C grath and e.j. crawford 70. Calissendorff-Selder M, Ljungman G. Quality of life varies with pain during treatment in adolescents with cancer. Ups J Med Sci 111:109–16, 2006. 71. Calaminus G, Kiebert G. Studies on health-related quality of life in childhood cancer in the European setting: an overview. Int J Cancer Suppl 12:83–6, 1999. 72. Calaminus G, et al. Quality of life in children and adolescents with cancer. First results of an evaluation of 49 patients with the PEDQOL questionnaire. Klin Padiatr 212:211–15, 2000. 73. Varni JW, et al. The PedsQL in pediatric cancer: reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer 94:2090–106, 2002. 74. Bhat SR, et al. Profile of daily life in children with brain tumors: an assessment of health-related quality of life. J Clin Oncol 23:5493–500, 2005. 75. Jocham HR, et al. Quality of life in palliative care cancer patients: a literature review. J Clin Nurs 15:1188–95, 2006.

8

Pain syndromes in cancer survivors rosemary c. polomano, michael ashburn, and john t. farrar The University of Pennsylvania

Introduction Over the past decades, aggressive therapies for cancer have led to improved statistics for long-term survival. From 1996 to 2002, the 5-year survival rate for all cancers was 66%, which represents a significant increase from 51% in the short span between 1975 to 1977.1 Although 5-year survival rates do not represent the numbers of patients who are cured from cancer, it is an indicator that many cancer patients are living longer. The actual numbers of cancer survivors in the U.S. populace remain unknown, but reported estimates are in the range of 10 million to 12 million.2–5 It is anticipated that life expectancies after a cancer diagnosis will continue to increase with new developments in cancer treatments. With increasingly aggressive therapies, survivors may face more residual problems that will ultimately affect their ongoing level of functioning, quality of life (QOL), and need for health care. Limited research has been conducted on cancer survivors relative to the large numbers of studies of patients actively undergoing treatment for cancer. As such, it is impossible to obtain precise estimates of the number of survivors with chronic problems as a result of their disease or its treatment, such as pain. Issues related to cancer survivorship have recently been brought to the national forefront. The American Journal of Nursing and the National Cancer Institute sponsored a consensus conference in July 2005. The proceedings of this meeting were published in a special supplement to the American Journal of Nursing, and pain among cancer survivors received considerable attention, with agreement that this growing problem is both underrecognized and undertreated.6 The Institute of Medicine formed a committee, Cancer Survivorship: Improving Care and Quality of Life, to address health problems experienced by cancer survivors.7 In the committee’s report, pain after surviving cancer is identified as a significant health care

concern, and the panel called for more research to better understand the magnitude of survivor pain syndromes and how they can be managed effectively.8 The term cancer survivor is interpreted in different ways. According to the National Cancer Institute, “survivorship covers the physical, psychosocial, and economic issues of cancer, from diagnosis until the end of life. It includes issues related to the ability to get health care and followup treatment, late effects of treatment, second cancers, and quality of life.”9 This definition would encompass survivors of cancer with and without evidence of disease. For the purpose of this chapter, defined pain syndromes among cancer survivors not attributed to disease progression are examined. Complaints of pain by cancer survivors must be taken seriously and thoroughly evaluated to rule out evidence of disease progression, especially in individuals who present with pain shortly after their diagnosis and course of treatment, as well as those who are at risk for recurrence. Cancer treatment–related pain syndromes should be identified early and treated aggressively to minimize needless suffering and the likelihood for long-term pain. Delayed interventions that are based on the pretense of “watch and wait” with the expectation that pain will subside over time may in the long run contribute to the development of chronic pain. For survivors who present with pain, comprehensive pain assessments should be performed to identify the etiology of the pain. These include assessing the location, intensity, character and quality (sharp, shooting, burning, aching, throbbing, or cramping), duration, pattern (continuous or intermittent), temporal or situational factors that aggravate or alleviate the pain, impact of the pain on function, psychological well-being, and overall QOL. Some individuals may be reluctant to report their pain for fear that this may be a sign that their cancer has returned. All survivors of cancer need to know that it is important to 145

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report pain, and that causes of pain may be unrelated to their cancer.

Pain among cancer survivors Pain is a significant problem for some cancer survivors. Pain caused by the cancer treatments and, less commonly, from damage caused by the disease itself may lead to persistent pain long after diagnosis. In some cases, painful conditions may resolve over time, but irreversible damage to tissues and nerves can cause pain and neuropathies that persist and sometimes progress. Because health professionals may not recognize these delayed problems or may be unaware of those at greatest risk for cancer or treatment-induced pain, cancer-free survivors with pain may go undiagnosed and untreated. Research on the incidence, prevalence, severity, and nature of pain among cancer survivors and consequences on QOL is limited. Moreover, existing research is of varying quality. Small samples are often studied, and ways in which pain is reported and measured differ significantly across studies. Some studies assess pain using a pain intensity scale, whereas others capture pain experiences in the context of multidimensional instruments of functionality, QOL, and symptom distress, making it difficult to pool findings and draw conclusions from larger samples. The majority of investigations of cancer treatment–induced pain syndromes focus on outcomes during and shortly after therapy. Cross-sectional or longitudinal studies to some degree have provided rates of pain, the time course, and long-term problems associated with pain. Observational studies and case reports have been published, but these typically involve small sample cohorts that may not be representative of the larger numbers of people living with persistent pain. There is a paucity of data from surveillance studies to identify patients most at risk for chronic pain. Few randomized controlled trials test interventions that alleviate symptoms and improve QOL. To determine the most effective treatments for the types of pain experienced by cancer survivors, it is necessary to draw from the literature addressing chronic pain from progressive cancer- or non–cancer-related pain. A few estimates have been obtained from general populations surviving cancer. A recent study analyzing data from the 2002 National Health Interview Survey found that of 1904 cancer survivors, 34% reported pain, which was significantly higher than in controls without cancer.10 Similarly, 36% of 964 adults age 55 years and older surviving cancer more than 4 years reported having pain in the 2002 Health and Retirement Study. This rate was also significantly greater than that in persons without a history of

cancer.11 Yet in another study of 1893 long-term survivors of endometrial and prostate cancers and non-Hodgkin’s lymphoma, adults ⬍70 years of age reported less body pain compared with those never having cancer.12 A qualitative study of 58 cancer survivors showed that those with the greatest lingering resentment around their disease were more likely to have lasting pain.13 Several studies have documented pain among long-term survivors of site-specific cancers. Several factors were identified that predispose patients to chronic pain after breast cancer treatment, including age, type of operation, size of tumor, number of lymph nodes removed, involvement of lymph nodes, complications of surgery, intensity of the acute postoperative pain remembered by the patient, number of doses of analgesics, number of months from surgery, and adjuvant radiotherapy, chemotherapy, and endocrine treatment.14 Chronic symptoms in the breast and arm areas were found to be present in as many as 56% of breast cancer survivors (n = 92) from low breast surgery volume units versus 47% (n = 129) from higher volume units; as such, rates for chronic pain vary according to practice variations based on surgical experience.15 In up to 80% of patients who had a thoracotomy, persistent pain occurred long after the procedure.16–18 Of 68 patients 2 years out from treatment for rectal cancer who did not have a stoma and were disease-free, about 18% reported abdominal or pelvic pain, as did 14.5% of 58 patients with a stoma.19 The incidence and prevalence of other pain syndromes are discussed in subsequent sections.

Treatment-related chronic pain syndromes Most chronic pain syndromes experienced by disease-free survivors of cancer originate from injury to tissues and peripheral nerves from surgical trauma,16,20,21 chemotherapy neurotoxicity,22–24 and, less commonly, damage to soft tissue, viscera, and nerves from radiation.25–29 Pain issues also are sometimes associated with bone and may include osteoradionecrosis, a radiation injury characterized by demineralization and vascularization of the bone;30 osteoporosis from prolonged effects of hormonal manipulation;31 and osteonecrosis, as noted in long-term survivors of hematological malignancies.32 Treatment-induced neuropathic pain is a common chronic pain syndrome among cancer survivors. According to the International Association for the Study of Pain, neuropathic pain is defined as “pain initiated or caused by a primary lesion or dysfunction in the nervous system” that disrupts impulse transmission and modulation of sensory input.33 Neuropathies also may result from nerve injury and

pain syndromes in cancer survivors Table 8.1. Chronic pain syndromes associated with cancer treatments Postoperative pain syndromes Postmastectomy syndrome Post-thoracotomy syndrome Post–radical neck dissection pain Postamputation pain Postoperative frozen shoulder Fistula formation Lymphedema Postradiation pain syndromes Brachial or lumbosacral plexopathy Myelopathy Enteritis or proctitis Lymphedema Burning perineum syndrome Osteoradionecrosis Postchemotherapy pain syndromes Peripheral neuropathy with or without pain Other pain syndromes Osteoporosis Avascular necrosis of femoral or humeral head

are disturbances in the function or a pathological change in one nerve – referred to as a mononeuropathy – or in several nerves, being diffuse and bilateral – referred to as a polyneuropathy.33 Neuropathies are generally associated with sensory or motor dysfunction, but it is important to recognize that not all neuropathies are painful. Other persistent or intermittent pain conditions include 1) myofascial pain syndrome – characterized by trigger points in muscle or at the junction of muscle and fascia that refer pain to other areas of the body – associated with surgery for breast, thorax, and head and neck cancer; 2) fistula formation following pelvic surgery; and 3) less frequent but persistent, nerve damage from tumor infiltration of nerves.34–36 Table 8.1 outlines the pain syndromes commonly experienced by cancer survivors.

Surgically induced pain syndromes: general issues Residual pain after surgery is not unique to cancer survivors. In fact, several surgical procedures are known to produce long-lasting pain. Invasion of soft tissues, muscles, and vasculature and direct or indirect damage to nerves seem to be the likely explanations for chronic pain syndromes associated with surgical interventions. Postsurgical injury to nerves that evoke chronic neuralgia is a relatively rare complication compared with the nerve damage caused by direct surgical injury to nerves, perioperative ischemia, nerve compression, and delayed scar entrapment.20 Unrelieved, severe postoperative pain is a significant predictor of subsequent persistent pain.37 Overall, anywhere from

147 2%–10% of patients undergoing surgical procedures end up with some form of severe chronic pain attributed to surgical interventions.37 It has not been possible to obtain reliable estimates for the overall incidence of painful neuralgia following traumatic nerve injury; however, some believe it is in the range of 2.5%–5%.38 Although the exact mechanisms of traumatic painful neuralgia are unclear, it appears that the abnormal neuronal discharges and afferent barrage of impulses leading to hyperactivity in spinal neurons may be possible etiologies. Carr and Goudas39 describe the cascade of tissue injury events that cause the release of numerous proinflammatory and neurochemicals that may be responsible for an increased sensibility of the dorsal horn neurons to pain (central sensitization), which is thought to lead to chronic pain. More recently, there have been case reports of sympathetically maintained pain occurring after radical neck dissection and orbital and maxillary exenteration, in addition to the more common syndromes, such as post-thoracotomy and postmastectomy pain.40 Preventive measures aimed at reducing chronic painful syndromes have focused on less invasive surgical approaches,41 preservation of nerves, and aggressive postoperative pain control using multimodal analgesia. However, it is important for the patient and health care team to balance concern over tissue preservation with cancer treatment outcomes related to different surgical techniques. Multimodal pain therapy at the time of surgery not only appears to improve perioperative pain control, but also may lower the incidence and severity of long-term painful conditions.42 White43 presents a comprehensive review of various analgesic approaches for preventing postoperative pain, and contends that early effective pain control improves postoperative outcomes and may reduce the incidence of chronic postsurgical pain syndromes. Multimodal pain therapy includes the integrated use of several pain treatment options, including regional anesthesia, spinal anesthesia, local anesthetics applied topically or infused into the surgical wound, systemic opioids, and systemic administration of nonopioid analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and gabapentinoids. The usefulness and availability of each option depend on the type of surgical procedure, patient preferences, and the skills and experience of the health care team. Although there are no specific data, it is generally believed that a broader use of multimodal pain therapy could improve patient outcomes. One approach to improved postoperative pain control is the use of regional anesthetic procedures such as major nerve blocks, which are usually placed before the start of

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surgery. These procedures can now be placed using ultrasound guidance, which appears to improve the success of these blocks and may lower the incidence of complications.44 Regional anesthetics can be used as the major anesthetic for the procedure, but more often are placed for postoperative pain control in patients who will receive a general anesthetic. Benefits include profound pain relief immediately after surgery and a lower reliance on systemic opioids for postoperative pain control.45 In addition, patients may ambulate more quickly, thus possibly avoiding the complications associated with prolonged bedrest following surgery. Finally, these procedures may avoid central windup, associated with the experience of severe pain, and potentially lower the incidence of long-term pain. Spinal anesthesia techniques including the use of epidural analgesics also are useful. Based on the type of surgery, thoracic or lumbar epidural catheters are placed before the start of surgery. Dosing with opioids, often in combination with dilute local anesthetics, can then be administered, often using the patient-controlled analgesia technique. The quality of pain relief is excellent. Some studies suggest that patients who have received epidural analgesia have fewer postoperative complications compared with patients receiving systemic opioids; however, it is not clear whether the use of this type of analgesia actually improves outcomes such as length of hospitalization.46,47 In addition, epidural analgesic techniques require physician and nursing services that may not be available at all hospitals. The increased monitoring and care may extend well into the postoperative period. Often, patients undergoing surgery do not receive acetaminophen or NSAIDs during the postoperative period. However, acetaminophen and NSAIDs have been documented to be effective in providing postoperative pain relief, and lower the opioid requirements of patients following surgery.48,49 Acetaminophen may be used in combination with NSAIDs, which is more effective than either drug alone. Both drugs are associated with adverse side effects, and health care providers should be aware of the risks as well as benefits before using them. However, unless contraindicated, these drugs should be used as part of the postoperative analgesic plan. Local anesthetics administered topically or via infusion into the surgical wound have been documented to be effective in providing postoperative pain control.50,51 It has been documented that the administration of a dilute local anesthetic into the wound by way of a catheter placed at the time of surgery is associated with lower systemic opioid requirements and improved postoperative pain relief.52 The incidence and severity of adverse side effects are low.

The antiseizure drugs gabapentin and pregabalin may be effective in treating postoperative pain and preventing chronic pain following cancer surgery. Two recent systematic reviews of 16 and 22 randomized controlled trials of perioperative administration of gabapentinoids revealed that these drugs reduced postoperative pain, opioid consumption, and opioid-related adverse effects after surgery.53,54 Although the long-term effects of these agents have not been clearly documented, recent research suggests that the incidence and severity of chronic pain may be reduced in patients undergoing mastectomy who receive gabapentin around the time of surgery.42 Postmastectomy pain syndrome Chronic pain after mastectomy or lumpectomy with axillary node dissection is reported by about 20% of women.55 Postmastectomy pain syndrome (PMPS), one of the most commonly seen postoperative pain syndromes, is thought to result from surgical injury to the intercostobrachial nerve, the lateral cutaneous branch of the second intercostal nerve in the majority of patients.56 PMPS is a neuropathic pain syndrome characterized by burning, shooting, and electric shock–like sensations in the skin around the surgical sites. Its severity has not been well documented, but in a small sample of 36 women, 67% reported pain intensities that were moderate to severe at their worst (Fig. 8.1).57 Pain and discomfort may be experienced in the chest wall and the armpit of the affected arm (Fig. 8.2).58 When it occurs, PMPS may interfere with both occupational and domestic activities.58,59 The risk factors for PMPS are only partially understood, but recent data suggest that it may be more common among younger women (age 30–49) and women of increased weight.59,60 Although PMPS implies that this pain syndrome is associated with mastectomy, PMPS has been reported in women after lumpectomy without lymph node dissection and in those who had their intercostobrachial nerve spared.56 One institution’s experience shows 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Percent of Women

148

22

0 17

0 44

45 83 56 33 Worst Pain

Least Pain

Mild (0-3)

Moderate (4-6)

Average Pain Severe (7-10)

Fig. 8.1. Pain intensity profile for postmastectomy/postlumpectomy (N = 36). Data from Carpenter et al.57

pain syndromes in cancer survivors

Percent of Respondents

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Chest wall and breast Armpit Affected arm, shoulder, tissue wrist No pain Pain 1-3 Pain 4-6 Pain 7-9 Pain Severe-10

Fig. 8.2. Areas of pain and discomfort among breast cancer survivors (N = 147). Data from Bosompra et al.59

that fewer numbers of patients who had sentinel lymph node dissection were referred to a pain clinic for PMPS compared with those having had complete lymph node dissection.61 One report associated ethnicity with more PMPS-like pains, fatigue, and depression among breast cancer survivors, with African American and Latina women reporting increased rates of pain compared with Caucasians.62 However, the underlying cause of this reported difference in pain experience is not clear. There is considerable variability in the natural course of PMPS. For some women, pain and the associated symptoms may subside over several months, whereas for others, pain may worsen. Women who experience chronic pain following mastectomy report worse health-related QOL. Of 113 women who were 7–12 years beyond their mastectomy, health outcomes measured by the Short Form (SF)-36 Health Survey showed significantly poorer scores in the 59 women with persistent PMPS compared with the 54 whose pain had resolved over time.60 Table 8.2 summarizes several studies addressing postmastectomy syndrome. Nonsurgical preventive strategies have been used in an attempt to reduce the risk for PMPS in several small studies. Gabapentin administered at the time of surgery has been reported to lower postoperative pain as well as the incidence of chronic pain following mastectomy.42 In general, studies of gabapentin for perioperative pain control with various surgeries have documented reduced pain and opioid requirements, and there is evidence that it is well tolerated.63 Preoperative and postoperative amantidine has also been tried to decrease the occurrence of PMPS, but in a double-blinded randomized controlled, it was not successful.64 A variety of treatments may be used for PMPS. The best outcomes have been reported in patients who have early diagnosis and treatment. Outcomes may be enhanced with early referral to an interdisciplinary pain program,

149 when such therapy is available. As with most chronic pain conditions, interdisciplinary pain care including medical management, interventional therapy, active physical therapy, and cognitive–behavioral therapy appears to be associated with the best outcomes. Medications that may be useful include antiseizure medications (especially gabapentin and pregabalin), tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors (venlafaxine and duloxetine), and opioids. In addition, topical medications, including capsaicin and lidocaine, may be helpful.65 Interventional therapy with concomitant active physical therapy is thought to be beneficial, especially when initiated soon after the onset of the pain. However, there are no well-controlled trials to guide therapy. Early physical therapy is thought to help prevent functional limitations in the affected arm and a frozen shoulder (a condition characterized by pain, stiffness, and limited motion). It is also used to treat the lymphedema and secondary myofascial pain these patients may experience. Even when other modalities are useful, cognitive–behavioral techniques can provide additional benefit to help these patients learn to live with their chronic syndromes, and should be considered early in therapy. Post-thoracotomy syndrome Persistent pain after a thoracotomy has been reported in up to 50%–80% of patients several months after surgery,16,17 and 30% of survivors may still have pain at 4–5 years.66 This neuropathic pain syndrome is characterized by pain that occurs along the surgical scar; however, patients frequently experience additional myofascial pain or pain from a frozen shoulder. Injury to an intercostal nerve is often mentioned as an explanation for this pain syndrome, but the precise pathophysiology is not known.67 In most patients, the pain is generally mild to moderate and decreases in severity over time. Unfortunately, some patients go on to develop a severe, disabling pain.16,68 Methods to prevent long-term pain include selecting the most minimally invasive procedure, such as video-assisted thoracotomy, and aggressively treating postoperative pain with multimodal therapy.17 The incidence and reported severity of pain at 6 months post thoracotomy have been reduced significantly with thoracic epidural analgesia with morphine and bupivacaine (Marcaine; Hospira, Lake Forest, IL) before and during surgery.69 Therapy for post-thoracotomy pain is similar to that described for postmastectomy pain; integrated, interdisciplinary care may be more effective than any individual therapy used alone.67 Table 8.2 highlights studies for both postmastectomy and postthoracotomy syndromes.

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Table 8.2. Evidence from selected studies on postsurgical pain syndromes Population and study design Carpenter et al., 199857 Descriptive cross-sectional survey: 134 breast cancer survivors. Mean age, 56.5 years; mean time since surgery, 37.6 months. Assessment method: telephone interviews, subsequent evaluation at pain clinic. Macdonald et al., 200560 Descriptive cohort study. Baseline to follow-up survey: 113 breast cancer survivors who reported PMPS in 1996, assessed 7–12 years after surgery.

Bosompra et al., 200259 Descriptive, cross-sectional survey: 148 breast cancer survivors surveyed by telephone 2–4 years after treatment. Measures: demographic, disease, and treatment variables; pain intensity and frequency; arm and shoulder functioning Tasmuth et al., 199915 Descriptive cross-sectional survey: respondents were 221 women who underwent breast cancer surgery in 1996; 129 were treated at hospitals experienced in breast surgery, 92 at less-experienced hospitals Senturk, et al., 200269 Randomized prospective longitudinal study: 69 thoracotomy patients receiving one of three analgesic techniques (thoracic epidural analgesia with or without preoperative initiation, or patient-controlled intravenous analgesia); measured postoperative pain outcomes and 6-month follow-up by blind investigator

Findings

Comments

r 27% had PMPS, at low to moderate pain intensities r Location of pain: affected breast (86%); ipsilateral arm (69%); ipsilateral axilla (81%) r Compared with women with no pain and other pains, those with PMPS experienced poorer mental health

r 52% reported persistent PMPS; 48% reported resolved PMPS r Women with persistent PMPS had significantly poorer SF-36 scores than those with resolved PMPS, but their scores had improved over time r Younger age was associated with persistent unresolved pain

r 63% reported numbness; 35% reported swelling in axillary areas, affected arm, and chest wall and breast tissue area r 13%–15% reported moderate to severe pain in these areas r Most respondents did not report problems with shoulder or arm function

r Chronic pain and strange or phantom sensations were less common in women treated at more experienced hospitals r Subjects with chronic pain were more depressed r Chronic pain was associated with more intense postoperative pain

r 62% reported pain at 6 months r Mean pain scores, both postoperatively and at 6 months, were lowest with preoperatively initiated thoracic epidural analgesia

Post–neck dissection pain Surgically induced pain and loss of function have been documented in head and neck cancer survivors following neck dissection for head and neck carcinomas.70,71 This pain may result from damage to the local muscle, bone, or nerve tissues. Nerve damage is common to the spinal accessory nerve or cranial nerve XI, which innervates the trapezius muscle,71 and typically involves both somatic and neuropathic components. One study reported severe pain after surgery of both nociceptive (myofascial and soft tissue)

Findings support the need to test effective interventions for this pain syndrome; 22% of women who reported severe pain were uninterested in analgesic therapy; therefore, further research is needed to explore the acceptance of pharmacologic interventions. One of the few studies to measure characteristics of PMPS and its effect on QOL over time. Results indicate better functional and health outcomes when PMPS resolves.

Variables were analyzed to test a specific disablement model.

Study demonstrated implications of surgical technique on pain and other outcomes. Study limitations: compared one more-experienced to six less-experienced hospitals; more patients from former group had breast conservation surgery. Study found a significant relationship between severity of acute pain and development of chronic pain. Study limitations: Patients were not evaluated for origin, character, or quality of pain; baseline and follow-up used different assessment methods.

and neuropathic origin in 52% of subjects (21/40), with a mean duration of pain complaints of 26.9 weeks (range 1– 92 weeks).72 The reported incidence of neuropathic-like pain ranges from 23% to 28%.73,74 Loss of sensation and decreased range of motion also have been observed.36 Reduced shoulder abduction, shoulder pain, and neck pain are associated with poorer QOL outcomes.36 Overall, fewer complaints of long-term pain and impaired function are observed with modified as opposed to radial neck dissections.75

pain syndromes in cancer survivors No carefully designed clinical trials have been conducted to investigate options for the treatment of chronic pain following neck cancer surgery. Most of the drug therapies described earlier have been tried, with limited success. Low concentrations of botulinum toxin type A may reduce neck and shoulder pain.76 In a small randomized trial, progressive resistance exercise training demonstrated significant improvements in active shoulder external rotation, with less shoulder pain and disability.77 It is likely that an interdisciplinary pain management approach, as described earlier, would be a reasonable approach to patients with chronic pain following this type of surgery. Postamputation pain Both peripheral and central mechanisms are thought to play an important role in pain following amputation, giving rise to two distinctive features of postamputation pain. Pain that can be localized to the actual area of the amputation is often referred to as stump pain. Pain or other unpleasant feelings that are reported to be experienced in the part of the body that has been amputated is referred to as phantom pain.20,35 Stump pain may be associated with delayed healing of the incision or improperly fitted prosthetic limbs. Stump pain also may be exacerbated by the development of a neuroma, which may require surgical revision of the residual limb. On the other hand, phantom pain is much more complex, and its treatment is often challenging. Flor78 presents an extensive review of the mechanistic neurophysiological explanations for phantom pain based on changes that occur with central processing of pain and memory imprinting of the pain. Phantom sensations are experienced by almost all patients who undergo an amputation. These may include nonpainful perceptions of a specific position, shape, or movement of the phantom limb; feelings of warmth or cold; or paresthesias (itching, tingling, or electric sensations).79 The majority of patients feel some degree of pain in the phantom limb, which may be quite distressing. In a review of epidemiologic studies, 50%–80% of patients reported phantom limb pain.80 The pain may subside within the first year after amputation, but if it persists beyond 1 year, it is likely to be a lifelong problem. Several risk factors have been associated with chronic phantom pain, including poorly controlled preamputation pain, being female, severe postoperative pain, more proximal amputations, and poorly fitted prostheses.81 Although the role of prevention is unclear, as with other postoperative syndromes, aggressive perioperative pain control may be important. Postoperatively, phantom pain should be identified and treated early. As a neuropathic pain syndrome, phantom pain does not

151 respond as well to conventional analgesics, but neuropathic pain drugs such as anticonvulsants and tricyclic antidepressants may sometimes be effective. Small-scale clinical trials with oral dextromethorphan (Delsym; Celltech Americas, Rochester, NY), an N-methyl-d-aspartate receptor antagonist, have shown some benefit in mitigating phantom limb pain in cancer survivors.82,83 Post-therapy lymphedema Lymphedema is a condition in which excess fluid collects in tissue, typically in an extremity, causing swelling, pain, tightness of the skin, and limited mobility. Removal of lymph tissues and damage to lymphatic vessels from radiation therapy are thought to be the primary cause. Lymphedema is complicated by gravitational influences, with increased swelling, redness, and pain when the limb is in a dependent position. Neuropathy from nerve entrapment can add sensory and motor impairment, and myopathy from reduced use of the limb may lead to further disability. Impaired mobility, decreased sensation, and poor circulation in the edematous limb increase the susceptibility to injury, skin breakdown, infection, and poor wound healing. In addition to functional limitations and pain, it is important not to underestimate its impact on body image, the difficulty in finding properly fitting clothing, and the experience of constantly bearing the excessive weight of an edematous limb(s). Lymphedema occurs in survivors of breast cancer after axillary lymph node dissection and radiotherapy,84,85 gynecological cancers following removal of pelvic lymph nodes and vessels,86,87 and urological malignancies, with edema of the lower extremities and genitals.88 Most commonly, lymphedema is observed in patients after treatment for breast cancer. Tremendous variation exists for the reported incidence of lymphedema among breast cancer survivors, ranging from 20% to 56%. Erickson et al.89 provide an extensive summary of studies estimating the incidence, risk, and time course for developing lymphedema following breast cancer treatment. Persistent lymphedema caused by axillary node dissection generally occurs within 3 years after surgery.90 Fewer survivors experience lymphedema as a result of sentinel node biopsy techniques, which generally limit the need for more extensive node dissection.91 Recent evidence shows that participating in active upperbody exercise is not a risk factor for breast cancer–related lymphedema.92 Survivors of gynecological malignancies also experience lymphedema as a complication of their surgical procedures; however, less is known about its rate of occurrence and

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natural history. A population-based cross-sectional mail survey of 802 gynecological cancer survivors revealed that 10% had been diagnosed with lymphedema, whereas another 15% reported undiagnosed “symptomatic” lowerlimb swelling. A higher incidence of diagnosed lymphedema was found for survivors of vulvar cancer (36%).86 The combination of lymph node dissection and being overweight may increase the likelihood of lower-extremity swelling in uterine and ovarian cancer survivors. The treatment of lymphedema requires a multidisciplinary approach. To prevent further damage to the affected limb, survivors with lymphedema need to be carefully informed about the need to protect the affected extremities, keeping the skin intact, inspecting the limb(s) for pressurerelated skin breakdown or sores, maintaining mobility, and participating in effective treatment strategies to reduce morbidity. Conservative approaches offer some benefit in reducing limb volume and discomfort. A systematic review of various techniques for lymphedema shows that many nonpharmacological therapies have varying degrees of effectiveness. These include complex physical therapy (manual compression drainage followed by bandaging), compression bandaging or garments, manual lymphatic drainage done by the survivor or partner, support hosiery, pneumatic compression or intermittent pump therapy, limb exercises, limb elevation, and low-level laser therapy.93 To date, pharmacological agents provide no demonstrable benefit for persistent lymphedema. Diuretics provide only temporary relief by mobilizing fluid, as the fluid will reaccumulate. Conflicting results have been obtained with the benzopyrones, which stimulate proteolysis.94

Radiation-induced neuropathy and pain Radiation-induced chronic pain syndromes are less common in cancer survivors than persistent pain caused by other cancer treatment modalities. Recent improvements in radiation therapy appear to be lowering the incidence and severity of radiation therapy–induced chronic pain. Advancements in radiological diagnostic imaging and techniques, including CT scans, MRI, positron emission tomography scans, and electronic portal imaging, have enabled better localization of tumors to guide radiation therapy, thus sparing more normal tissues from the effects of radiation exposure.95 Likewise, treatment regimens combining radiation therapy with surgery and/or chemotherapy have minimized the need for aggressive radiotherapy for some site-specific cancers. Ongoing research is now needed to demonstrate the impact of current advances in radiotherapy in reducing long-term toxicities.96 Unfortunately, there are a limited

number of studies examining the prevalence and nature of chronic pain syndromes among patients treated in earlier decades, making it difficult to compare outcomes. Radiation nerve damage Radiation can damage any portion of the nervous system, including peripheral nerves (radiation neuritis), the spinal cord (radiation myelopathy), and the brain (radiation encephalopathy). Damage at any level is caused by the initiation of a neurovasculitic process, leading to dysfunction of the associated nerve structures. This generally results in weakness, loss of sensation, and often pain. Significant radiation neuronitis is most often seen when radiation is applied to an area that includes either the brachial or lumbar plexus, where major nerve structures are located. Radiation myelopathy is less common and may sometimes be associated with Brown-S´equard syndrome, in which one side of the spinal cord is damaged, causing weakness and altered proprioception on the same side and loss of pain and temperature sensation on the other. In general, radiation damage does not resolve over time, and more serious cases may result in loss of muscle function or even paralysis. The associated pain is characterized by a lancinating and burning sensation localized in the area of the distribution of the nerve structures affected, which may occur many months to years after treatment.34 Cancer survivors who were treated years ago using older techniques are more likely to experience chronic radiation damage compared with individuals receiving therapy using current techniques. Limited information is available about nerve damage with early use of radiotherapy. In one study by Johansson et al.,97 a group of 71 breast cancer patients received aggressive postoperative telecobalt therapy to the parasternal, axillary, and supraclavicular lymph node regions after total mastectomy and axillary dissection during the period from 1963 to 1965. Ninety-two percent of the survivors had paralysis of their affected arm progressing 5–34 years after treatment. Fibrosis around nerve trunks was noted in 86% and neuropathy in 64% of the cases. Pain was more evident with brachial plexus neuropathy. Another recent case report described a patient with severe cervical neuropathy three decades after being treated for Hodgkin’s lymphoma.98 Delayed radiation damage also has been reported in patients treated with cervical radiation over the past 15 years.99–101 Other pain syndromes have been reported to occur long after radiation treatment. In a clinical trial of 143 cervical and endometrial cancer survivors conducted to examine the effects of dietary modifications on radiation-induced

pain syndromes in cancer survivors diarrhea 3–4 years after treatment, low back pain was observed in 17 women and pains in the hips and thighs in 14 women.102 The etiology of these pains was unclear. Of 195 cancer survivors who received radiation therapy for various cancers, 12% suffered from peripheral neuropathy 5 years after treatment.25 Radiation enteritis Chronic radiation enteritis occurs in about 5%–20% of patients undergoing pelvic and abdominal radiation.103 At doses of 45 Gy, the incidence is 5%, and with 65 Gy, it may be as high as 50%.104 Although the incidence of chronic abdominal pain in this population has not been consistently measured, Miller et al.105 found that 24 of 263 patients (9%) with chronic radiation enteritis after being treated for rectal cancer reported pain. From a smaller sample of 65 survivors of gastrointestinal malignancies with chronic radiation enteritis, 38% had pain.106 Pain can be constant – from mucosal ulceration, submucosal fibrosis, or rectal excoriation from chronic diarrhea and fistula formation – or intermittent – related to cramping, bloating, diarrhea, and acute bowel obstruction or fistula.107,108 Chronic proctitis Pelvic radiation for prostate, cervical, and endometrial carcinomas leads to chronic proctitis in about 2%–5% of cancer survivors. However, there does not seem to be a relationship between acute proctitis and the development of chronic pain.109 Chronic proctitis is less frequently reported following therapy for ovarian cancer. The incidence of chronic proctitis is much higher, about 12%, following radiation therapy for rectal cancer.105 For the majority of patients with chronic radiation-induced intestinal damage, rectal damage also is evident.110 Patients may experience diarrhea, rectal pain, urgency, bleeding, tenesmus, mucous discharge, constipation, and stricture formation.111,112 Pain on defecation may occur, which can be treated conservatively with antidiarrheal medications, topical steroids, and sucralfate enemas;113 hyperbaric oxygen therapy,114 formalin application for hemorrhagic proctitis,115 endoscopic laser,116 and argon plasma coagulation117 also have been reported as successful treatments. Chronic headache Chronic headache syndromes have been reported as a delayed complication of radiation therapy for brain tumors. Several case reports have been published describing

153 stroke-like migraine attacks after radiation therapy (SMART syndrome).118–121 Although the exact etiology of these events remains unknown, some speculate that damage to the vascular endothelium, trigeminovascular system, ion channels, and mitochondria may be the cause.118 SMART syndrome may present up to 35 years following cranial radiation in pediatric populations, but also may occur years later in adults. Presentations differ from patient to patient, and may include confusion, aphasia, visual disturbances, numbness, throbbing pain, and hemiparesis, which may be brief (⬍15 minutes) or last days to weeks. Some patients have auras and show seizure activity on electroencephalography. MRI-confirmed cortical enhancements are not evident in all patients. Considerable variations in the occurrence and nature of these events and the possible influence of preexisting migraines unrelated to radiation complicate the study of this syndrome. Importantly, these events must be taken seriously and thoroughly evaluated, especially for the possibility of tumor recurrence.

Chemotherapy-induced neuropathy and pain Several classes of chemotherapeutic drugs cause neurotoxicity, including the plant alkaloids (vincristine [Oncovin; Eli Lilly and Company, Indianapolis, IN] and vinblastine[Velban; Eli Lilly and Company]), taxanes (paclitaxel [Taxol; Mead Johnson, Princeton, NJ] and docetaxel [Taxotere; Sanofi Aventis, Bridgewater, NJ]), platinum-based compounds (cisplatin [Platinol; Bristol-Myers Squibb, Princeton, NJ], carboplatin [Paraplatin; Bristol-Myers Squibb], and oxaliplatin [Eloxatin; Sanofi Aventis]), and antimitotics (methotrexate [Trexall; Barr Laboratories, Pomona, NY], cytosine arabinoside [Cytosar-U; Upjohn, Kalamazoo, MI], and fluorouracil [Adrucil; Bigmar, Johnstown, OH]). The most common type of chemotherapyinduced peripheral neuropathy (CIPN) involves neurotoxic damage to peripheral nerves. Biological mechanisms for toxicity from drugs such as paclitaxel, vincristine, and cisplatin are being explored in animal models.122–125 In addition to producing pain, CIPN is a frequent reason for altering the chemotherapy regimen, which may interfere with optimal dosing, delay sequencing of therapy, and sometimes result in the discontinuation of treatment. Less frequent are neurotoxic effects from chemotherapy drugs on the central nervous system. For example, cytosine arabinoside may cause irreversible cerebellar ataxia and impaired motor coordination.126 Estimates for the incidence of CIPN vary considerably from one regimen to another. Consequently, it is difficult to determine the percentage of patients who will develop

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neurotoxicity. The development of both short- and longterm toxicity is highly dependent on several factors, such as age, single-dose intensity, cumulative dose, combinations of neurotoxic agents, coexisting neuropathies (e.g., diabetic neuropathy), genetic susceptibility, alcohol abuse, impaired drug metabolism, and excretion of active metabolites.24,127,128 Older age was not associated with increased risk for CIPN from paclitaxel- and cisplatin-based regimens for lung or breast cancer in one study of 35 cancer patients.130 Hundreds of studies documented the onset and severity of CIPN during treatment with various agents and combination regimens, yet the long-lasting effects of neurotoxicity with chemotherapy have not been adequately studied. Few well-designed longitudinal or cross-sectional studies capture the number of cancer survivors who continue to experience pain and functional limitations years after therapy or the time course, severity, and patterns of neurologic impairment. Several clinical reviews do, however, summarize the relevant literature on this widespread problem (Table 8.3).6,22,24,127,129,131 Considerable variation exists among chemotherapy agents with regard to the onset, severity, characteristics, and duration of symptoms associated with CIPN. For example, paclitaxel can induce sensory impairment and pain, whereas vincristine often causes a sensorimotor neuropathy that also includes motor dysfunction, such as foot drop.24,128 Peripheral neuropathies generally affect the distal parts of extremities symmetrically and are characterized by a “stocking-and-glove” distribution of the feet and hands with paresthesia and dysesthesia, which may be quite unpleasant. Vincristine and platinum-containing compounds also can induce autonomic symptoms such as orthostatic hypotension, constipation, paralytic ileus, and bladder dysfunction.131 The time course for the onset of peripheral neurotoxicity has been well described for some agents. For example, patients receiving cisplatin develop signs of neuropathy about 1 month after the first course of therapy.132 Oxaliplatin can typically produce symptoms within 30–60 minutes after the infusion, with resolution after a few days.129 In many patients, the length of time the symptoms remain gets longer with each dose, and in some, it may become constant. Delayed neurotoxicity has not been well studied; however, some reports document that some long-term survivors experience persistent residual effects of chemotherapy neurotoxicity after treatment for testicular cancer,133–135 non-Hodgkin’s lymphoma,136 small cell lung cancer,137 and advanced ovarian cancer.138 Treatment for painful peripheral neuropathy includes anticonvulsants, tricyclic and serotonin–norepinephrine

reuptake inhibitor antidepressants, and opioids.139 Prevention strategies have been studied but have not proven very effective. Novel pharmacological agents such as neuroprotective compounds (amifostine or WR-2721), glutamine and l-carnitine (amino acids), glutathione (an antioxidant and product of glutamine metabolism), and neurotrophic factors (e.g., nerve growth factor) are of limited benefit in preventing or minimizing CIPN.139 Glutamine, which acts as a substrate for dividing cells, may help prevent or reduce the severity of peripheral neuropathy related to paclitaxel-induced neurotoxicity.140 Vitamin E has shown some promising results in small trials for prophylaxis of CIPN with cisplatin and paclitaxel.141 Nonpharmacological and alternative therapies have been tried as strategies for treating CIPN. In a clinical case report, two patients benefited from an implanted spinal cord stimulator that alleviated pain, increased leg flexibility, and led to improvements in sensory threshold detection.142 Exercise and occupational therapy may be helpful in restoring function of extremities, but studies of their effectiveness have been done mostly in the early treatment phase. Other nutritional supplements, such as evening primrose oil, ␣-lipoic acid, and capsaicin, may be effective with advanced peripheral neuropathy from diabetes but have not been adequately studied in cancer survivors.143

Other pain syndromes Osteoporosis is a significant problem among cancer survivors. Loss of bone density may lead to pain and bone fractures with delayed healing secondary to the cellular damage from radiation or chemotherapy. Several populations are known to be at risk from cancer treatment, including survivors of hemopoietic stem cell transplantations,144,145 breast cancer,146,147 and lymphoma and prostate cancers.148,149 Treatment with steroids and hormonal therapy are most likely factors in the development of osteoporosis; however, chemotherapy for breast cancer poses considerable risks.150 Moreover, chemotherapy-induced ovarian failure, often attributed to alkylating agents, is also a contributing factor regardless of cancer type.151 In a major study of health profiles for a heterogeneous sample of 5836 cancer survivors varying by diagnosis, two thirds of whom were women, approximately 33% of the women and 16% of the men were found to have arthritis/osteoporosis.152 Other skeletal complications included avascular necrosis of the femoral head, which may be very debilitating and often painful, and is a known consequence of steroid therapy.153 Data show that oral bisphosphonates may be an

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Table 8.3. Clinical reviews for chemotherapy-induced peripheral neuropathy Highlights Visovsky 2003127 r Overall estimates for the prevalence and incidence of CIPN remain relatively unknown r Gives mechanisms for peripheral neuropathy (PN) associated with specific agents r Describes motor and sensory signs of PN and autonomic dysfunction r Identifies lack of systematic, longitudinal studies correlating measures of PN with clinical manifestations r Interventions discussed: pharmacologic, educational, exercise therapy, and occupational therapy Quasthoff & Hartung, 2002131 r Provides agent- and compound-specific information on vincristine, platinum compounds, paclitaxel and suramin, and combinations of different drugs r Discusses therapy for CIPN and prophylactic measures r A table summarizes each compound with clinical symptoms, diagnostic findings, and morphologic changes elucidating the mechanisms of neurotoxicity r A table outlines commonly used grading scales used to quantify and characterize the severity of PN Armstrong et al., 2005162 r Describes pathophysiology, assessment, prevention, and treatment r Details chemotherapeutic agents that induce PN r Tables contrast differential diagnoses of PN, distinguish types of neuropathies, outline screening assessment criteria, and give usual starting doses and effective doses for pharmacologic agents used to treat PN pain Polomano and Bennett, 200122 r Overview of vincristine- and paclitaxel-induced PN r Dosing models and methods of assessing neuropathic pain in rodent models are discussed for both drugs r Discusses importance of accurately quantifying the severity of pain and degree of sensory impairment from neurotoxic chemotherapeutic agents Verstappen et al., 2003129 r Discusses neurotoxicity of individual agents in several chemotherapeutic drug classifications in terms of the central and peripheral nervous systems, and neuroprotection r Tables present neurotoxic complications and specific nerve conduction abnormalities associated with several chemotherapeutic agents Dropcho, 200424 r Discusses neurotoxicity of individual agents in several chemotherapeutic drug classifications in terms of central and peripheral nervous systems r Describes extrapyramidal dysfunction and myelopathy

effective bone loss prevention strategy for women after chemotherapy for breast cancer.154 The National Comprehensive Cancer Network (NCCN) offers guidelines for prevention, screening, and treatment approaches.155 Reduced cell-mediated immunity associated with some lymphomas, leukemias, and HIV infection place patients at

Usefulness of information

r Extensive literature review, with clinical implications for nursing practice

r Discusses methodological limitations, including patient variables, treatment variables, and lack of universal and specific measurement and clinical assessment criteria r Highlights the dearth of published data on nonpharmacologic approaches to manage PN and the need for more research

r The authors translate findings from animal experiments into clinically relevant information

r Unique to this article is information on suramin, an investigational agent, and criteria for determining changes in treatment based on patient outcomes r Tables provide useful and clinically meaningful information

r Nursing-focused content; offers clinically relevant information in assessing and managing patients at risk for or suffering from CIPN r Summarizes benefits of alternative and complementary therapies r Provides instructions to protect patients from injury and provide comfort

r Article focuses on translating laboratory findings in animals into clinically relevant information. Identifying mechanisms for specific agents will allow researchers to correlate anatomic and neurophysiologic abnormalities with clinical observations.

r Comprehensive review of chemotherapeutic agents that exert any type of neurotoxic effect

r Includes drug-specific diagnostic and clinical assessment criteria

risk for herpes zoster and subsequently postherpetic neuralgia.156 To date, no published data indicate any greater risk for postherpetic neuralgia following acute zoster in cancer survivors compared with the general population. Although precise estimates are not available for the number of cancer survivors who develop herpes zoster, there are inherent

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risks for survivor populations. Long-term effects of cancer treatment on immune responses most likely play an important role in the development of herpes zoster among cancer survivors. Treatments for acute herpes zoster and postherpetic neuralgia are similar to those for other neuropathic pains.157,158

restoring optimal function. Given the frequently long-term nature of the necessary therapies, it is important to assess patients’ acceptance of the various therapeutic options and to establish a partnership in working toward an improvement in their QOL.

Supportive care for survivors and families Assessment of pain Based on available information on posttreatment pain syndromes experienced by cancer survivors, there are important implications for assessing pain beyond routine pain assessment practices. As cancer survivors age, they are also at risk for developing the more typical back and joint pains seen in the general population, but their history dictates the need for a more comprehensive approach to their assessment to ensure that other possibilities are considered. As such, it is critical to take a careful and comprehensive health history to identify cancer survivors who might be at risk for long-term painful sequelae and neurological impairment. This includes eliciting or retrieving all information about the type of cancer and primary treatment modalities used to treat the cancer, and specifically chemotherapeutic agents, doses, and duration of therapy. In addition to the severity, quality and character, and duration of pain, for neuropathic pain, as for other pain syndromes, there should be a careful assessment of related factors. Admittedly, better assessment tools are needed to measure the different components of neuropathy and neuropathic pain, as well as the overall effects these have on physical and psychosocial aspects of life in routine clinical practice. Almadrones et al.159 tested two instruments to measure functional status and neuropathy in ovarian cancer patients: the GOG (Gynecological Oncology Group) Performance Status Scale and the Peripheral Neuropathy Scale. These instruments provide pertinent questions to help patients communicate their functional limitations and performance in activities of daily living, and establish criteria for evaluating the presence and severity of peripheral neuropathy–related symptoms. Lastly, a careful neurological examination should be conducted to identify the presence of sensitivity to touch or numbness of the affected areas, motor weakness, abnormal reflexes in deep tendons, disturbances in gait and balance, and orthostatic hypotension.160 In all cancer survivors, treatment options that are known to be effective for other types of neuropathic pain should be considered when nonpharmacological approaches such as exercise, occupational therapy, and alternative and complementary therapies alone are not helpful in relieving pain and

Recent attention to persistent and intermittent pain among cancer survivors by federal and professional organizations is likely to promote more research in this area; however, clinicians must still overcome the barriers to dealing with the pain issues in survivors who are free of their disease but are experiencing the lasting effects of having had cancer. There are many obvious and subtle issues that complicate the care of survivors with pain (Table 8.4). First, there is a lack of knowledge regarding the incidence and prevalence of pain among cancer survivors, which is a major deterrent to identifying pain syndromes and promptly treating them. Although there is an increasing number of studies on cancer survivors, there are still significant gaps in research that could substantially improve our understanding of cancer survivor pain syndromes. Second, many cancer survivors are lost to follow-up by their oncology providers and may seek care from health care professionals who may not be familiar with the longlasting painful consequences of cancer and its treatment. Health professionals in all clinical settings must pay close attention to complaints of pain among survivors, including a thorough health history, physical examination, and pain evaluation, but also must not delay treatment for the symptoms. Patients with pain unresponsive to standard pain treatment or pain that is complex to start with will likely benefit from referral to a pain management specialist or pain center. Common reasons for these referrals include uncontrolled, severe pain (e.g., pain that is unresponsive to escalating doses of medication); significant, ongoing disruption of physical and/or psychosocial functioning (e.g., deteriorating coping skills, excessive disability); comorbid psychiatric disorders (e.g., severe depression or anxiety); evaluation for a diagnostic workup for pain of unknown etiology or complex pain syndromes (e.g., neuropathic pain); validation of the pain diagnosis and treatment plan; assistance in interpreting physical or radiological findings; and consultation for physical therapy, acupuncture, epidural injections, counseling, or other modalities that may not be available in primary care settings.161 Third, cancer patients should be informed about the longterm effects of their treatments, and how to deal with them. Lyne and colleagues34 emphasize the importance

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Table 8.4. Factors contributing to underreporting and treatment of pain among cancer survivors Limited research addressing: Prevalence and incidence of pain among survivors Magnitude and severity of pain Characterization of sensory and motor impairment Effect of pain on activities of daily living and QOL Likelihood for developing pain following curative therapies Time course and trajectory of long-term sequelae Relationship between symptoms and type of tumor, stage at diagnosis, and treatment-related variables Wide variations in estimates of prevalence and incidence of pain syndromes and neuropathies among survivors Inadequate sample sizes Heterogeneity of samples Lack of control over confounding variables Few prediction models for risk assessment Lack of universal measurements and diagnostic and clinical assessment criteria for cancer-related pain Insufficient data from well-designed studies evaluating the effectiveness of pain management interventions for treatment-induced pain Gaps in research assessing health-related QOL along the continuum of cancer survivorship Practice-related Knowledge deficits Limited awareness of the prevalence and incidence of pain among survivors Inexperience in diagnosing complex treatment-induced pain syndromes Underappreciation for patients at risk Limited education and training in pain management Limited clinical experience using well-established pain management interventions to treat neuropathic pain in cancer survivors Failure to acknowledge the potential for chronic pain following curative cancer therapies Failure to inform patients about the potential long-term consequences of cancer therapies Infrequent follow-up Follow-up by health care professionals who are not cancer specialists Limited practice-based surveillance of health-related QOL and symptomatology with well-established measurement indices Perceptions that treatment-induced pain will improve over time Concerns regarding regulatory scrutiny of chronic opioid therapy Failure to refer patients to pain management specialists Patient-related Reluctance to report symptoms Fear of being perceived as ungrateful for being disease-free Fear of reoccurrence of cancer Lack of awareness that some pain states are common “Don’t ask, don’t tell” mind-set Worries about the long-term use of pain medications Beliefs that pain relief may not be possible

of informational support around pain issues. The problem of “don’t ask – don’t tell” may prevent patients from freely reporting symptoms of pain and signs of neurological impairment, and feeling comfortable doing so. It is the responsibility of all health care professionals caring for cancer survivors to educate them about the possible long-term consequences from cancer and cancer treatments, including pain and neurological damage. This will foster an environment in which patients will be more comfortable reporting their symptoms. Education should focus on promoting self-management, and for individuals who have developed peripheral neuropathies, practical tips may be useful in preventing further injury and pain.162,163 Survivors with neuropathies should learn how to protect their hands and feet

against injury by assessing water temperature to prevent burns and using protective gloves and pot holders. They should also try to prevent falls by keeping rooms well lit, clearing walkways, and using nonskid mats in showers and bathtubs.162 Resources are available to help cancer survivors engage in self-help activities and interventions.164 Cancer survivors should also be encouraged to use credible web-based resources for information about pain and social support. Polomano et al.165 conducted a review of websites capable of offering content about pain and social support and monitored interactive chat rooms where patients can share their experiences with others. Other Internet sites that may provide useful information for patients are listed in Table 8.5.

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Table 8.5. Internet sites for cancer survivors American Cancer Society, Cancer Survivors Network: http://www.acscsn.org/Resources http://www.cancer.org/docroot/SHR/SHR 0.asp City of Hope Beckman Research Institute: http://www.cityofhope.org/prc/patiented.asp National Cancer Institute: Home page: http://cancernet.nci.nih.gov Publications: https://cissecure.nci.nih.gov/ncipubs Cancer Information Service (CIS): U.S. residents may call the CIS toll free at 1–800–4–CANCER (1–800–422–6237) National Comprehensive Cancer Network: Information for patients: http://www.nccn.org National Pain Foundation: http://www.painconnection.org/MyPain/contentdirectory Cancer.asp http://www.painconnection.org/MyTreatment/MyTreatment Tips For Dealing With Your Pain.asp OncoLink: http://www.oncolink.upenn.edu Partners against Pain: http://www.partnersagainstpain.com/index-pc.aspx?sid=9

Conclusion It is evident that more research is needed to provide accurate estimates of the extent and severity of chronic pain syndromes in cancer survivors. Although an extensive body of literature addresses the pain and symptoms of progressive cancer, the cancer survivor’s experiences with long-term pain have received far less attention, despite evidence that residual pain from cancer treatment may be just as severe and debilitating. More data are needed to chart the onset, duration, severity, and characteristics of pain among survivors. Studies of cancer survivors with latent pain syndromes must also measure the effects of chronic pain on QOL. The significant void in scientific knowledge and practice-based experiences with survivors’ responses to various pain-relieving interventions must also be addressed to determine the most effective treatment strategies. Few studies have examined the efficacy of neuropathic pain agents in treating pain in long-term cancer survivors, especially those with significant neuropathic postmastectomy or postthoracotomy pain and those with CIPN. Similarly, there are no large-scale investigations to document success rates of analgesics, specific interventional techniques, cognitive and behavioral therapies, exercise, and other alternative therapies, such as nutraceuticals. The benefits of specialized multidisciplinary pain management through referrals to pain clinics or centers have not yet been determined. Although few guidelines for cancer survivors are available, information accumulated from the treatment of cancer-related pain can be extrapolated. Some helpful criteria for when to refer patients with cancer-related pain to

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transplantation: results from the Bone Marrow Transplant Survivor Study. Blood 104:1898–906, 2004. Majhail NS, Ness KK, Burns LJ, et al. Late effects in survivors of Hodgkin and non-Hodgkin lymphoma treated with autologous hematopoietic cell transplantation: a report from the bone marrow transplant survivor study. Biol Blood Marrow Transplant 13:1153–9, 2007. Rugo HS. Strategies for the prevention of treatment-related bone loss in women receiving adjuvant hormonal therapy. Clin Breast Cancer 7(Suppl 1):S21–8, 2007. Reeves KW, Faulkner K, Modugno F, et al. Study of Osteoporotic Fractures Research Group. Body mass index and mortality among older breast cancer survivors in the Study of Osteoporotic Fractures. Cancer Epidemiol Biomarkers Prev 16:1468–73, 2007. Brown JE, Ellis SP, Silcocks P, et al. Effect of chemotherapy on skeletal health in male survivors from testicular cancer and lymphoma. Clin Cancer Res 12:6480–6, 2006. Chen AC, Petrylak DP. Complications of androgendeprivation therapy in men with prostate cancer. Curr Urol Rep 6:210–16, 2005. Limburg CE. Screening, prevention, detection, and treatment of cancer therapy-induced bone loss in patients with breast cancer. Oncol Nurs Forum 34:55–63, 2007. Molina JR, Barton DL, Loprinzi CL. Chemotherapy-induced ovarian failure: manifestations and management. Drug Saf 28:401–16, 2005. Schultz PN, Beck ML, Stava C, et al. Health profiles in 5836 long-term cancer survivors. Int J Cancer 104:488–95, 2003. Tauchmanov`a L, De Rosa G, Serio B, et al. Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and a review. Cancer 97:2453–61, 2003. Greenspan SL, Bhattacharya RK, Sereika SM, et al. Prevention of bone loss in survivors of breast cancer: a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab 92:131–6, 2007. Theriault RL, Biermann JS, Brown E, et al. NCCN Task Force

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report: bone health and cancer care. J Natl Compr Canc Netw 4(Suppl 2):S1–20, 2006. Johnson RW, Whitton TL. Management of herpes zoster (shingles) and postherpetic neuralgia. Expert Opin Pharmacother 5:551–9, 2004. Gordon DB, Love G. Pharmacological management of neuropathic pain. Pain Manag Nurs 5(Suppl 1):19–33, 2005. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132:237–51, 2007. Almadrones L, McGuire DB, Walczak JR, et al. Psychometric evaluation of two scales assessing functional status and peripheral neuropathy associated with chemotherapy for ovarian cancer: a gynecologic oncology group study. Oncol Nurs Forum 31:615–23, 2004. Visovsky C, Daly BJ. Clinical evaluation and patterns of chemotherapy-induced peripheral neuropathy. J Am Acad Nurse Pract 16:353–9, 2004. Gruener D, Lande S, eds. Pain control in the primary care setting. Glenview, IL: American Pain Society, 2006. Armstrong T, Almadrones L, Gilbert MR. Chemotherapyinduced peripheral neuropathy. Oncol Nurs Forum 32:305–11, 2005. Arnstein P. Chronic neuropathic pain: issues in patient education. Pain Manag Nurs 5(4 Suppl 1):34–41, 2004. Tesauro GM, Rowland JH, Lustig C. Survivorship resources for post-treatment cancer survivors. Cancer Pract 10:277–83, 2002. Polomano RC, Droog NM, Purinton MCP, Cohen AS. Can social support be found on the World Wide Web?: an evaluation of resources for patients with chronic pain. J Pain Palliat Care Pharmacother 21:49–55, 2007. Panchal SJ, et al. Adult cancer pain. Jenkintown, PA: National Comprehensive Cancer Network, 2005. (Clinical practice guidelines in oncology, v.2.2005). Available at: http://www. nccn.org/professionals/physician_gls/PDF/pain.pdf. Carr DB, Goudas LC, Balk EM, et al. Evidence report on the treatment of pain in cancer patients. J Natl Cancer Inst Monogr (32):23–31, 2004.

SECTION

IV

PHARMACOLOGICAL TREATMENT

9

Pharmacology of analgesia: basic principles charles e. inturrisi

Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center

Introduction The opioid analgesic drugs remain the most effective and commonly used modality for the alleviation of moderate to severe pain due to cancer.1 The purpose of this chapter is to focus on the pharmacological properties of opioids that form the basis for their use in pain management. Recently, there has been a dramatic increase in our knowledge of the sites and mechanisms of action of opioids.2 Pharmacokinetic studies together with the recent discoveries of pain- and opioid-receptor–related genetic polymorphisms have begun to offer us a better understanding of some of the sources of interindividual variation in the response to opioids and to suggest ways to minimize some of their adverse effects.1,3 Although there are major gaps in our knowledge of opioid pharmacology, ultimately the rational and appropriate clinical use of these drugs is based on the knowledge of their pharmacological properties derived from well-controlled clinical trials.

Individualized dosage The fundamental concept that underlies the appropriate and successful management of cancer pain by the use of opioid and nonopioid analgesics is individualization of analgesic therapy.4,5 This concept entails selection of the right analgesic, administered in the right dose, and on the right schedule so as to maximize pain relief and minimize adverse effects.4,5 This comprehensive approach begins with the nonopioids or mild analgesics for mild pain (see Chapter 11). In patients with moderate pain that is not controlled by nonopioids alone, the so-called weak opioids alone or in combination should be prescribed, whereas in patients with severe pain, a strong opioid is the drug of choice, given alone or in combination (see Chapters 11 and 12).

At all levels, certain adjuvant drugs are used for specific indications4–6 (see also Chapter 11).

Classification of the opioid analgesics The opioid analgesics can be classified based on their interactions with opioid receptors. The opioid receptors of interest are designated as mu, delta, and kappa. Mu opioid receptor (MOR) ligands are the major source of clinically used opioid agonist and antagonist drugs. Kappa opioid receptor ligands provide a few drugs; however, their clinical pharmacology is complicated by concurrent mu opioid receptor antagonist activity (see later). Delta opioid receptor ligands are of research interest but currently do not provide any clinically used opioids. Each of the opioid receptors belong to the G protein–coupled receptor family, and they signal via a second messenger, cyclic adenosine monophosphate or an ion channel.2 Molecular genetic approaches have used gene-targeting (knockout) technology to disrupt the gene that codes for each of the three opioid receptors. Mice that lack the mu receptor (MOR-deficient mice) do not respond to morphine with analgesia, respiratory depression, constipation, physical dependence, reward behaviors, or immunosuppression.7 These results confirm and extend previous pharmacological and receptor-binding studies and demonstrate that the mu receptor mediates the analgesic and adverse effects of morphine. MORs are found in the periphery (following inflammation) at pre- and postsynaptic sites in the spinal cord dorsal horn and in the brainstem, thalamus, and cortex, in what constitutes the ascending pain transmission system.8 In addition, MORs are found in the midbrain periaqueductal gray, the nucleus raphe magnus, and the rostral ventral medulla, where they comprise a descending inhibitory system that modulates spinal cord

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168 pain transmission.8 At the cellular level, opioids decrease calcium ion entry, resulting in a decrease in presynaptic neurotransmitter release (e.g., substance P release from primary afferents in the spinal cord dorsal horn). They also enhance potassium ion efflux, resulting in the hyperpolarization of postsynaptic neurons and a decrease in synaptic transmission. A third mode of opioid action is to inhibit ␥ aminobutyric acid (GABA)ergic transmission in a local circuit, such as in the brainstem, where GABA acts to inhibit a pain inhibitory neuron. This disinhibitory action of the opioid has the net effect of exciting a descending inhibitory circuit. The opioid receptors are part of an endogenous opioid system that includes a large number of endogenous opioid peptide ligands. Based on cloning, three distinct families of classical opioid peptides – the enkephalins, endorphins, and dynorphins – have been identified.2 The physiological roles of the endogenous opioid peptides are not completely understood. They appear to function as neurotransmitters, neuromodulators, and, in some cases, neurohormones.7 The morphine-like agonist drugs represent one end of the pharmacodynamic spectrum. They bind predominately or exclusively to the MOR and produce analgesia and the other MOR-mediated effects described later. The opioid antagonists, such as naloxone, represent the other end of the spectrum because their binding to an opioid receptor does not trigger the signaling cascade that leads to the pharmacodynamic effects seen with opioid agonists. Rather, receptor occupancy by a sufficient concentration of an opioid antagonist results in the prevention or reversal of the opioid receptor–mediated effects of an agonist. Between these two types of pharmacodynamic actions fall the effects of the mixed agonist-antagonist drugs. These opioid drugs (see Table 9.1) can demonstrate agonist (at the kappa receptor) or antagonist (at the mu receptor) activity. What is observed clinically depends on whether the patient is opioid na¨ıve or has prior exposure to a mu opioid agonist. Within this spectrum is also buprenorphine, an opioid that is classified as a partial agonist.

Morphine-like agonists Morphine is the prototype and standard of comparison for opioid analgesics. The morphine-like agonists (Table 9.1) share with morphine a similar profile of pharmacodynamic effects, both desirable and undesirable. However, they differ in factors critical in dosage selection, that is, relative analgesic potency and oral-to-parenteral analgesic potency. They also differ in pharmacokinetics (e.g., elimination halflife) and biotransformation to pharmacologically active

c.e. inturrisi metabolites.1 These latter characteristics are of particular importance when opioid administration is continued beyond 1 or 2 days. Much of this information is summarized in Table 9.1. This dosage information is, for the most part, derived from controlled clinical trials employing singledose comparisons of opioids with morphine. Although its oral bioavailability varies from 35% to 75%, its 3-hour average plasma half-life is somewhat shorter than its duration of analgesia (4–6 hours), which limits accumulation. Furthermore, with repetitive administration, its pharmacokinetics remain linear and there does not appear to be autoinduction of biotransformation, even following large chronic doses.9 These pharmacokinetic properties contribute to the safe use of morphine. Morphine6-glucuronide (M6G) is an active metabolite of morphine that appears to contribute to its analgesic activity.10,11 M6G is eliminated by the kidneys and will accumulate relative to morphine in patients with renal insufficiency. In a survey that measured steady-state morphine and M6G levels and adverse effects in 109 cancer patients, the presence of myoclonus or cognitive impairment was not associated with M6G accumulation.12 In a subset of 20 patients with the highest M6G levels (⬎2000 ␮g/mL), the M6G level and concurrent organ failure were associated with the most severe toxicity (respiratory depression and/or obtundation).12 It is appropriate to consider an alternate opioid for a patient receiving morphine who experiences a decrease in renal function and a concomitant increase in undesirable effects. Morphine-3-glucuronide (M3G), the predominate metabolite of morphine in humans, is devoid of opioid activity but has excitatory effects in animals after direct injection into the central nervous system CNS. This has led to the suggestion that M3G may be responsible for the neuroexcitatory effects sometimes seen with large chronic morphine dosing.13 Based on single-dose studies in patients with either acute or chronic pain, the relative potency of intramuscular to oral morphine is 1:6. However, with repeated administration, when patients are dosed on a regular schedule (around the clock), the intramuscular/oral ratio is reduced to 1:2 or 1:3 (Table 9.1). The delayed-release morphine preparations provide analgesia for 8–12 hours (MS-Contin [Purdue Frederick Co., Stamford, CT], Roxanol SR [AAIPharma, Wilmington, NC) or 24 hours (Kadian [Actavis US, Morristown, NJ], Avinza [King Pharmaceuticals, Bristol, TN]) and allow the cancer patient greater freedom from repetitive dosing, especially during the night. Patients may be titrated using the immediate-release morphine and, once stabilized, converted to the delayed-release preparation according to an

pharmacology of analgesia: basic principles

169

Table 9.1. Opioid analgesics commonly used for severe pain

Name

Equianalgesic intramuscular dosea

Morphine-like agonists Morphine 10

Intramuscular/ oral potency

Starting oral dose range (mg)

6b

30–60b

Hydromorphone (Dilaudid)

1.5

5

4–8

Methadone (Dolophine)

10

2

5–10

Levorphanol (Levo-Dromoran) Oxymorphone (Opana)

2

2

2–4

1

6b

5–10

Oxycodone

15

2

5–20

Fentanyl

0.1

–

–

Meperidine (Demerol)

75

4

Not recommended

Codeine

130

1.5

30–60

Hydrocodone

–

30

2.5–10

Comments

Precautions

Standard of comparison for opioid analgesics. Extended-release preparations: MS-Contin, Oramorph SR, Kadian, and Avinza Slightly shorter acting. HP intramuscular dosage form for tolerant patients. Good oral potency. Long but variable plasma half-life. Rotation dose depends on prior opioid dosage. See text. Like methadone

Those with impaired ventilation, bronchial asthma, increased intracranial pressure, and liver failure. Lower doses for elderly. Like morphine

Immediate-release (Opana) and extended-release (Opana ER) oral dosage. Also available as a rectal suppository. Immediate-release (Roxicodone and OxyIR) and extended-release (OxyContin) oral dosage. Also in combination with nonopioids for less severe pain. Transdermal fentanyl (Duragesic). Also as oral transmucosal fentanyl citrate (Actiq) for breakthrough pain. Slightly shorter acting than morphine. Used orally for less severe pain.

Like morphine. Do not take with food or alcohol.

Used orally in combination with nonopioids for less severe pain Used orally in combination with nonopioids for less severe pain (Vicodin, Lorcet, Lortab, and many others)

Like morphine. May accumulate with repetitive dosing, causing excessive sedation. Like methadone

Like morphine

Transdermal creates skin reservior of drug and 12-hour delay in onset and offset. Fever increases absorption. Normeperidine metabolite accumulates with repetitive dosing, causing CNS excitation. Not for patients with impaired renal function or receiving monoamine oxidase inhibitors.c Like morphine

(continued)

c.e. inturrisi

170 Table 9.1 (continued)

Intramuscular/ oral potency

Starting oral dose range (mg)

Mixed agonist–antagonists Pentazocine (Talwin) 60

3

Nalbuphine (Nubain)

10

Butorphanol (Stadol) Partial agonists Buprenorphine (Buprenex)

Name

Equianalgesic intramuscular dosea

Comments

Precautions

See comments

Used orally for less severe pain. A mixed agonist–antagonist; see precautions.

See comments

See comments

2

See comments

See comments

Not available orally. Like intramuscular pentazocine but not scheduled. Not available orally. Like intramuscular nalbuphine.

May cause psychotomimetic effects. May precipitate withdrawal in opioid-dependent patients. Not for pain due to myocardial infarction. Incidence of psychotomimetic effects lower than with pentazocine Like nalbuphine

0.3

See comments

See comments

Not available orally. Only parenteral form approved in U.S. for pain. Does not produce psychotomimetic effects.

May precipitate withdrawal in opioid-dependent patients. Not readily reversed by naloxone. Avoid in labor.

For these equianalgesic intramuscular doses (also see comments), the time of peak analgesia in nontolerant patients ranges from 0.5 to 1 hour and the duration from 4 to 6 hours. The peak analgesic effect is delayed and the duration prolonged after oral administration. a These doses are recommended starting intramuscular doses from which the optimal dose for each patient is determined by titration and the maximal dose limited by adverse effects. For single intravenous bolus doses, use half the intramuscular dose. b A value of 3 is used when calculating an oral dosage regimen of every 4 hours around the clock. c Irritating to tissues on repeated administration. Abbreviations: HP, high potentcy.

8- or 12-hour dosing schedule. To manage acute “breakthrough” pain, “rescue” medication (immediate-release morphine) should be made available to patients receiving delayed-release preparations (see Chapter 23). Hydromorphone Hydromorphone is a short–half-life opioid used as an alternative to morphine by the oral and parenteral routes. It is more soluble than morphine and available in a concentrated dosage form at 10 mg/mL. This preparation is intended for parenteral administration to the opioid-tolerant, cachectic patient in whom the volume of the opioid solution to be injected must be limited. Methadone The use of methadone in pain management has dramatically increased in the past several years, with mixed effects.

The original interest in methadone was based on its high (1:2) oral-to-parenteral potency ratio, which is a reflection of its high oral bioavailability that averages 85%. It was found to be useful in opioid rotation, because its incomplete cross-tolerance to opioids such as morphine allows a significant reduction in dose when switching from morphine to methadone. Methadone is relatively inexpensive, and its metabolites do not have opioid activity or apparent toxicity. As with other opioids, it may provide a larger therapeutic window in a particular patient, although this cannot be determined before a therapeutic trial. Finally, preclinical studies demonstrated the N-methyl-d-aspartate (NMDA) receptor antagonist activity of both isomers of methadone. In animals, this NMDA receptor antagonist activity included antihyperalgesic activity and the ability to prevent the development of morphine tolerance.1,14 However, it remains to be determined whether these effects occur in humans at the doses of methadone used clinically.

pharmacology of analgesia: basic principles A major limitation of methadone’s use as a first-line opioid for pain management is related to its safety. Its population pharmacokinetics are variable, with a plasma half-life that averages 24 hours but may range from 13–50 hours. Because initially the duration of analgesia is often only 4–8 hours, repetitive analgesic dosing of methadone may lead to drug accumulation because of this discrepancy between its plasma half-life and the duration of analgesia during initial dosing. Sedation, confusion, and even death may occur when patients are not carefully monitored and the dosage adjusted during the accumulation period, which may last 5–10 days. More recently, a second safety issue relates to concerns about the potential for methadone to prolong the QTc interval and predispose patients to torsades de pointes, a life-threatening arrhythmia.15–17 Finally, there is the stigma among pain patients and the public attached to methadone’s use for the treatment of opioid addiction. Oxymorphone Oxymorphone, a congener of morphine, is approximately 10 times more potent than morphine following parenteral administration. Immediate- and extended-release oral formulations (Opana and Opana ER [Endo Pharmaceuticals, Chadds Ford, PA]) have recently been released. The extended-release dosage is indicated for every-12-hour dosing. As with other extended-release dosage forms, it should not be used on an as-needed schedule or in opioid-na¨ıve patients. It is contraindicated in patients with severe hepatic impairment. Opana ER is available as 5- to 40-mg tablets. The usual starting oral dose is 5 mg. Food enhances its bioavailability, so Opana ER should be taken 1 hour before or 2 hours after a meal. Co-ingestion of alcohol with Opana ER also may increase plasma levels of oxymorphone. Oxymorphone remains available for parenteral and rectal (suppository) administration. Levorphanol Levorphanol, which is a longer–half-life opioid (Table 9.2), is also a useful alternative to morphine, but it must be used cautiously to prevent accumulation. For patients who are unable to tolerate morphine and methadone, levorphanol represents a useful medication with a good oralto-parenteral potency ratio of 1:2. Oxycodone Oxycodone is available in immediate-release and continuous-release (8- to 12-hour duration) preparations (Oxy-

171

Table 9.2. Plasma half-life values for opioids and their active metabolites Plasma half-life (hours) Short–half-life opioids Morphine Morphine-6-glucuronide Hydromorphone Oxycodone Fentanyl Codeine Meperidine Pentazocine Nalbuphine Butorphanol Buprenorphine Longer–half-life opioids Oxymorphone Levorphanol Propoxyphene Normeperidine Methadone Norpropoxyphene

2–3.5 2 2–3 2–3 3.7 3 3–4 2–3 5 2.5–3.5 3–5 7.5–9.5 12–16 12 14–21 13–50 30–40

Contin [Purdue Pharma, Stamford, CT]), and these dosage forms may be used for moderate to severe pain. However, lower doses (e.g., 5 mg) in combination with nonopioids (aspirin, acetaminophen) are frequently used for mild to moderate pain. The fixed-dose oxycodone combinations should not be used chronically in large doses for more severe pain because of the risk of dose-related toxicity from the nonopioid ingredients. Fentanyl Fentanyl is estimated to be approximately 80–100 times as potent as morphine.1,4 It is a highly lipophilic drug with shorter duration of action than parenteral morphine. Fentanyl is used for the management of postoperative pain by the intravenous and epidural routes of administration; a transdermal patch device is used for chronic pain requiring opioid analgesia, and a transmucosal dosage form is used for breakthrough cancer pain (see later). Meperidine Studies of meperidine in cancer patients have demonstrated that repetitive dosing may lead to accumulation of its toxic metabolite, normeperidine, resulting in CNS hyperexcitability,18 characterized initially by subtle mood effects, followed by tremors, multifocal myoclonus, and occasionally seizures. This CNS hyperexcitability occurs commonly

c.e. inturrisi

172 in patients with renal disease, but it may occur following repeated administration in patients with normal renal function.18

Agonist-antagonist analgesics The mixed agonist-antagonist analgesics (Table 9.1) include pentazocine, butorphanol, and nalbuphine. They produce analgesia in the nontolerant patient but may precipitate withdrawal in patients tolerant to or dependent on morphine-like drugs. The mixed agonist-antagonist opioids have an apparent ceiling effect that limits their dosage. These dosage limits often are the result of the appearance of psychotomimetic effects, including confusion and hallucinations, especially in elderly patients and patients with renal impairment. Although an apparent ceiling on the ability of the mixed agonist-antagonists to produce respiratory depression may be an advantage over other opioids in some situations, these drugs play a very limited role in the management of chronic pain because of the limitations described earlier and because they are not available in convenient oral dosage forms. Thus, nalbuphine is available only for parenteral use, and the oral preparation of pentazocine is marketed in combination with aspirin, acetaminophen, or naloxone. Butorphanol is available for both parenteral and intranasal use. Buprenorphine Buprenorphine is a schedule III partial agonist that is available in two sublingual preparations. The buprenorphineonly preparation (Subutex; Reckitt Benckiser Pharmaceuticals, Richmond, VA]) is approved for the treatment of opioid addiction and detoxification, whereas the naloxone/ buprenorphine combination (Suboxone; Reckitt Benckiser Pharmaceuticals) is used for opioid maintenance treatment. Neither of these preparations is approved for use in chronic pain. Buprenorphine can precipitate opioid withdrawal when given to patients who have received chronic treatment with a morphine-like agonist.

Opioid pharmacokinetics The opioids differ significantly in one measure of drug elimination, the plasma half-life value (Table 9.2). Thus, although morphine and hydromorphone are short–half-life opioids that on repeated dosing reach steady state in 10– 12 hours, levorphanol and methadone are long–half-life opioids that, on the average, may require 70–120 hours, respectively, to achieve steady state. During dose titration,

the maximal (peak) effects produced by a change in dose of a short–half-life opioid will appear relatively quickly, whereas the peak effects resulting from a change in the dose of a long–half-life opioid will be achieved after a longer accumulation period. For example, a patient who reports adequate pain relief following the initial doses of methadone may experience excessive sedation if this dosage is fixed and not modified as required during the accumulation period of 5–10 days. Also, note that the active (toxic) metabolites normeperidine and norpropoxyphene have much longer plasma halflife values than their corresponding parents (meperidine and propoxyphene), so administration of the parent on a schedule designed to produce continued pain relief results in accumulation of the metabolite.

Routes of administration Oral When given orally, the opioids differ substantially with respect to their presystemic elimination, that is, the degree to which they are inactivated as they are absorbed from the gastrointestinal tract and pass through the liver into the systemic circulation. As indicated in Table 9.1, morphine, hydromorphone, and oxymorphone have ratios of oral to intramuscular potency of 1:5 to 1:12. Methadone, levorphanol, and oxycodone are subject to less presystemic elimination, resulting in an oral-to-intramuscular potency ratio of at least 1:2. Meperidine and pentazocine have intermediate ratios. The failure to recognize these differences often results in a substantial reduction in analgesia when a change from parenteral to oral administration is attempted without upward titration of the dose. In general, orally administered drugs have a slower onset of action, delayed peak time, and a longer duration of effect, whereas drugs administered parenterally have a rapid onset of action but a shorter duration of effect. Transdermal The development of a transdermal system for the delivery of fentanyl through the skin (TTS fentanyl) provides a convenient mode of opioid administration that avoids frequent parenteral or oral dosing for patients with relatively constant cancer pain. This system is currently available in five dosage strengths that vary in drug delivery rate from 12– 100 ␮g/hour and is to be applied at 72-hour intervals. The package insert provides estimates of the equivalence of morphine to TTS fentanyl. Donner et al.19 found that

pharmacology of analgesia: basic principles cancer patients who were switched from oral morphine to transdermal fentanyl required approximately 25 ␮g/hour of fentanyl to replace 45 mg/day of oral morphine. The system creates a drug reservoir, probably in the striatum corneum at the site of application of the system, so there is a lag in the systemic absorption of the fentanyl.20 It takes 12–16 hours to achieve a therapeutic effect and 48 hours to reach approximately steady-state blood levels.20 Therefore, patients should be titrated to adequate pain relief with short-acting opioids and then switched to transdermal fentanyl. In addition, supplemental short-acting opioids should be available for breakthrough pain (BTP; see Chapter 27). The tissue reservoir limits fluctuations in drug concentrations in blood over the dosing interval. However, following removal of the system, drug concentrations in the blood decline relatively slowly with an apparent elimination halflife of 17 hours. This half-life is considerably longer than the 3.7-hour average half-life seen after parenteral administration (Table 9.2). Therefore, if the system is removed because of an adverse effect, the patient should be monitored for at least 24 hours. This dosage form should not be used for acute pain because the duration of drug delivery may exceed the pain stimulus, resulting in a substantial risk of respiratory depression. Cutting or damaging the patch will increase the release rate, with potentially adverse consequences. Fever or application of external heat sources to the patch may increase the rate of absorption. Used patches should be disposed of properly in a tamper-proof container, because there is enough residual medication to harm a nontolerant individual if accidentally ingested. Ionsys (fentanyl iontophoretic transdermal system; Janssen-Cilag International, Titusville, NJ) is a very recently approved patient-activated analgesic system. This new dosage form is indicated for the short-term management of acute postoperative pain in adults requiring opioid analgesia during hospitalization. Ionsys uses iontophoresis, a process in which a low-intensity electric field (generally imperceptible to the patient) is used to rapidly transport fentanyl across the skin and into the blood. The Ionsys system securely adheres to the upper outer arm or chest and is “needle–free.” When analgesia is needed, the patient double-clicks the dosing button, which delivers a preprogrammed, 40-␮g dose of fentanyl through the skin. Each dose is delivered over a 10-minute period. Although intended for an acute pain population, the same precautions with respect to drug interactions described earlier for the other fentanyl systems also apply to this dosage form. This system may serve as an alternative modality for the management of acute pain and should prevent adverse effects of conventional patient-controlled analgesia (PCA), including

173

bleeding, intravenous catheter infiltration, or manual pump malfunction.21 Transmucosal/buccal Oral transmucosal fentanyl citrate (OTFC, Actiq; Cephalon, Salt Lake City, UT) is a solid dosage form of fentanyl incorporated into a sweetened lozenge on a handle that is intended for application to the buccal mucosa. Approximately half the fentanyl dose is rapidly absorbed through the mucosa, whereas the rest is swallowed and absorbed from the gastrointestinal tract. Plasma concentrations are proportional to the dose and peak approximately 20–40 minutes after the start of administration.22 A systematic review concluded that although there are only a limited number of randomized trials of OTFC in the management of BTP, there is evidence that OTFC is an effective treatment for BTP.23 Actiq use is limited to the treatment of cancer-related BTP in patients who are already tolerant to a mu opioid (the equivalent of at least 60 mg/day of oral morphine or 25 ␮g/hour of transdermal fentanyl). Recent warnings also indicate that use of Actiq with “strong to moderate CYP450 3A inhibitors” may result in respiratory depression (see package insert for a list of these CYP inhibitors). The optimal dose is found through titration and is not predicted by the around-the-clock dose of opioids. A more recent fentanyl buccal tablet (FBT) delivery system is Fentora (Cephalon). Fentora dissolves with a localized effervescent reaction, creating transient shifts in pH that facilitate tablet dissolution and enhance the rate and extent of absorption of fentanyl across the buccal mucosa.24 Like the OTFC, the FBT dosage form is intended for BTP in opioid-tolerant patients and may be expected to be subject to the same drug interactions as those indicated for Actiq. Intramuscular The intramuscular route provides a longer onset (30–60 minutes) compared with the intravenous route and a shorter duration than after the oral route. Intramuscular injections are often painful; therefore, this route is not usually appropriate for the management of persistent pain. Intravenous bolus, continuous infusion, and patient-controlled analgesia An intravenous bolus provides the most rapid onset and shortest duration of action. Time to peak effect correlates

174 with the lipid solubility of the opioid, ranging from 2–5 minutes for methadone to 10–15 minutes for morphine. Opioids given by intravenous bolus may be used to titrate analgesia in patients with acute or escalating severe pain.4 A continuous intravenous infusion is useful for some patients who cannot be maintained on oral opioids. This mode of administration allows for complete systemic absorption and can be supplemented with bolus injections to conveniently titrate opioid dosage in patients with rapidly escalating pain. Loading and maintenance doses can be estimated as described by the American Pain Society.4 PCA is a mode of opioid administration that employs the concept of individualization of analgesic dosage, wherein the patient, within limits, can titrate his or her analgesia requirements. This mode of administration allows for variations in response to therapy that result from interpatient differences in pharmacokinetics and pharmacodynamics. PCA has been used widely for acute postoperative pain. A meta-analysis of the published controlled trials concluded that compared with conventional opioid treatment, PCA with opioids improves analgesia, decreases the risk of pulmonary complications, and is preferred by patients.25 PCA has been used effectively for the short- and long-term management of cancer pain in adults26 and in adolescents and children who are able to use the device correctly.27 Dosing guidelines for opioids administered by PCA are given by the American Pain Society.4 Continuous subcutaneous infusion For patients who cannot absorb adequate amounts of orally administered opioids because of nausea and vomiting, gastrointestinal intolerance, or obstruction, the parenteral routes described earlier may be used. However, in addition to circumventing oral absorption, the continuous subcutaneous infusion mode of opioid delivery avoids the problems associated with intramuscular/subcutaneous injection and the need for intravenous access and can be used by ambulatory patients. Most opioids available for parenteral use can be administered by continuous subcutaneous infusion.28 Rectal The rectal route is an alternative to the parenteral route for patients unable to take opioids orally. Rectal suppositories containing hydromorphone, oxymorphone, or morphine are available.

c.e. inturrisi Epidural and intrathecal (intraspinal) Opioid receptors are expressed on primary afferents, and spinal cord dorsal horn neurons are the target of intraspinal opioids. This relatively localized administration usually requires lower doses than systemic routes and may produce a segmental analgesia. These techniques are used to provide intra- and postoperative as well as obstetrical pain relief. The two most commonly used opioids are morphine and fentanyl. Morphine is a hydrophilic compound that slowly distributes into tissues; therefore, a substantial fraction remains in the cerebrospinal fluid. This reservoir of drug results in a long duration of analgesia but also allows for the rostral spread to supraspinal sites, where sedation and, rarely, respiratory depression may occur. The much more lipid-soluble fentanyl is rapidly taken up into tissues and cleared into the systemic circulation, reducing the duration of action and the risk of supraspinally mediated adverse effects.29 Intraspinal opioids can be administered in a single dose or by continuous infusion. Other issues and considerations include the choice of epidural or intrathecal intraspinal route,30 the contribution of an added local anesthetic to the degree of analgesia, and whether intraspinal opioids have an advantage over a well-managed systemic dosing regimen.31 Dosing guidelines for intraspinal opioids are given by the American Pain Society.4

Changing the route of administration The slower onset of analgesia after oral administration often requires some adaptation on the part of a patient who is accustomed to the more rapid onset seen after parenteral opioid. The problems associated with switching from the parenteral to the oral route of opioid administration can be minimized by slowly reducing the parenteral dose and increasing the oral dose over a 2- to 3-day period. When patients are switched from the intramuscular to intravenous or the intravenous to intramuscular route, we have made the assumption that the equianalgesic doses by these two routes are the same. However, there are no studies of the relative potency of drugs comparing these routes. When patients are switched from one opioid analgesic to another or from one route of administration to another, it is the lack of attention to the route-dependent differences in opioid dose that accounts for the common reports of undermedication of patients. In patients who have been receiving one opioid repeatedly to the point at which some degree of tolerance has developed and are then switched to another opioid, half the analgesic drug dose of the new drug

pharmacology of analgesia: basic principles should be given as the initial starting dose. This information has been gained empirically but is based on the concept that cross-tolerance is not complete among opioids, and conforms to our recognition that the relative potency of some of the opioid analgesics may change with repetitive dosing, particularly opioids with a long plasma half-life. In using Table 9.1, it becomes important to recognize that the equianalgesic dose estimates are based on the single-dose studies, and they represent a useful reference point for the initiation of dose titration. They are not meant to be used as the standard dose for every patient.

Scheduled opioid administration The schedule of opioid administration should be individualized for each patient. In general, patients with persistent pain should receive opioids on a regular schedule once the patient’s dosage has been established by titration. A regular around-the-clock schedule of opioid administration can prevent severe pain from recurring and may allow for a reduction in the total opioid required per day. For many patients, supplemental opioid (rescue) doses between the regularly scheduled doses may be required to provide adequate pain relief.

Drug combinations that enhance analgesia Drug combinations may provide additive analgesia, reduce adverse effects, and reduce the rate of escalation of the opioid portion of the combination.1,4 There are several combinations that produce additive analgesic effects, including an opioid plus one of the following: a nonopioid analgesic (acetaminophen, a salicylate, or a nonsteroidal anti-inflammatory drug of either the mixed cyclooxygenase [COX]-1 and COX-2 or COX-2 inhibitor type), caffeine, hydroxyzine (an antihistamine), methotrimeprazine (a phenothiazine), or dextroamphetamine (a stimulant). Other adjuvant analgesics that are commonly used with opioids are the tricyclic antidepressants (amitriptyline, imipramine, nortriptyline, and desipramine) and the anticonvulsants (gabapentin pregabalin, carbamazepine, and clonazepam) (see Laird et al.30 and Chapters 8, 10, and 11).

Adverse effects of opioids A number of side effects associated with the use of opioid analgesics may, depending on the circumstances, be categorized as desirable or undesirable1 (see also Chapter 9). It is the development of adverse effects that markedly limits the

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use of analgesics in cancer pain, and these limitations have been a major impetus in the development of novel routes of opioid administration, such as epidural, intrathecal, and continuous subcutaneous infusion. The mechanisms that underlie these various adverse effects are only partly understood and, as discussed previously, appear to depend on a number of factors, including the patient’s age, extent of disease, and organ dysfunction; concurrent administration of certain drugs; prior opioid exposure; and the route of drug administration. Studies comparing the adverse effects of one opioid analgesic to another in this population are often lacking. Similarly, controlled studies comparing the adverse effects produced by the same opioid given by various routes of administration also are lacking. The most common adverse effects are sedation, nausea and vomiting, constipation, and respiratory depression. Other adverse effects include confusion, hallucinations, nightmares, urinary retention, multifocal myoclonus, dizziness, and dysphoria, which have been reported by patients receiving these drugs.32 Respiratory depression Respiratory depression is potentially the most serious adverse effect. The morphine-like agonists act on brainstem respiratory centers to produce, as a function of dose, increasing respiratory depression to the point of apnea. In humans, death from overdose of a morphine-like agonist is nearly always the result of respiratory arrest. Therapeutic doses of morphine may depress all phases of respiratory activity (rate, minute volume, and tidal exchange). However, as Co2 accumulates, it stimulates central chemoreceptors, resulting in a compensatory increase in respiratory rate that masks the degree of respiratory depression. At equianalgesic doses, the morphine-like agonists produce an equivalent degree of respiratory depression. For these reasons, individuals with impaired respiratory function or bronchial asthma are at greater risk of experiencing clinically significant respiratory depression in response to usual doses of these drugs. Respiratory depression and Co2 retention result in cerebral vasodilation and an increase in cerebrospinal fluid pressure unless Pco2 is maintained at normal levels by artificial ventilation. When respiratory depression occurs, it is usually in opioid-na¨ıve patients after acute administration of an opioid and is associated with other signs of CNS depression, including sedation and mental clouding. Tolerance develops rapidly to this effect with repeated drug administration, allowing the opioid analgesics to be used in the management of chronic

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176 cancer pain without significant risk of respiratory depression. If respiratory depression occurs, it can be reversed by the administration of the specific opioid antagonist naloxone. In patients chronically receiving opioids who develop respiratory depression, naloxone diluted 1:10 should be titrated carefully to prevent the precipitation of severe withdrawal symptoms while reversing the respiratory depression. An endotracheal tube should be placed in the comatose patient before administering naloxone to prevent aspirationassociated respiratory compromise with excessive salivation and bronchial spasm. In patients receiving meperidine chronically, naloxone may precipitate seizures by blocking the depressant action of meperidine and allowing the convulsant activity of the active metabolite, normeperidine, to be manifest.1 If naloxone is to be used in this situation, diluted doses slowly titrated with appropriate seizure precautions are advised. The mixed agonist–antagonists and the partial agonist (buprenorphine) appear to differ from the morphinelike drugs with regard to the dose–response characteristics of their respiratory depression curves; therefore, although therapeutic doses of pentazocine produce respiratory depression equivalent to that of morphine, increasing the dose does not ordinarily produce a proportional increase in respiratory depression. Whether this apparent ceiling for respiratory depression offers any clinical advantage remains to be determined. Also, the clinical symptoms of a large overdose of these drugs, with particular respect to respiratory depression, have not been well defined.33 In a recent observational study, Webster et al.34 found that sleep-disordered breathing was common in chronic pain patients receiving opioids, particularly those on a combination of benzodiazepines and methadone, and that it may be related to the sleep apnea observed in these patients. Nausea and vomiting The opioid analgesics produce nausea and vomiting by an action on the medullary chemoreceptor trigger zone. The incidence of nausea and vomiting is markedly increased in ambulatory patients, suggesting that these drugs also alter vestibular sensitivity. The ability of opioid analgesics to produce nausea and vomiting appears to vary according to drug and patient, so some advantage may result from switching to an equianalgesic dose of another opioid. Alternatively, an antiemetic may be used in combination with the opioid. For some patients, initiating treatment by the

parenteral route and then switching to the oral route may reduce the emetic symptoms.35 Sedation The opioid analgesics produce sedation and drowsiness. Although these effects may be useful in certain clinical situations (e.g., preanesthesia), they are not usually desirable concomitants of analgesia, particularly in ambulatory patients. The CNS-depressant actions of these drugs can be expected to be at least additive with the sedative and respiratory depressant effects of sedative–hypnotics such as alcohol, the barbiturates, and the benzodiazepines. Although it has been suggested that methadone produces more sedation than morphine, this has not been supported by single-dose controlled trials or surveys in hospitalized patients.35 However, the half-life of methadone is substantially longer than that of morphine and may result in cumulative CNS depression after repeated doses. A reduction in dose and interval so that a lower dose is given more frequently may counteract excessive sedation. In addition, other CNS depressants that potentiate the sedative effects of opioids, such as sedative–hypnotics and antianxiety agents, should be discontinued. Concurrent administration of dextroamphetamine in 2.5- to 5.0-mg oral doses twice daily has been reported to reduce the sedative effects of opioids. Tolerance usually develops to the sedative effects of opioid analgesics within the first several days of chronic administration. Constipation The most common adverse effect of the opioid analgesics is constipation. These drugs act at multiple sites in the gastrointestinal tract and spinal cord to produce a decrease in intestinal secretions and peristalsis, resulting in a dry stool and constipation. Tolerance develops slowly to the smooth muscle effects of opioids, so constipation will persist when these drugs are used for chronic pain. When the use of opioid analgesics is initiated, provision for a regular bowel regimen, including cathartics and stool softeners, should be instituted to diminish this adverse effect. Urinary retention Because the opioid analgesics increase smooth muscle tone, they can cause bladder spasm and an increase in sphincter tone, leading to urinary retention. This is most common in the elderly patient. Attention should be directed at this

pharmacology of analgesia: basic principles potential side effect, and catheterization may be necessary to manage this transient side effect. Multifocal myoclonus At high doses, all the opioid analgesics can produce multifocal myoclonus.32 This complication is most prominent with the use of repeated administration of large parenteral doses of meperidine (e.g., 250 mg or more per day). As previously discussed, accumulation of normeperidine is responsible for this toxicity. Opioid tolerance and opioid-induced hyperalgesia Tolerance develops when a given dose of an opioid produces a decreasing effect, or when a larger dose is required to maintain the original effect. Some degree of tolerance to analgesia appears to develop in most patients receiving opioid analgesics chronically.36 The hallmark sign of the development of tolerance is the patient’s complaint of a decrease in the duration of effective analgesia. The rate of development of tolerance varies greatly among cancer patients, so some will demonstrate tolerance within days of initiating opioid therapy whereas others will remain well controlled for many months on the same dose.37 A sudden dramatic increase in opioid requirements may represent a progression of the disease rather than the development of tolerance per se. In these patients, objective evidence of progression of disease is sought and pain management techniques reevaluated accordingly.37 With the development of tolerance, increasing the frequency and/or the dose of the opioid are required to provide continued pain relief. Because the analgesic effect is a logarithmic function of the dose of opioid, a doubling of the dose may be required to restore full analgesia. There appears to be no limit to the development of tolerance and, with appropriate adjustment of dose, patients can continue to obtain pain relief. Preclinical studies suggest that apparent opioid tolerance may result from excitatory CNS changes that facilitate transmission of pain and increase the sensitivity to pain.38 This condition is termed opioid-induced hyperalgesia (OIH). The basic phenomenon appears to result from the upregulation of pronociceptive systems. The neuroanatomical substrates and signaling pathways involved in OIH are emerging.38 However, the magnitude of the contribution of OIH to clinical opioid tolerance and its consequences for continued opioid therapy remain controversial. There is general agreement that during opioid withdrawal, OIH may occur and contribute to an exacerbation

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of pain.39 Therefore, acute withdrawal should be avoided. Switching from a morphine-like opioid to a mixed agonist– antagonist (pentazocine, nalbuphine, or butorphanol) or the partial agonist buprenorphine must be avoided because of these drugs’ ability to induce abrupt opioid withdrawal and cause concomitant hyperalgesia in opioid-dependent individuals.1 Using a combination of an opioid and a nonopioid may enhance analgesia and reduce the rate of tolerance development because tolerance does not develop to the nonopioid component of the mixture. Opioid dose-sparing strategies can be used at the initiation of opioid therapy. Rotation to an alternative mu opioid agonist usually results in a relative reduction of opioid dosage due to incomplete cross-tolerance (see later) among this class of opioids.40 The use of bolus or continuous epidural local anesthetics in patients with localized pain, such as perineal pain, may dramatically reduce the need for systemic opioids and thus diminish opioid tolerance.

Opioid dependence and addiction Physical and psychological dependence The properties of the opioid analgesics that are most likely to lead to their being misused, or the patient mistreated, are effects mediated in the CNS and seen following chronic administration, including psychological and physical dependence. It must be emphasized that although the development of physical dependence and tolerance are predictable pharmacologic effects seen in humans and laboratory animals in response to repeated administration of an opioid, these effects are distinct from the behavioral pattern seen in some individuals and described by the terms psychological dependence and addiction.41 Psychological dependence is used to describe a pattern of drug use characterized by a continued craving for an opioid that is manifest as compulsive drug-seeking behavior, leading to an overwhelming involvement with the use and procurement of the drug. Within these definitions, most but not all individuals who are addicted to opioids will have acquired some degree of physical dependence. However, the converse is not true: An individual may be physically dependent on an opioid analgesic without being addicted. Fear of addition is a major concern limiting the use of appropriate doses of opioids in hospitalized patients in pain. Physical dependence is the term used to describe the phenomenon of withdrawal when an opioid is abruptly discontinued or if an opioid antagonist is administered. The severity of withdrawal is a function of the dose and duration

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178 of administration of the opioid just discontinued (i.e., the patient’s prior opioid exposure). The administration of an opioid antagonist to a physically dependent individual produces an immediate precipitation of the withdrawal syndrome. Patients who have received repeated doses of a morphine-like agonist to the point at which they are physically dependent may experience an opioid withdrawal reaction when given a mixed agonist-antagonist. Prior exposure to a morphine-like drug can be shown to greatly increase a patient’s sensitivity to the antagonist component of a mixed agonist-antagonist. Therefore, for chronic pain, the mixed agonist-antagonist opioids should be tried before initiating prolonged administration of a morphine-like agonist. The abrupt discontinuation of an opioid analgesic in a patient with significant prior opioid experience will result in signs and symptoms characteristic of the opioid withdrawal or abstinence syndrome.41 The time course of the withdrawal syndrome is a function of the elimination halflife of the opioid to which the patient has become dependent. Abstinence symptoms will appear within 6–12 hours and reach a peak at 24–72 hours following cessation of a short–half-life drug such as morphine, whereas onset may be delayed for 36–48 hours with methadone, a long–halflife drug. Therefore, it is important to emphasize that even in a patient in whom pain has been completely relieved by a procedure (e.g., a cordotomy), it is necessary to slowly decrease the opioid dose to prevent withdrawal. Experience indicates that the usual daily dose required to prevent withdrawal is equal to approximately one fourth of the previous daily dose. This dose, called for want of a better term the detoxification dose, is given in four divided doses. The initial detoxification dose is given for 2 days and then decreased by one half (administered in four divided doses) for 2 days until a total daily dose of 10–15 mg/day (in morphine equivalents) is reached; after 2 days on this dose, the opioid can be discontinued. Thus, a patient who had been receiving 240 mg/day of morphine for pain would require an initial detoxification dose of 60 mg given in 15-mg increments every 6 hours. Alternately, the patient may be switched to the equieffective oral analgesic dose of methadone, using one fourth of this dose as the initial detoxification dose and proceeding as described previously. Although beyond the scope of this chapter, it is important to note that the recent rise in prescription opioid abuse may result in regulations that are intended to decrease the diversion of opioids (see Chapter 27). If a proper balance is not achieved between the needs of society to limit opioid diversion and the needs of pain patients, then an unintended but

inevitable consequence of these regulations may be limits on the availability of opioids for cancer pain management. References 1. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain 18:S3–13, 2002. 2. Gutstein HB, Akil H. Opioid analgesics. In: Bruton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill, 2006, pp 547– 90. 3. Lotsch J, Geisslinger G. Current evidence for a genetic modulation of the response to analgesics. Pain 121:1–5, 2006. 4. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain, 5th ed. Glenview, IL: American Pain Society, 2003. 5. World Health Organization. Cancer pain relief. Geneva: World Health Organization, 1986. 6. Farrar JT, Portenoy RK. Neuropathic cancer pain: the role of adjuvant analgesics. Oncology 15:1435–53, 2001. 7. Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol 66:285–306, 2002. 8. Terman GW, Bonica JJ. Spinal mechanisms and their modulation. In: Loeser JD, et al., eds. Bonica’s management of pain. Philadelphia: Lippincott Williams and Wilkins, 2001, pp 73– 152. 9. Inturrisi CE, Hanks GWC. Opioid analgesic therapy. In: Doyle D, Hanks GWC, MacDonald N, eds. Oxford textbook of palliative medicine, eds. Oxford: Oxford University Press. 1993, pp 166–82. 10. Portenoy RK, Thaler HT, Inturrisi CE, et al. The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function. Clin Pharmacol Ther 51:422–31, 1992. 11. Lotsch J. Opioid metabolites. J Pain Symptom Manage 29:S10– 24, 2005. 12. Tiseo PJ, Thaler HT, Lapin J, et al. Morphine-6-glucuronide concentrations and opioid-related side effects: a survey in cancer patients. Pain 61:47–54, 1995. 13. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 27:524–8, 2000. 14. Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther 289:1048–53, 1999. 15. Cruciani RA, Sekine R, Homel P, et al. Measurement of QTc in patients receiving chronic methadone therapy. J Pain Symptom Manage 29:385–91, 2005. 16. Fredheim OM, Borchgrevink PC, Hegrenaes L, et al. Opioid switching from morphine to methadone causes a minor but not clinically significant increase in QTc time: a prospective 9-month follow-up study. J Pain Symptom Manage 32:180–5, 2006. 17. Krantz MJ, Lowery CM, Martell BA, et al. Effects of methadone on QT-interval dispersion. Pharmacotherapy 25:1523–9, 2005.

pharmacology of analgesia: basic principles 18. Kaiko RF, Foley KM, Grabinski PY, et al. Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol 13:180–5, 1983. 19. Donner B, Zenz M, Tryba M, Strumpf M. Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain. Pain 64:527–34, 1996. 20. Portenoy RK, Southam MA, Gupta SK, et al. Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics. Anesthesiology 78:36–43, 1993. 21. Mayes S, Ferrone M. Fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain. Ann Pharmacother 40:2178–86, 2006. 22. Egan TD, Sharma A, Ashburn MA, et al. Multiple dose pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers. Anesthesiology 92:665–73, 2000. 23. Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev CD004311, 2006. 24. Darwish M, Kirby M, Robertson P Jr, et al. Absolute and relative bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl citrate. J Clin Pharmacol 47:343–50, 2007. 25. Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand 45:795–804, 2001. 26. Kerr IG, Sone M, Deangelis C, et al. Continuous narcotic infusion with patient-controlled analgesia for chronic cancer pain in outpatients. Ann Intern Med 108:554–7, 1988. 27. Ferrante FM, Orav EJ, Rocco AG, Gallo J. A statistical model for pain in patient-controlled analgesia and conventional intramuscular opioid regimens. Anesth Analg 67:457–61, 1988. 28. Coyle N, Mauskop A, Maggard J, Foley KM. Continuous subcutaneous infusions of opiates in cancer patients with pain. Oncol Nurs Forum 13:53–7, 1986.

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29. Sabbe MB, Yaksh TL. Pharmacology of spinal opioids. J Pain Symptom Manage 5:191–203, 1990. 30. Laird B, Colvin L, Fallon M. Management of cancer pain: basic principles and neuropathic cancer pain. Eur J Cancer 44:1078– 82, 2008. 31. Cousins MJ, Plummer JL. Design of studies of spinal opioids in acute and chronic pain. In: Max MB, Portenoy RK, Laska EM, eds. The design of analgesic clinical trials. New York: Raven Press, 1991, pp 457–80. 32. Bruera E, O’Pereira J. Neuropsychiatric toxicity of opioids. In: Jensen TS, Turner JA, Wiesenfeld-Hallin Z, eds. Proceedings of the 8th World Congress on Pain. Seattle: IASP Press, 1997, pp 717–38. 33. Gal TJ. Naloxone reversal of buprenorphine-induced respiratory depression. Clin Pharmacol Ther 45:66–71, 1989. 34. Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleepdisordered breathing and chronic opioid therapy. Pain Med 9:425–32, 2008. 35. Foley KM. Problems of overarching importance which transcend organ systems. In: Bennett JC, Plum F, eds. Cecil’s textbook of medicine. Philadelphia: Saunders, 1996. 36. McQuay H. Opioids in pain management. Lancet 353:2229–32, 1999. 37. Kanner RM, Foley KM. Patterns of narcotic drug use in a cancer pain clinic. Ann N Y Acad Sci 362:161–72, 1981. 38. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 104:570–87, 2006. 39. Carroll IR, Angst MS, Clark JD. Management of perioperative pain in patients chronically consuming opioids. Reg Anesth Pain Med 29:576–91, 2004. 40. Inturrisi CE. Opioid rotation. In: Schmidt RF, Willis WD, eds. Encyclopedia of Pain. Berlin, Heidelberg, New York: Springer, 2007, pp 1561–4. 41. O’Brien C. Drug addiction and drug abuse. In: Bruton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill, 2006, pp 607–27.

10

Pharmacogenetic considerations in the treatment of cancer pain ˚ klepstad p al

St. Olavs University Hospital and Norwegian University of Science and Technology

Introduction Pain perception shows interindividual variability. This variability is partly related to gender and ethnicity, suggesting that genetic factors cause interindividual differences in pain.1–3 Besides genetic variability related to pain perception, genetic variants are associated with painful conditions such as migraine or fibromyalgia.4,5 Finally, and the primary focus of this book chapter, the pain experience may be subject to genetic variability related to efficacy of analgesics.6,7 For cancer pain, this variability is supported by the large variations among individuals in opioid doses needed for pain control, a variation that partly remains if the observations include patients at a defined stage of cancer pain.8,9 Similar variations in need for opioid doses are observed in studies in patients receiving opioids for postoperative pain following a standardized surgical procedure, even when factors such as pain intensity or age are controlled.10,11 The complexity of genetic variability related to drug effects is high. Most drugs effects, including those of opioids, are influenced by several gene products. These gene products are involved in both pharmacokinetics (metabolism and transport) and pharmacodynamics (receptor interaction, opioid signaling, and modulation of opioid effects).12 Thus, effects elicited by opioids are truly polygenic traits. In addition, genes can interact with one another. Interactions between genes – gene joint effects – may enhance, suppress, or have no effect on the outcome.13

the same phenomenon as a mutation, but the term SNP usually is used for changes more frequent than 1%. An SNP may be silent, which means that the change in DNA base does not change the amino acid sequence of the protein, or an SNP may be a conservative missense SNP, in which the amino acid sequence is altered but the shift in amino acid sequence does not influence protein function. Both these SNPs are clinically of no consequence. The SNPs of clinical interest in the coding part of the DNA are the nonconservative missense polymorphism. For these polymorphisms, the change in DNA base results in an amino acid change, which alters protein function (i.e., increases enzyme activity). Finally, there are SNPs that change the DNA base triplet to a stop codon that effectively stops the production of the protein (Fig. 10.1).14 Only SNPs located in the coding part of the DNA can change the structure of the protein. However, SNPs located in the noncoding part of a gene can influence the expression of the gene; that is, function is altered not by changing the structure of the protein but by changing the amount of protein produced. Furthermore, it has been proposed that polymorphisms in the noncoding part of the DNA also can affect the timing

Mechanisms of genetic variation Single nucleotide polymorphisms A single nucleotide polymorphism (SNP) is a change in a single DNA base in the DNA sequence. An SNP represents

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Fig. 10.1. Single nucleotide polymorphisms.

pharmacogenetic considerations in the treatment of cancer pain

DNA

Exon

Exon

Exon

181

Exon 3

5 Transcription pre 5′

AAAAAA

“Splicing” of exons Protein mRNA A

5′

B

5′

C

5′

1

2

3

4 AAAAAA

1

3

4 AAAAAA

1

2

A

B

4 AAAAAA

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Fig. 10.2. Alternative splicing of DNA to mRNA may result in different proteins originating from the same gene.

of cotranslational folding and insertion of the protein into membranes, thereby altering the three-dimensional structure of the protein.15 The SNPs within one gene often are linked with each other, which means they will be inherited as blocks consisting of two or more SNPs. As a consequence, for many genes it is too simplistic to analyze genetic variability as related to a single SNP. For these genes, haplotypes are constructed, with each haplotype consisting of a certain combination of SNP variations. One example of genetic research progressing from analyses related to one SNP to those based on combinations of SNPs as haplotypes is the catecholO-methyltransferase gene (COMT), described later in this chapter.16–19 The nomenclature concerning SNPs is confusing. An SNP may be named after its nucleotide substitution, the change of amino acid associated with the SNP, or adherence to the single nucleotide polymorphism database (dbSNP) system.20 For instance, one of the SNPs within the opioid receptor mu 1 gene (OPRM1) is named in various sources as the A118G polymorphism (nucleotide shift), the 118 A⬎G polymorphism (nucleotide shift), the N40D polymorphism (the amino acid change), or the rs1799971 polymorphism (the dbSNP system).21 To facilitate recognition among readers, the polymorphisms described in this book are named adhering to the usual term applied for each particular SNP in the existing literature.

Splice variants Genetic variability in OPRM1 may be caused by mechanisms other than SNPs. Differences in selection of exon regions during translation to messenger RNA (mRNA) may result in one gene producing different mRNA variants (splice variants) (Fig. 10.2). Animal studies have identified that differences in selection of exon regions during translation to mRNA result in multiple mu-opioid receptor variants (splice variants).22,23 Animal studies have shown that opioid receptor splice variants have different analgesic responses and adverse effects from morphine and morphine-6-glucuronide (M6G).24 The presence of different opioid receptor splice variants adds complexity to opioid pharmacology, as the distribution of the variants vary between different parts of the central nervous system (CNS) and because more than one splice variant can coexist in one specific part of the pain pathways. Within the brain area with coexisting slice variants, the distribution of splice variants is specifically organized at an ultrastructural level.25,26 It is speculated that the preclinical findings of splice variant OPRM1 biology explain clinical issues such as interindividual differences in efficacy between opioids, a principle applied clinically in opioid rotation, and the potential synergism between opioids.27,28 Pan et al.29 reported the identification of mu-opioid receptor splice variants in the human brain. Supported by evidence from animal

182 studies, the human splice variants are hypothesized to influence clinical opioid efficacy, but this phenomenon has not yet been studied in clinical trials.

Genetic variation of pain sensitivity It is well established through experimental studies that pain sensitivity is influenced by genetic disposition and that the proportional influence from genetics on nociception is different for different nociceptive stimuli.30,31 Traditional twin studies of various models of human experimental pain confirm that genetic factors contribute to some of the variability in pain sensitivity.32 The importance of genetics in pain sensitivity is also supported by ethnic differences in humans.33 Some of the genes believed to be important for opioid efficacy may also influence pain perception. Carriers of the G118 allele in OPRM1 have decreased cortical activation induced by painful stimuli in healthy volunteers34 and higher pressure pain thresholds for experimental pain.35 Another example of a gene related to both opioid efficacy and variations in pain perception is COMT. Zubieta et al.,16 using positron emission tomography, showed that individuals homozygous for the met158 allele in COMT had decreased opioid activation and more pain following a painful stimulus. This changed nociceptive response due to variability in COMT recently was linked to altered adrenergic activation.36 However, although data from experimental studies are convincing, little is known about the influence of genetic variability on clinical pain, including the pain associated with a malignant disease.

Pharmacological targets for genetic variation Opioid metabolism Genetic variability in genes coding enzymes may affect opioid metabolism. For opioids with biologically inactive or low-activity metabolites, such as fentanyl and methadone, decreased metabolism results in increased opioid efficacy, whereas for opioids whose metabolites have high biological activity, such as the conversion of codeine to morphine37 and morphine to M6G, increased metabolism results in a more pronounced opioid effect.38,39 The CYP2D6 gene has several polymorphisms, resulting in about 100 different alleles that can change CYP2D6 activity.40 The influence of genetic variability in the CYP2D6 gene on codeine analgesia, which is increased in utrarapid metabolizers and decreased in slow metabolizers, is well established.41 In experimental pain models, CYP2D6 slow metabolizers are shown to have inferior

p. klepstad pain relief. Despite the fact that the relationship between CYP2D6 activity and the analgesic action of codeine is widely recognized, it is worthwhile to mention that the findings from some clinical studies are less consistent.37,42,43 CYP2D6 variability may also influence the metabolism of dihydrocodeine, hydrocodone, and oxycodone,44–48 but the clinical consequences of CYP2D6 variability for these opioids are not established. The clinical importance of CYP2D6 variability on another substrate for the enzyme, tramadol, is also uncertain as some studies observe a difference in tramadol pharmacokinetics and efficacy and others do not.49,50 In some investigations, CYP2D6 ultrarapid metabolizers were shown to have lower methadone serum concentrations in patients undergoing opioid maintenance treatment;51,52 however, this finding was not replicated in a recent study by Coller et al.53 Other CYP enzymes genes, which are proposed to influence the variability of methadone serum concentrations, are CYP3A4, CYP2C8, and CYP2B6 gene.51,54,55 However, an influence of genetic variability from these genes was not supported by a study on the effects of methadone in a human experimental model using pupillary constriction as a proxy measure for opioid efficacy. In this study, none of the CYP enzymes studied (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A5) was associated with variable methadone effects caused by CYP gene variations.56 Furthermore, in the study by Crettol et al.54 showing that CYP2B6 variability influences methadone pharmacokinetics, this variability was not reflected clinically in a change of success for methadone used as maintenance treatment in opioid addicts. The influence on genetic variability for metabolism of morphine is not established. The conversion from morphine to M6G is catalyzed in the liver by the UGT2B7 enzyme.57 In a study including cancer pain patients, 12 SNPs were identified in the UGT2B7 gene (Fig. 10.3), but this study did not find any differences in M6G/morphine ratios between the genotypes.58 A later study by Sawyer et al.59 included 99 patients receiving patient-controlled morphine, mostly for postoperative pain. This study observed a trend for decreased M6G/morphine ratios in patients homozygous for tyrosine at position 802 in the UGT2B7 gene. The two studies were different in terms of origin of pain (cancer vs. postoperative) and ethnicity (Caucasian only vs. a mixed population of Caucasian and African Americans). Finally, a study on a polymorphism located in the regulatory part of UGT2B7 (SNP –79 G⬎T) showed that carriers of the nondominant allele had significantly lower levels of M6G compared with wild-type patients.60 Thus, genetic variability may influence the activity of the UGT2B7 enzyme, not

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Fig. 10.3. Sequence variations caused by SNPs in the human UGT2B7 gene.

through a change in enzyme configuration but by altered expression of the gene and, hence, altered enzyme activity. Finally, and perhaps more important, variable UGT2B7 activity may be the result of changes in the regulation of UGT2B7 expression. One factor involved in the regulation of UGT2B7 gene expression is hepatocyte nuclear factor1␣.61 Genetic variation in the gene coding this regulatory factor can indirectly influence UGT2B7 activity. However, although genetic variability in the UGT2B7 gene may or may not influence serum concentrations of morphine and metabolites, present studies have not shown that this variability translates into altered morphine consumption58,62 or the need for an opioid switch from morphine.63 Thus, the clinical influence from UGT2B7 genetic variability for patients receiving morphine is limited. Also, the potential influence from the UGT1A1 gene, the gene associated with Gilbert syndrome, has been investigated in relation to morphine pharmacokinetics. None of these studies showed any influence on morphine pharmacokinetics from variability within the UTG1A1 gene.64,65

Opioid receptors The low association between serum concentrations of opioids and clinical outcomes suggests that some of the interindividual variability in opioids is related to ligand interaction with the OPRM1 receptor.66 Hoehe et al.67 identified 43 variants within the OPRM1 gene, several of which result in an altered amino acid sequence of OPRM1 (Fig. 10.4). One of these SNPs results in an amino acid substitution at position 268 (serine → proline), which strongly impairs receptor signaling after stimulation with opioid agonists, including morphine.68,69 This observation is of principal interest because it establishes that genetic variability has the potential to change receptor function. However, because of the low frequency of this variation (one of 250 individuals was heterozygous), the significance of this SNP for the population variability of opioid efficacy is limited. Also, other polymorphisms located together with the S286P polymorphism in the third intracellular loop of OPRM1, R260H and R265H, reduce signaling,68 again showing that

N40D A6V S4N

NH2 EXTRACELLULAR N152D

S147C

R260H COOH

INTRACELLULAR

R265H S268P

D274N

Fig. 10.4. The mu-opioid receptor consists of an extracellular, a transmembrane, and an intracellular part. The figure identifies SNPs that result in an altered amino acid sequence in the mu-opioid receptor.

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184 changes in the part of the receptor interacting within the cell have functional consequences. However, these polymorphisms also are too infrequent to have any importance in population variability. A more common SNP associated with a change in the amino acid sequence is an A to G substitution (A118G), located in the extracellular part of the OPRM1 receptor. The frequency of the 118G variant allele is about 10%– 14% in Caucasians.67 Experimental studies have shown that the118G allele decreases OPRM1 mRNA and OPRM1 protein production.70 Human experimental studies using pupillary constriction as a proxy measure for opioid efficacy observed reduced response in carriers of the G allele after M6G or morphine administration.71,72 More experimental evidence for the effect of A118G polymorphisms was supplied by Romberg et al.,73,74 who in two studies on human experimental pain showed that patients with the G allele needed about a threefold M6G serum concentration to increase their threshold to painful electric stimulation, and by Oertel et al.,75 who showed that higher alfentanil doses are needed to produce the same degree of analgesia for experimental electrical and chemical pain. The experimental finding of decreased opioid efficacy in individuals with the variant 118G allele has been confirmed in clinical studies. Cancer patients homozygous for the variant needed about twice the morphine doses needed by wildtype patients to achieve adequate pain relief. This difference also was reflected in serum concentrations of morphine and M6G.76 The patients homozygous for the variant allele also have less pain relief after starting with morphine for cancer pain.77 Corresponding results supporting the interaction of the A118G polymorphism with opioids also were reported for alfentanil and morphine doses used for postoperative pain78–80 and for the miotic potency of levomethadone.56 The same relationship between A118G genotype and morphine efficacy was observed for morphine given by the intrathecal route for postcesarean analgesia.81 However, some studies did not demonstrate an influence of the A118G polymorphism on acute postoperative opioid analgesic requirements62,82 and failed to find an effect of the A118G polymorphism on binding and receptor signalling after opioid stimulation.83 In a study of the use of intrathecal fentanyl for labor pain, Landau et al. observed that women with the 118G allele needed less fentanyl for pain control.84 This finding of an opposite direction in the change of opioid sensitivity compared to the observations in other studies may be caused by labor pain representing a different pain modaility. Moreover, experimental studies showed the opposite of what has been observed with

exogenously administered opioids: The binding and activity of ␤-endorphin, an endogenous opioid, are increased in the variant receptor.85 However, these studies have partly compared homozygous wild-type patients with heterozygous patients, whereas the major difference observed in the positive clinical studies has been observed for the homozygous variant patients.76,79 The other polymorphisms of the OPRM1 gene, which are present in clinically relevant frequencies, do not influence the clinical efficacy of morphine.76 As for the UGT2B7 gene, polymorphisms in the noncoding part of the OPRM1 gene also may influence the production of the protein. In neuroblastoma cell lines, two polymorphisms, G-554A and A-1320G, were associated with mRNA transcription and hence resulted in altered OPRM1 expression.86 The allele frequency of the -1320G allele previously was shown to be 9.1% in an African-American population but only 0.2% in the Caucasian population included in this study, thereby excluding the possibility of assessing any association with clinical outcomes. An intriguing result of a polymorphism demonstrated in in vitro assays and in an animal study is that a polymorphism changing serine to alanine or leucine at position 196 changed the properties of naloxone from an antagonist to a partial agonist, eliciting antinociceptive effects.87 As this polymorphism is not relevant in humans, this finding has no practical consequences; however, it points out potential directions for future gene therapy. Also, genetic variability in the opioid receptor, kappa 1 (OPRK1) and opioid receptor, delta 1 (OPRD1) genes theoretically may influence opioid efficacy, either because some opioids act partly on kappa or delta opioid receptors88 or because such variability could interfere with the interaction between endogenous and exogenous opioids. However, studies of genetic variation at opioid receptors other than OPRM1 are sparse. Kim et al.89 showed that males heterozygous for an SNP at the OPRD1 gene (T80G) had lower pain perception in a human experimental pain model. However, the genetic variations in these two genes have not been studied with respect to opioid efficacy. Opioid transport The effect sites, OPRM1 receptor–binding sites, are located primarily in the extracellular fluid in the CNS. Several opioids, including morphine, methadone, fentanyl, and loperamide, are transported from the brain through the blood– brain barrier by multidrug resistance (MDR) transporter proteins.90,91 Decreased function of the MDR transporters

pharmacogenetic considerations in the treatment of cancer pain has been shown in animal studies to increase the concentrations of morphine in the extracellular fluid of the brain and to increase the antinociceptive efficacy of morphine.92 The influence of abolished MDR transporter activity varies between opioids, with no influence on meperidine to an eightfold increase in CNS loperamide uptake.93 Genetic variability results in different functions of MDR transporters, and pharmacokinetic modeling has suggested that this variability causes differences in extracellular brain concentrations of morphine and M6G.94 To date, the information from clinical studies on the influence on opioid efficacy from SNPs in the MDR genes are inconsistent.90 A preliminary report observed that cancer patients with the 3435 C⬎T variant polymorphism, an SNP known to influence the expression of MDR transporters,95 need more morphine.96 Other studies have disputed this finding by showing a lack of influence by inhibiting MDR activity on respiratory depression or pupillary constriction after methadone or morphine administration to healthy volunteers,56,97 by observing that carriers of a haplotype including the 3435T allele needed less methadone during substitution treatment for addiction,51,98 by observing that cancer patients with the 3435T allele had a higher decrease of pain after start with morphine treatment,77 and by observing a more pronounced respiratory depression after intravenous fentanyl in patients with the 3435TT genotype.99 Furthermore, Crettol et al.51 observed that opioid maintenance patients homozygous for the T allele needed lower methadone serum concentrations. Finally, in a study on postoperative pain after colorectal surgery, Coulbault et al.62 observed that MDR polymorphisms did not influence the use of morphine for pain, and L¨otsch et al.56 did not observe a significant association between the MDR1 3435 C⬎T polymorphism and the miotic effect of methadone. Because of linkage between several of the MDR1 SNPs, haplotype analyses could be more appropriate. In line with this assumption, Coulbault et al.62 found that an MDR1 GG2677/CC3435 diplotype predicted better clinical effects than the two SNPs analyzed separately, and Coller et al.,98 who included three more SNPs in the haplotypes, found distinct haplotype groups needing more methadone for opioid maintenance treatment. The genotype G2677T/A included in the diplotype studied by Coulbault et al. also was recently associated with a higher frequency of sedation or hallucinosis in cancer patients treated with morphine.19 In summary, the current status of genetic variability in the MDR1 gene with respect to clinical efficacy of opioids is that despite the convincing results from animal research, the clinical evidence is still too scarce and conflicting to make a conclusion. Adding to the complexity is that opioids can be transported by other

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transporter proteins, such as MDR-associated proteins or organic anion-transporting polypeptides.100 The eventual influence on clinically used opioids from genetic variability in the genes coding these transporters has not been investigated.90 Nonopioid systems that influence opioid signaling Catecholamines Catecholamines and the descending inhibitory adrenergic system are well known to influence opioid analgesia.101 This interaction of nonopioid substances with opioid analgesia is used clinically by the addition of catecholamines as coanalgesics to enhance the efficacy of opioids.102 COMT metabolizes catecholamines such as dopamine, adrenaline, and noradrenaline. Low COMT activity can lead to increased pain sensitivity via ␤2 - or ␤3 -adrenergic mechanisms.36 A frequent polymorphism in the COMT gene results in a valine (Val) to methionine (Met) substitution, resulting in a threefold reduction in enzyme activity.103 Patients with the Met/Met genotype have lower concentrations of enkephalin,16 and might therefore be hypothesized to need more morphine to compensate for a reduction in endogenous enkephalin production. However, Zubieta et al.16 also observed an increase of mu-opioid receptors in individuals with the Met/Met genotype. This increase in the density of opioid receptors might result in an improved efficacy of opioids; therefore, patients with the Met/Met genotype might need lower opioid doses. The last hypothesis was confirmed in a clinical study in which cancer patients with the Val/Val genotype needed more morphine compared with the Val/Met and Met/Met genotype groups.17 Later studies have suggested that it may be too simplistic to analyze variability related to a single SNP in the COMT gene, reporting that the variability perhaps is related more to differences in haplotypes. Haplotypes of the COMT gene are related to central side effects of morphine,19 need of morphine doses by cancer patients,103 and protein expression of the COMT gene.18 These findings underline the potential importance of genetic variability, not in the opioid system per se but in other biological systems that interact with the opioid system, and of the complexity of genetic variability, which must be related not only to individual SNPs but also to patterns of SNPs. Melanocortin The role of melanocortin-1 receptor (MC1R) in pain perception and action of opioids is not established, but the receptor is found in the periaqueductal gray substance in the midbrain, an area crucial for pain signaling.104 Morphine

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186 and M6G had increased antinociceptive action in mice and analgesic effects with nonfunctional alleles of the MC1R gene. Similarly, M6G analgesic effects were increased in human volunteers with nonfunctional alleles of the MC1R gene.105 This change in opioid efficacy is speculated to be the result of less antiopioid action. An interesting observation is that for the kappa agonist pentazocine, this influence from MC1R gene variability was observed to be specific to women.106 Interleukin Interleukin (IL)-1␤ and its endogenous IL-1 receptor antagonist (IL-1Ra) are involved in pain modulation after inflammation and nerve injury.107 Bessler et al.108 studied the relation of variability in the IL-1␤ and IL-1Ra genes with morphine consumption after hysterectomy. Whereas IL-1␤ genetic variation was not related to morphine consumption, genetic polymorphisms in the IL-1Ra gene were associated with a medium need for morphine. However, this finding is intriguing as the patients needing a medium morphine dose were different from both low- and high-dose patients, and thus a lack of a gene dose effect was observed.

polymorphisms in STAT6 were associated with unsuccessful morphine treatment. The complexity of the regulation of OPRM1 gene transcription was further described in an experimental study by Kraus et al.112 In neuronal cultures, they showed that a polymorphism in the promoter part of the OPRM1 gene known to bind STAT6 decreased the transactivating potential of IL-4. This finding illustrates the close relationship between the immune system and the opioid system. Opioid tolerance Opioid tolerance in animal models is associated with downregulation of OPRM1 mRNA after exposure to morphine.113 After termination of morphine, the OPRM1 mRNA level is restored to control values. Thus, changes in genetic expression may be one of the mechanisms for development of opioid tolerance. However, no studies have reported whether the development of opioid tolerance is related to genetic variation in genes coding proteins involved in the process of developing opioid tolerance. Opioid hyperalgesia

Opioid signaling ␤-Arrestin-2 The binding of morphine to the OPRM1 receptor elicits a response from the cell. Still, studies of genetic variability in genes coding intracellular processes related to opioid analgesia are scarce. ␤-Arrestin-2 is a substance involved at several points in the intracellular sequence of events following opioid agonist stimulation. Animal research has shown that for ␤-arrestin-2 knockout mice, opioid analgesia is enhanced,109,110 respiratory depression and constipation caused by morphine are attenuated,110 and tolerance is inhibited.111 The potential clinical influence on variability in opioid efficacy caused by variation in the ␤arrestin-2 gene is supported in a study by Ross et al.63 This study observed that in patients treated for cancer pain, polymorphisms in the ␤-arrestin-2 gene were associated with the need to switch from morphine to an alternative opioid. STAT6 One of the substances involved in regulatng OPRM1 receptor expression is STAT6. The STAT6 gene has several SNPs, which make it a candidate for explaining genetic variation of opioid efficacy by changes in production of OPRM1 receptors. Clinical data on the consequences of STAT6 gene variability are limited, but Ross et al.63 observed that

Genetic variation may influence opioid hyperalgesia. Liang et al.114 showed in an animal study that genetic variability within the ␤2 -adrenergic receptor gene was associated with mechanical hyperalgesia and that this hyperalgesia was reversed by a ␤2 -adrenergic receptor antagonist. The close relationship between various nonopioid mechanisms and opioid-induced hyperalgesia was established previously and is further strengthened by the finding that variability in the ␤2 -receptor gene is also related to the risk for developing chronic pain.115 In animal studies, Liang et al.116 also observed a relationship between morphineelicited hyperalgesia and MDR1 haplotypes. However, for opioid hyperalgesia, again the lack of knowledge is more impressive than the actual knowledge of genetic factors contributing to the clinical variability of opioid-related effects.

Adverse effects If adverse effects are elicited by the same opioid mechanism as pain relief, the risk for opioid-induced adverse effects would be expected to increase parallel to changes in its analgesic efficacy. Contrary to a linear relationship between analgesia and adverse effects, the ideal genetic variability would be the one that increases the therapeutic window between analgesia and adverse effects. The implications of

pharmacogenetic considerations in the treatment of cancer pain genetic variability for adverse effects from opioids have been investigated in a few studies. Many of these studies included a small number of patients, used animal models, or used proxy measures of adverse effects. The findings are often conflicting, as exemplified by two studies on the influence of CYP2D6 variability on codeine-induced reduction in orocecal transit time. One study showed that extensive metabolizers decreased gastrointestinal motility;117 the other did not observe any such effect.118 Similar discouraging results for CYP2D6 variability and risk for adverse effects were observed in clinical studies assessing various adverse effects after codeine119 or oxycodone.47 For variability in the OPRM1 gene, Oertel et al.75 showed that homozygous carriers of the 118G allele needed two to four times more alfentanil for pain relief from electrical and chemically human experimental pain and 10–12 times more alfentanil to produce the same degree of respiratory depression. Thus, theoretically the variant carriers had a broadened therapeutic window. However, this finding did not agree with a study by Romberg et al.,74 who did not find an association between OPRM1 A118G polymorphism and hypoxic respiratory response following M6G administration. However, this study included only four individuals who were homozygous and none who were heterozygous for the variant 118G allele. Some preliminary data exist from animal studies showing that for ␤-arrestin-2 knockout mice, opioid analgesia is enhanced whereas respiratory depression and constipation caused by morphine are attenuated.110 This finding was supported in a clinical study by Ross et al.,63 who observed that genetic variation in the ␤-arrestin-2 gene was associated with a need for opioid change from morphine to an alternative opioid. The study by Ross et al.63 also observed that polymorphisms in the STAT6 gene were associated with the need for an opioid switch. This observation may be associated with altered STAT6 regulation of OPRM1 transcription. Ross et al.19 also reported that variability in the MDR1 and COMT genes is associated with the risk for central side effects from morphine. In summary, regarding the relationship between opioidinduced adverse effects and genetic variability, the available information is not sufficient to present a solid conclusion.

Genetic variation for different analgesics Codeine The influence from genetic variability on the pharmacokinetics of codeine is well recognized. The enzyme CYP2D6 converts codeine to its more active metabolite,

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morphine. Several variant alleles of the CYP2D6 gene are nonfunctional and if homozygous result in poor codeine metabolism. Because poor metabolizers convert less codeine to the more active metabolite, morphine, patients with these variant alleles will experience inferior analgesic treatment with codeine.37,42,43 This is clinically relevant as about 7% of the Caucasian population are poor CYP2D6 metabolizers.41 Opposite these observations in poor metabolizers, other patients are fast metabolizers because of other variant CYP2D6 gene alleles. Such gene variants, which are common in Asians, increase the opioid efficacy of codeine. Tramadol Tramadol is also metabolized to its active metabolite, Odesmethyltramadol, by CYP2D6, and poor metabolizers have decreased analgesic effects from tramadol.50,120 However, because tramadol also exerts its analgesic effects through nonopioid mechanisms, the efficacy of tramadol is only partly reduced in poor metabolizers.49 Morphine Traditionally, the interindividual variation in analgesic efficacy has been explained by variable bioavailability, differences in pain stimuli, and variation in metabolism.121,122 However, in cancer patients, the serum concentrations of morphine and M6G are not closely associated with morphine clinical effects.123 Therefore, factors other than bioavailability or metabolism must contribute to the interindividual variability. Such factors may be differences in pharmacodynamics or in transport of morphine to its effect site. Hence, as outlined earlier, several studies investigated whether genetic variability in genes coding opioid receptors, opioid transporters, or opioid-modulating systems can explain the differences in morphine potency observed in the clinic. In summary, several studies originating from more than one research group established that two genes have genetic variability causing variable morphine efficacy. First, the A118G polymorphism in the OPRM1 gene has been shown in human experimental models,71–74 in cancer pain,76,77 and in postoperative pain79,81 to decrease morphine or M6G efficacy. Second, variations in the COMT gene, either as the Val158Met polymorphism or as haplotype variants, are associated with the potency of morphine given to cancer pain patients17,103 and the success rate of morphine treatment in cancer pain patients.19 Several other genes have been studied in relation to morphine efficacy, but the findings obtained so far

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188 for these gene candidates are negative, inconclusive, or not confirmed. Oxycodone The metabolism of oxycodone is influenced by variability in the CYP2D6 and CYP3A4 genes.46 However, in the only study investigating cancer pain patients, inhibiting CYP2D6 activity did not result in any changed clinical action of oxycodone. Whether oxycodone is also subject to genetic variation similar to that of morphine in its interaction with the OPRM1 receptor or its interaction with the adrenergic system has not been studied. Fentanyl Studies investigating the relation between use of fentanyl and genetic variability are nearly nonexistent. Landau et al. demonstrated that patients with the OPRM1 118G allele had improved efficacy of intrathecal fentanyl for labor pain.84 A minor finding is that in Koreans, a more pronounced respiratory depression was observed after intravenous fentanyl in patients with the MDR1 3435TT genotype.99 As for oxycodone, the lack of information precludes any firm conclusions regarding the influence of genetic variations on fentanyl efficacy. Alfentanil Variability in the activity in CYP3A4 changes the metabolism of alfentanil,124 but this variation has not been coupled to any specific genetic variations. Alfentanil seems to be subject to the same influence from the OPRM1 A118G polymorphism as morphine. Caracao et al.78 reported in an abstract that variant carriers needed more alfentanil for postoperative pain. As stated earlier, Oertel et al.75 observed that homozygous carriers of the A118G variant gene needed two to four times more alfentanil for pain relief in a human experimental pain model and 10–12 times more alfentanil to produce the same degree of respiratory depression. Thus, theoretically the variant carriers had a broadened therapeutic window. However, this finding so far has not been reproduced. Methadone CYP2D6 ultrarapid metabolizers have lower methadone serum concentrations in patients undergoing opioid maintenance treatment.51,52 Other CYP enzymes for which variability influences methadone serum concentrations are

CYP3A4, CYP2C8, and CYP2B6.51,54,55 However, these genetic variations related to methadone metabolism by CYP enzymes are not reflected in changes in methadone efficacy as measured by pupillary constriction and success during opioid maintenance treatment.54,56 To some extent, methadone has been assessed for the influence from variation in the genes studied for morphine. Carriers of the OPRM1 A118G polymorphism had decreased miotic responses to methadone administration,56 and carriers of a haplotype including the 3435T allele needed less methadone during substitution treatment for addiction.51 However, although these results point toward some contribution from genetic variability to methadone efficacy, no data are available for the relationship of methadone genetics to pain in general or to cancer pain specifically.

General considerations for genetic research and opioids The studies available today do not give confident information about the relationship between genetic variability and opioid efficacy for symptoms other than pain, and about the contribution from genetic variability to the efficacy for several of the opioids given to cancer pain patients. It is also likely that in the future, genes other than those studied so far will be identified as important for opioid efficacy. Such genes can involve genes logically associated with opioid mechanisms or new genes. Studies applying techniques such as genome-wide SNP association studies with artificial intelligence analysis techniques or microarray techniques are in progress to identify potential new candidate genes contributing to variability in opioid pharmacology.125 Some other general issues related to studies of opioids and genetics that merit consideration are described in the following sections. Ethnicity It is important to not directly compare different populations and to address potential bias from having a patient population with several ethnicities. For obvious reasons, the latter is a larger problem in studies originating from regions with ethnic diversity, such as North America, and less problematic in studies from more homogenous populations, such as in northern Europe. Ethnicity will influence findings if there are alleles with different frequencies in different ethnic groups, or if there are differences between the populations with respect to other non-genetic issues (e.g., socioeconomic conditions). The simple method used to get some control of this potential bias is to compare the allele

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Table 10.1. Genes, which are candidates to be involved in opioid pharmacology Gene

Mechanisms of action

Drugs studied

Clinical evidencea

␤2 -Adrenergic receptor ␤2 -Adrenergic receptor antagonist ␤-arrestin-2 COMT CYP3A4

Opioid hyperalgesia Opioid hyperalgesia Opioid signaling Adrenergic action Metabolism

No No Uncertain Yes Uncertain

CYP2B6 CYP2D6

Metabolism Metabolism

MC1R

Unknown

MDR1

Opioid transport Opioid hyperalgesia

IL-1 receptor antagonist OPRM1

Unknown Opioid receptor function

STAT6 UGT2B7

Opioid receptor expression Morphine metabolism

Morphine Morphine Morphine Morphine Methadone Oxycodone Methadone Codeine Methadone Tramadol Morphine M6G Pentazocine Fentanyl Morphine Methadone Morphine Morphine Alfentanil Naloxonenaltrexone Methadone Morphine M6G Morphine Morphine

a

Uncertain Yes Uncertain Uncertain No Uncertain Yes

Uncertain Uncertain

Clinical evidence is defined as present for genes shown to contribute to variability in opioid outcome in two or more studies performed by two or more study centers, and where the available studies in general show an effect.

frequency and outcomes before pooling the results from different ethnic groups.126 Samples of the population A major limitation of clinical genetic research is low sample sizes. In general, the clinical papers included in the references for this chapter include 100 to about 200 patients in each study, with several examples of studies including fewer patients. Several genetic variations are relatively infrequent, and patients in clinical cohorts are subject to multiple confounders, which must be controlled in the analyses. These points emphasize the need to perform studies with larger samples size. The benefit of having a larger sample size is also evident by the fact that a linear increase in sample size exponentially increases the number of candidate genes that can be included in the analyses.126,127 Statistics Many studies investigate several potential genetic variations, thereby often finding by chance at least one SNP that

is statistically associated with the outcome studied. Therefore, findings of genetic association should be replicated in another sample, and the plausibility could be demonstrated by basic animal or laboratory studies showing the biological parallel to the clinical observation.128 Furthermore, the investigators studying an outcome must recognize that the outcome may be related to several different genes; an example of such an outcome, as reviewed in this chapter, is the genetics related to opioid efficacy. Owing to the several gene candidates for pain or opioid efficacy, new studies that are investigating only one or two such candidates should be discouraged. This view is emphasized by the understanding that genetic variations may be linked or may cancel each other out, or that the combination of two variations may result in a synergism (gene joint effect).13 Linkage of gene variants can explain that although there is an association between one gene variant and an outcome, this association does not necessarily reflect a causal relationship. The true gene variant causing the change in phenotype may be a gene variant linked to the studied gene variant, the former may be located in a gene not even known to have a relationship with the studied outcome.

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Conclusion Some of the clinically observed interindividual variability in efficacy of opioids is related to genetic variability. However, a well-established clinical relevance for genetic variability so far is present in only three genes: CYP2D6, OPRM1, and COMT. For other opioids or other candidate genes, clinical data are not available or the data are too limited for a firm conclusion (Table 10.1). Current guidelines for the treatment of cancer pain have been developed with the aim of giving the best pain treatments for large populations and hence are not tailored to individualized treatment. Although treatment guidelines lead to improved pain relief for large populations, they still do not result in optimal pain control for all patients. The findings from genetic research strongly suggest that increased understanding of the genetic basis of pain perception and efficacy of analgesics could in the future evolve into the ability to predict an individual response to opioids, thus bringing cancer pain therapy from population guidelines to individually guided treatment.

Acknowledgments This chapter was written on behalf of the Pain and Palliation Research Group at the Medical Faculty, Norwegian University of Science and Technology.

Abbreviations COMT IL-1␤ IL-1Ra MC1R MDR mRNA M6G OPRD1 OPRK1 OPRM1 SNP UGT1A1 UGT2B7

catechol-O-methyltransferase interleukin-1␤ interleukin-1 receptor antagonist melanocortin-1 receptor multidrug resistance messenger RNA morphine-6-glucuronide opioid receptor, delta 1 opioid receptor, kappa 1 opioid receptor, mu 1 single nucleotide polymorphism UDP-glucuronosyltransferase 1A1 UDP-glucuronosyltransferase 2B7

References 1. Kim H, Dionne RA. Genetics, pain, and analgesia. Pain Clinical Updates XII:1–4, 2005. 2. Cepeda MS, Farrar JT, Roa JH, et al. Ethnicity influences morphine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 70:351–61, 2001.

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69. Befort K, Filiol D, Decalliot FM, et al. A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. J Biol Chem 276:3130–7, 2001. 70. Zhang Y, Wang D, Johnson AD, et al. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 280:32618–24, 2005. 71. Skarke C, Darimont J, Schmidt H, et al. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 73:107–21, 2003. 72. L¨otsch J, Skarke C, Grosch S, et al. The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 12:3–9, 2002. 73. Romberg R, Olufsen E, Sarton E, et al. Pharmacokineticpharmacodynamic modeling of morphine-6-glucuronide analgesia in healthy volunteers. Anesthesiology 100:120–33, 2004. 74. Romberg R, Olufsen E, Bijl H, et al. Polymorphism of ␮opioid receptor gene (OPRM1:c.118A⬎G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 102:522–30, 2005. 75. Oertel BG, Schmidt R, Schneider A, et al. The ␮-opioid receptor gene polymorphism 118A⬎G depletes alfentanilinduced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet Genomics 16:625– 36, 2006. 76. Klepstad P, Rakv˚ag TN, Kaasa S, et al. The 118 A⬎G polymorphism in the human ␮-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 48:1232–9, 2004. 77. Campa D, Gioia A, Tomei A, et al. Association of ACCB1/MDR1 and OPRM1 gene polymorphism with morphine pain relief. Clin Pharm Ther 83:559-66, 2008. 78. Caraco Y, Maroz Y, Davidson E. Variability in alfentanil analgesia may be attributed to polymorphism in the ␮-opioid receptor. Clin Pharmacol Ther 69:P63, 2001. 79. Chou WY, Yang LC, Lu HF, et al. Association of mu opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 50:787–92, 2006. 80. Chou WY, Wang CH, Liu P-H, et al. Human opioid receptor A118G polymorphisms affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 105:334–7, 2006. 81. Sia AT, Lim Y, Lim ECP, et al. A118G single nucleotide polymorphism of human ␮-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology 109:520–6, 2008. 82. Janicki PK, Shculer G, Francis D, et al. A genetic association study of the functional A118G polymorphism of the human ␮-opioid receptor gene in patients with acute and chronic pain. Anesth Analg 103:1011–17, 2006.

pharmacogenetic considerations in the treatment of cancer pain 83. Beyer A, Koch T, Schroder H, et al. Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem 89:553–60, 2004. 84. Landau R, Kern C, Columb MO, et al. Genetic variability of the ␮-opioid receptor influences intrathecal fentanyl variability in labouring women. Pain 139:5–14, 2008. 85. Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci U S A 95:9608–13, 1998. 86. Bayerer B, Stamer U, Hoeft A, Stuber F. Genomic variations and transcriptional regulation of the human mu-opioid receptor gene. Eur J Pain 11:421–7, 2007. 87. Law PY, Yang JW, Guo X, Loh HH. In vivo activation of a mutant ␮-opioid receptor by antagonist: future direction for opiate pain treatment paradigm that lacks undesirable side effects. Proc Natl Acad Sci U S A 100:2117–21, 2003. 88. Ross FB, Smith MB. The intrinsic antinociceptive effects of oxycodone appear to be k-opioid receptor mediated. Pain 73:151–7, 1997. 89. Kim H, Neubert JK, Miguel AS, et al. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 109:488–96, 2004. 90. Somogyi A, Barrat DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 81:429–44, 2007. 91. Wandel C, Kim R, Wood M, Wood A. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 96:913–20, 2002. 92. Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking Pglycoprotein. Anesthesiology 92:1392–9, 2000. 93. Daganais C, Graff CL, Pollack GM. Variable modulation of brain uptake by P-glycoprotein in mice. Biochem Pharmacol 15:269–76, 2004. 94. Meineke I, Freudenthaler S, Hofmann U, et al. Pharmacokinetic modeling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. Br J Clin Pharmacol 54:592–603, 2002. 95. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug resistance gene: multiple sequence variations and correlation of one allele with Pglycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97:3473–8, 2000. 96. Klepstad P, Dale O, Skorpen F, et al. Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand 49:902–8, 2005. 97. Skarke C, Jarrar M, Erb K, et al. Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine. Clin Pharmacol Ther 74:303–11, 2003. 98. Coller JK, Barrat DT, Dahlen K, et al. ABCB genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther 80:682–90, 2006.

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11

Pharmacology of opioid analgesia: clinical principles carla ida ripamonti and claudia bareggi National Cancer Institute Milano (Italy)

Introduction According to the World Health Organization (WHO) guidelines, opioid analgesics are the mainstay of analgesic therapy and are classified according to their ability to control mild to moderate pain (codeine, dihydrocodeine, tramadol, dextropropoxyphene [DPP]) (second step of the WHO analgesic ladder) and to control moderate to severe pain (morphine, methadone, oxycodone, buprenorphine, hydromorphone, fentanyl, heroin, levorphanol, oxymorphone) (third step of the WHO analgesic ladder).1,2 Opioid analgesics may be associated with nonopioid drugs such as paracetamol or with nonsteroidal anti-inflammatory drugs (NSAIDs) and to adjuvant drugs.3 The current recommended management of cancer pain consists of the regular administration of opioids and intermittent rescue doses of opioids or NSAIDs for excess pain.4 Individualized pain management should take into account the onset, type, site, duration, intensity, and temporal patterns of the pain (from this, it is often possible to define the cause of the pain), concurrent medical conditions, and, above all, the subjective perception of the intensity of pain that is not proportional to the type or to the extension of the tissue damage but depends on the interaction of physical, cultural, and emotional factors. Oral opioid administration remains the preferred route. However, in some clinical situations, such as vomiting, dysphagia, or confusion, or in cases in which rapid dose escalation is necessary, oral administration may be impossible, and alternative routes must be implemented.5,6 Table 11.1 shows the potential application of the different routes of opioid administration in clinical practice.7 Intraindividual variability in response to different opioids is a common clinical phenomenon. Different explanations have been proposed, such as genetic makeup, tolerance to different opioid effects, the incomplete cross-tolerance

among opioids selective for the same receptor subtype due to differential affinity for receptor subtypes, the differences in profile of active metabolites between various opioids,8–13 and the pain mechanism.14 Neuropathic pain has been associated with a less favorable response to opioid analgesics with respect to other types of pain.15,16 However, opioids may also be effective in neuropathic pain even if high doses are often required.17–19 Patients have an unpredictable predilection to develop adverse effects with opioids. Some patients may be able to tolerate very large doses of opioids without developing common adverse effects such as sedation or nausea and vomiting, whereas others may develop these effects at very small doses. Recent clinical experience and research suggest that some patients experience more pain and/or additional pain symptoms as a consequence of opioid therapy.20–23 This phenomenon has been termed opioid-induced hyperalgesia and need further investigation. A regular and continuous assessment about the possible causes, frequency, intensity, and type of adverse effects is mandatory to obtain adequate symptomatic treatment.24 It is not always possible to determine whether the symptom(s) referred by the patient is a consequence of opioid administration and/or if a result of the presence or progression of the cancer or concomitant diseases. Thus, it is important to evaluate whether the administration of the opioid worsens the symptoms already present or if it provokes new symptoms. Before thinking that the opioid administration is the only and/or main cause of the symptom(s) – in particular, cognitive failure – a series of other factors must be ruled out (Table 11.2). Over the past few years, data have shown that in patients with cancer-related pain, the type of opioid analgesic and/or the route of administration must be changed once or more often,16,25,26 so the therapy is tailor-made to face specific 195

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Table 11.1. Potential applications of the different routes of opioid administration Symptoms

Oral

Sublingual, buccal

Rectal

CSI

Intravenous

Transdermala

Spinal

Vomiting Bowel obstruction Dysphagia Cognitive failure Diarrhea Hemorrhoids, anal fissures Coagulation disorders Severe immunosuppression Generalized edema Frequent dose changes Titration Breakthrough pain

– – – – – ++ ++ ++ ++ ++a ++ ++b

++ ++ ++ – ++ ++ ++ ++ ++ ++ ++ ++

++ ++ ++ – – – ++ ++ ++ – + ++

++ ++ ++ ++ ++ ++ – – – ++c ++c ++c

++ ++ ++ ++ ++ ++ ++ ++ ++ ++c ++c ++c

++ ++ ++ ++ ++ ++ ++ ++ – – – –

++ ++ ++ – ++ ++ – – ++ + – –

a

Fentanyl. Only IR formulations. c PCA. Abbreviations: +, may be indicated; ++, is indicated; –, is contraindicated. Modified from Bruera and Ripamonti.7 b

clinical circumstances, improve pain control,27–30 and/or reduce opioid toxicity.31–41 This chapter considers the most-used opioid analgesics in clinical practice, their administration routes, the coadministration of different opioids, and the potential role of opioids, as well as route switching in the management of pain and/or opioid-related adverse effects.

Opioids for mild to moderate pain Although the role of “strong” opioids is universally recognized in the treatment of moderate to severe pain, there is no common agreement regarding the role and the utility of the second step of the WHO analgesic ladder (“weak” opioids for mild to moderate pain). No significant differences in pain relief between nonopioids alone and nonopioids plus weak opioids have been reported in a meta-analysis of data from published randomized controlled trials.42

Different results were obtained by Moore et al.43 in a systematic review of randomized controlled trials on analgesia obtained from single oral doses of paracetamol alone and in combination with codeine in postoperative pain. The authors found that 60 mg of codeine added to paracetamol produced worthwhile additional pain relief, even in single oral doses. Uncontrolled studies show that the efficacy of the second step of the WHO ladder is limited in time to 30–40 days in the majority of the patients and that switching to strong opioids is mainly the result of poor analgesia rather than adverse effects.44–46 In a study of 944 patients treated with drugs of the second step, 24% of the patients still benefited after 1 month of treatment, and the percentage decreased to 4% after 90 days.45 This study evaluated several drugs, including oxycodone at low doses and buprenorphine, which are now considered drugs for moderate to severe pain.2 In a study of 745 home care cancer

Table 11.2. Main causes of cognitive impairment in cancer patients Metabolic/endocrine Sepsis Brain involvement Drug–drug interactions Withdrawal Dehydration Psychological distress Others

Hypercalcemia, hyper/hypoglycemia, hypoxia, hyponatremia, hypomagnesemia, liver failure, renal failure, adrenal insufficiency, hyper/hypothyroidism Pneumonia, urinary tract infection, other Metastasis, edema, leptomeningeal involvement, encephalitis (bacterial, viral, fungal), cerebellar degeneration, limbic encephalitis, progressive multifocal leucoencephalopathy, vascular disorders Opioids, antidepressants, benzodiazepines, other psychoactive drugs, NSAIDs, ranitidine, ciprofloxacin, steroids, anticholinergics, interleukin-2 Alcohol, opioids, benzodiazepines, barbiturates Emesis, anorexia, bowel obstruction, decreased fluid intake Fear, anxiety, sleep deprivation, isolation, feeling of dependence, hopelessness, loss of dignity Severe constipation, fecal impaction, bladder distention

pharmacology of opioid analgesia: clinical principles patients, more than 60% of those with pain were administered “weak” opioids until death, with adequate pain relief and no need to switch to strong opioids.47 However, most of the patients were still opioid na¨ıve in the advanced stage of the disease before starting the home care program. Several authors have suggested abolishing the second step and initiating earlier low-dose morphine therapy.42,48–53 The role and utility of the second step of the WHO analgesic ladder have been debated by various authors. Moreover, in routine clinical practice, the question that arises is, What really changes regarding the analgesia and tolerability of weak opioids, or low-dose strong opioids, if one or the other is used, even for mild–moderate pain? Low-dose oral morphine is a reliable method in opioid-na¨ıve advanced cancer patients.50 Controversial points regarding the use of the second step are that 1) there are insufficient data regarding the effectiveness of the so-called weak opioids; 2) there are few studies showing a real advantage in their use compared with strong opioids; 3) the second-step drugs are often marketed in combination with a nonopioid such as paracetamol, aspirin, or an NSAID, and it is the latter component that limits the dose; and 4) these drugs are often expensive in relation to their potential benefits (cost–benefit ratio). Low dose oral morphine is a reliable treatment in opioidna¨ıve advanced cancer patients. Relevant to this study53 on 110 patients showed the efficacy and tolerability of morphine at the initial dose 10/15 mg/day in the control of cancer pain, for the whole duration of the observation (4-week) period. In opioid-na¨ıve patients with mild– moderate pain, Maltoni et al.54 carried out a randomized prospective study with the aim to evaluate the efficacy and tolerability of two different approaches: using second step versus moving directly from the first to third step. Results from such a study have shown that moving from the first to third step is associated with a reduction in the number of days with either pain intensity ≥5 (22.8% vs. 28.6%, P = 0.001) or pain intensity ≥7 (8.6% vs. 11.2%, P = 0.023), but also with an increased incidence of complications (grade 3/4 anorexia and constipation).

Codeine Codeine is an opium alkaloid. In single-dose studies, codeine is approximately one tenth to one twelfth as potent as morphine when given parenterally, and one third to one quarter as potent as morphine when given by mouth.55 However, the potency ratio changes with repeated dosing. The efficacy of codeine (200–400 mg/day) in

197

moderate cancer-related pain has been confirmed in a controlled trial.56 Codeine is almost always commercially available in association with paracetamol. Codeine is a prodrug of morphine with a biotransformation of about 10%. The pharmacodynamic effects of codeine are largely the result of the production of its active metabolite, morphine.57 Codeine is metabolized to active drugs within the body by CYP2D6, an enzyme of the hepatic P450 microsomal enzyme system.57,58 Poor metabolizers produce no or undetectable levels of CYP2D6, thus preventing them from metabolizing drugs that are substrates of this enzyme. Without CYP2D6, codeine provides little or no analgesia.59,60 Data from an animal study show that when the Odemethylation of codeine to morphine is blocked, codeine lacks significant analgesic activity.61 Moreover, a patient who takes codeine or its derivatives in combination with a high-affinity substrate or potent inhibitor of CYP2D6 (such as quinidine, paroxetine, or fluoxetine) will experience attenuated analgesia, whether this person is a poor or an extensive metabolizer.62,63 A rare adverse event linked to codeine use is acute pancreatitis. Previous cholecystectomy seems to predispose to codeine-induced pancreatitis.64 In a recent study, the efficacy and tolerability of codeine in chronic moderate cancer pain were compared with those of hydroxycodone and tramadol. There were no significative differences in analgesic efficacy, but the use of codeine showed lower rates of adverse events compared with tramadol.65 In a double-blind, randomized, prospective study, codeine/acetaminophen and hydrocodone/acetaminophen were comparable in terms of efficacy and tolerability.66 The combination of codeine and diclofenac did not provide further analgesia versus diclofenac alone.67 The presence of renal failure affects the pharmacokinetics of many opioids.68 Codeine is metabolized in codeine6-glucuronide (81%), norcodeine (2.16%), morphine-3glucuronide (2.1%), morphine-6-glucuronide (0.80%), and morphine (0.56%). The renal clearance of these metabolites is significantly reduced in patients with advanced renal failure.69 A relevant accumulation of codeine has been reported in patients treated with codeine and undergoing hemodialysis when compared with normal subjects.70

Dihydrocodeine Dihydrocodeine is a semisynthetic analogue of codeine with an oral bioavailability of about 20%71 and the same equianalgesic when administered orally but a narrower

198 therapeutic range. Palmer et al.72 showed that 60 mg of dihydrocodeine produced greater analgesia than 30 mg, but there was little difference in analgesia between doses of 60 and 90 mg; moreover, the adverse effects were dose related. When administered subcutaneously, 30–70 mg of dihydrocodeine is equivalent to 10 mg of morphine.72 Its use is not widely diffused. In a survey among 141 palliative care centers in 21 European countries, dihydrocodeine was used in 2% of the 3030 patients considered. The United Kingdom and Portugal were the two countries where the drug was used in 5% of the population.73 The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine.74 Dihydrocodeine can produce severe toxicity when administered in patients with renal impairment.75,76 Oxidation of dihydrocodeine is reduced in patients with hepatic cirrhosis, resulting in increased oral bioavailability caused by a reduced first-pass metabolism.77

Tramadol Tramadol is a synthetic drug with opioid and nonopioid properties.78,79 Tramadol consists of two enantiomers: 1) (+)-tramadol and its metabolite (+)-O-desmethyltramadol, which are agonists of the mu-opioid receptor and also inhibit serotonin reuptake, and 2) (–)-tramadol, which inhibits norepinephrine reuptake. These complementary and synergic actions are responsible for tramadol’s analgesic properties.80 After repeated oral administration, the bioavailability is about 90%–100%; the excretion is mostly via kidneys (90%). O-desmethyltramadol is the active metabolite and is two to four times more potent than the parent compound. The elimination time of this metabolite is double in patients with hepatic or renal impairment.79 Oral tramadol (200–400 mg/day) is considered effective and safe in the treatment of cancer pain.81–83 Although tramadol is considered to be a drug at low risk of causing respiratory depression, two cases of severe respiratory depression after tramadol use have been described in children79 and in one adult with cancer pain and renal insufficiency.84 With respect to morphine, tramadol’s potency is considered to be about one tenth when administrated via parenteral route and one fifth when administered orally.85 Other authors have found morphine/tramadol ratios ranging from 1:3.8 to 1:5.3.81–83 In a retrospective study of a large number of patients, Grond et al.86 found that a dose of tramadol up to 600 mg/day was effective and safe and was similar to 60 mg/day of oral morphine. Furthermore, patients on

c.i. ripamonti and c. bareggi morphine received corticosteroids, laxatives, and antiemetics more often and experienced constipation, neuropsychological symptoms, and pruritus more frequently than patients treated with tramadol. Tramadol extended-release (ER) tablets release tramadol gradually, permitting once-daily administration. Its bioavailability is equivalent to immediate-release (IR) tramadol administered four times daily, but with a prolonged absorption and lower peak plasma concentration. Common adverse events reported with tramadol ER 100–300 mg once daily are dizziness, nausea, constipation, somnolence, and flushing.87 Tramadol induces fewer opioid adverse reactions for a given level of analgesia compared with traditional opioids. Common adverse events, such as nausea and dizziness, usually occur at the beginning of treatment and can be minimized by uptitration of the drug over several days.88 Osipova et al.81 compared cancer patients treated with oral tramadol with those treated with morphine. Tramadol was effective and safe for 1–3 months in the majority of patients at mean dose of about 370 mg/day. Compared with tramadol, morphine produced better analgesia but was associated with more frequent and intense adverse effects, such as nausea and constipation. Similar results have been reported by other authors.82,83 Grond et al.89 compared high-dose tramadol (≥300 mg/ day) with low-dose morphine in cancer patients. The analgesic efficacy was similar in both groups, whereas some adverse events (constipation, neuropsychological symptoms, and pruritus) were observed more frequently in the morphine group. Sindrup et al.90 carried out a randomized, double-blind, placebo-controlled, crossover trial to evaluate the analgesic efficacy of tramadol in 34 patients with chronic painful polyneuropathy. The tramadol dose was increased to a maximum of 200 mg twice daily; however, 11 patients needed doses between 200 and 300 mg/day. Pain scores, paresthesia, and allodynia were significantly lower in the tramadol group than in the group receiving placebo. The authors suggest that the analgesic effect of tramadol is the result of a reduction in central hyperexcitability. In a double-blind placebo-controlled study, Arbaiza and Vidal91 showed that tramadol is a therapeutic option for neuropathic pain in cancer patients, also improving quality of life. In fact, in the tramadol group (18 patients), there were significant improvements in pain intensity, Karnofsky scores, sleep quality, and daily living activities, as well as a reduction in the use of analgesics that had been taken since before the study, compared with the placebo group. Similar positive

pharmacology of opioid analgesia: clinical principles results were obtained in a multicenter trial of tramadol in patients with diabetic neuropathy.92 Mullican and Lacy93 compared the efficacy and tolerability of tramadol/acetaminophen and codeine/acetaminophen in a randomized double-blind multicenter trial in which 462 patients with chronic pain were randomly assigned to treatment. Pain relief and changes in pain intensity were comparable in the two groups. Adverse events also were comparable, but with a higher proportion of patients in the codeine group reporting somnolence and constipation. These results suggest that tramadol/acetaminophen is as effective as codeine/acetaminophen and is better tolerated in patients with chronic pain. A recent double-blind comparative trial94 showed that the use of tramadol produces higher rates of adverse events than codeine and hydrocodone. Tramadol can be administered rectally in cancer patients who are unable to take drugs orally. Mercadante et al.95 carried out a double-blind, double-dummy crossover trial in 60 patients with cancer pain no longer responsive to nonopioid drugs, with the aim of comparing tramadol administered orally and rectally. Each patient initially received oral tramadol, 50 mg (drops), followed by tramadol sustained release (SR), 100 mg orally, and placebo rectally, or tramadol, 100 mg rectally, and placebo orally twice a day in a randomized sequence, each of 3 days. Patients were allowed to take 50 mg of oral tramadol by drops as needed (four doses per day, to reach a maximum of 400 mg/day, including the basal dose given by oral or rectal route). Patients’ pain intensity and relief and symptom scores were recorded every day and at the end of each phase of the crossover. No differences between the two treatment groups with regard to pain intensity, relief scores, rescue doses, or other symptoms were observed. No differences were found in treatment efficacy, as judged by a clinician (P = 0.73); patients’ compliance (P = 0.35); or patients’ satisfaction regarding treatment (P ⬍ 0.35). No differences in adverse effects were found between the two treatment groups (25% and 20% in the oral and rectal treatment groups, respectively). The preference for oral administration was greater for both physicians (P = 0.0002) and patients (P = 0.002). Rectal administration of tramadol appears to be a reliable, noninvasive alternative method of pain control for patients no longer responsive to nonopioid analgesics who are unable to take oral tramadol.95 Case reports of hyponatremia have occurred during tramadol treatment.96–98 Natremia must be measured when neurological abnormality occurs with tramadol treatment.

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Withdrawal syndrome may present occasionally during tramadol treatment.99,100 Seizures have been reported with tramadol at normal doses,101 so the drug should be avoided in patients with epilepsy. A severe serotonin syndrome may occur when tramadol is combined with drugs that increase serotonin activity.102

Dextropropoxyphene Propoxyphene is a synthetic derivative of methadone, and its analgesic properties are the result of a dextrogyral isomer called DPP. It is a mu agonist and a weak N-methyl-daspartate (NMDA) antagonist receptor.103 DPP has a mean beta half-life of about 15 hours. When it is administered regularly, the plasmatic concentration gradually increases, with a plateau after 2–3 days. It is metabolized in the liver to norpropoxyphene, which can accumulate in the body because of its long half-life (about 23 hours) and may produce central nervous system (CNS) toxicity. The analgesic effect of DPP hydrochloride in doses of 65 mg or more has been established in controlled studies.104 In a prospective randomized study comparing controlledrelease (CR) oral morphine (20 mg/day) with DPP (120– 240 mg/day), titrated doses of DPP were associated with a more favorable adverse effect–analgesia balance in opioidna¨ıve patients; however, this study did not exclude a similar result with lower doses of oral morphine.105

Opioids for moderate to severe pain Oral morphine Since 1977, oral morphine has been used by hospices and palliative care units as the drug of choice for the management of chronic cancer pain of moderate to severe intensity106,107 because it provides effective pain relief, is widely tolerated, is simple to administer, and is comparatively inexpensive. Morphine is considered the gold standard “step 3” opioid (WHO), and WHO has it on its essential drug list.108 However, among cancer patients, morphine is often considered a last resort.109 Important studies investigated the clinical pharmacology and pharmacokinetics of oral morphine.110–115 Morphine by mouth is not an especially effective pain-relieving drug when administered in a single dose, owing to its limited bioavailability.116 Conversely, the effectiveness of repeated

c.i. ripamonti and c. bareggi

200 doses seems to result from the presence of the enterohepatic circulation, which allows a recirculation of morphine and its metabolites.117 The effective analgesic dose varies considerably among patients.115 This variability is the result not only of a difference in pain severity and perception by the patient but also of other factors previously described. For this reason, it is necessary to administer it in an individualized dose and thoroughly monitor its analgesic effect, especially during the titration phase. Morphine clearance decreases in patients over 50 years old, which helps explain elderly patients’ higher sensitivity to the drug.118 This clinical observation implies that younger patients may need larger doses of morphine to achieve the same analgesic effect.119 Experimental studies carried out in animals show that morphine is glucuronized in the liver and intestinal mucosa.120 Morphine has three different metabolites: morphine-3-glucuronide (M3G), morphine-6-glucoronide (M6G), and normorphine.11,121–125 Morphine administered via the oral, buccal, and sublingual routes resulted in higher metabolite production compared with routes of administration that avoid first-pass metabolism.126 M6G is an opioidbinding metabolite with analgesic properties.121 M3G is a non–opioid-binding agent that has the ability to cause generalized hyperexcitability, myoclonus, and grand mal seizures in animals.11,123 Normorphine also may cause central hyperexcitability.124 M6G is known to accumulate during renal failure121,125,127,128 and cause late opioid toxicity. Wolff et al.129 found an accumulation of both morphine glucuronides in patients with elevated serum creatinine. Oral morphine’s adverse effects are common to all opioids and may occur during titration or the therapy maintenance phase (Table 11.3). Multiple approaches have been described for the management of excessive adverse effects of oral morphine. The European Association for Palliative Care (EAPC) Research Network Recommendations underlined the need for careful evaluation to distinguish Table 11.3. Side effects during morphine therapy Titration

Continuing

Nausea Vomiting Constipation Sedation Xerostomia Pruritus Respiratory depression

Constipation Sedation Xerostomia Hallucinations Hyperalgesia, allodynia Myoclonus Cognitive failure Respiratory depression

between morphine adverse effects and comorbidity, dehydration, drug interactions, or too-high dose administration. If side effects persist, the clinician should consider options of symptomatic management of the adverse effect, morphine dose reduction with the addition of a co-analgesic or opioid rotation, or switching the route of systemic administration.130 Individual titration of dosages and the prevention of some adverse effects (e.g., nausea, vomiting, constipation) are strongly recommended. Ideally, two types of oral morphine formulation are required: normal-release morphine (NRM) and CR morphine.6 The NRM formulation is indicated for dose titration (every 4 hours) and breakthrough pain (BTP; as required). The regular dose must be adjusted according to how many rescue doses have been administered. In a recent study, 159 consecutive cancer patients na¨ıve to strong opioids received NRM, 5 or 10 mg, every 4 hours during the titration phase (first 5 days), depending on previous analgesic therapy. The primary end point was the proportion of time with pain control (a reduction of at least 50% with respect to the baseline pain score) during the titration phase. Pain control was observed for 75% (95% CI, 70–80) of the follow-up period in the intent-to-treat population. Overall, 50% and 75% of patients achieved pain control within 8 and 24 hours, respectively, after starting NRM therapy. The mean pain score was 7.63 points at baseline, decreasing to 2.43 and 1.67 points (both P ⬍ 0.001) at days 3 and 5, respectively.131 Once the optimal dose requirements for at least a 24-hour period have been established by titration, a CR formulation may be indicated for maintenance treatment to be administered every 12 hours or every 8 hours in association with IR morphine as a rescue dose. In a double-blind, placebocontrolled, crossover study carried out in a group of 34 patients, Finn et al.132 compared an IR morphine formulation administered every 4 hours with an SR morphine formulation administered every 12 hours. No difference with respect to pain, adverse effects, or incidence of BTP was found. Another CR formulation can provide up to 24 hours of pain relief with a single daily dose. In a controlled clinical trial, Gourlay et al.133 studied the pharmacokinetics and pharmacodynamics of two CR oral morphine formulations administered every 24 hours and 12 hours, respectively. No significant differences were found between the two formulations with regard to analgesic effectiveness, adverse effects, need for rescue doses, or preference of treatment at the end of the study. Similar results were obtained by Smith et al.135 Once-daily morphine provides analgesia

pharmacology of opioid analgesia: clinical principles

201

Table 11.4. Intravenous titration (dose finding) with morphine for severe cancer pain Study design and patient population

Initial morphine dosage and route

Following dosage and route

Radbruch et al.137

Prospective study; 26 inpatients with uncontrolled pain, on step 2a opioids

IV PCA pump programmed for 24 hours; 1-mg bolus, lockout interval of 5 . Max. dose of 12 mg/hour

Oral SR morphine every 12 hours; dose on the basis of the previous IV requirements IV–oral conversion 1:2 BTP treated with IV PCA until stable analgesia was reached

Mercadante et al.138

Prospective study; 45 inpatients with severe (NRS ≥7) and prolonged pain. At entry, 30 patients were on step 2 opioids, 15 were on step 3 opioids.

IV bolus (2 mg every 2 ), repeated until analgesia or adverse effects were reported

Harris et al.139

RCT; 62 strong opioid-na¨ıve inpatients Pain intensity NRS ≥5 Patients were randomized to receive IV morphine (n = 31) or oral IR morphine (n = 31)

IV group: 1.5-mg bolus every 10 until pain relief (or adverse effects). Oral group: IR morphine 5 mg every 4 hours in opioid-na¨ıve patients 10 mg in patients on weak opioids Rescue dose: the same dose every 1 hour max.

Oral SR morphine; dose on the basis of the previous IV requirements. IV–oral conversion: 1:3 for lower IV dosages, 1:2 for higher IV dosages. The same IV dose was maintained for BTP in the first 24 hours. IV group: Oral IR morphine every 4 hours on the basis of the previous IV requirements IV:oral conversion 1:1 Rescue dose: the same dose every hour max. Oral group: follow the same scheme

Study

Results Mean pain intensity (NRS 0–100): At entry: 67 After 5 hours: 22 At day 7: 17 At day 14: 12 Mean morphine dosage (IV PCA) in the first 24 hours: 32 mg (range, 4– 78 mg) Mean daily morphine dosage (oral + IV PCA for BTP) at PCA termination (range, 2–6 days): 139 mg (range, 20–376 mg) Mean morphine dosage (oral) at day 14: 154 mg (range, 20–344 mg) No significant adverse events Mean pain intensity (NRS 0–10): At entry: 8.1 After 9.7 : 3.0 with a mean IV morphine dosage of 8.5 mg Mean daily oral morphine dosage at time of discharge: 131 mg (107– 156 mg) + 10.8 mg (IV extra doses) No significant adverse events

Percentage of patients achieving satisfactory pain relief: After 1 hour: IV group, 84%; oral group, 25% (P ⬍ 0.001) After 12 hours: IV group, 97%; oral group, 76% (P ⬍ 0.001) After 24 hours: IV group and oral group similar IV group: Median morphine dosage (IV) to achieve pain relief: 4.5 mg (range, 1.5–34.5 mg). In the same group, mean morphine dosage (oral) after stabilization: 8.3 mg (range, 2.5– 30 mg). Oral group: Median morphine dosage to achieve pain relief: 7.2 mg (range, 2.5–15 mg) No significant adverse events

a

Step 2 on the WHO analgesic ladder. Abbreviation: NRS, numerical rating scale.

similar to twice-daily CR morphine.135 According to Klepstad et al.,136 dose titration of opioids using SR morphine once daily is as effective as IR morphine, with a significant degree of asthenia reported by patients. Although titration of strong opioids is commonly performed using IR oral morphine every 4 hours, there are some clinical situations, such as severe pain, in which pain relief has to be achieved as quickly as possible.

Table 11.4137–139 shows the studies reporting “fast titration” resulting in rapid relief of moderate to severe pain in cancer patients treated with bolus doses of intravenous (IV) morphine or fentanyl and then switched to oral morphine. These authors showed that fast titration with IV opioids is effective and safe. A series of controlled studies compared CR or IR morphine to analogue formulations of oxycodone

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202

Table 11.5. Studies comparing oral morphine and oxycodone Study

Study design

Patients, n

Route

Route

Results

Lo Russo et al.140

Parallel-group study

101

CR morphine

CR oxycodone

Bruera et al141

Prospective double–blind crossover

32 23 completed the study

CR morphine for 7 days

CR oxycodone

Kalso & Vainio142

Double–blind crossover

20

Oral morphine every 4 hours 4.0 mg/mL after IV PCA for titration

Oral oxycodone every 4 hours 2.7 mg/mL after IV PCA for titration

Heiskanen & Kalso143

Double–blind randomized crossover

27

CR morphinea

CR oxycodone

Comparable efficacy and tolerability; two patients on CR morphine and none on CR oxycodone reported hallucinations Comparable efficacy and tolerability; conversion rate from 1.5 to 2.3 oxycodone more potent than morphine Comparable pain relief Morphine caused more nausea Hallucinations occurred only during morphine treatment Both drugs produced sedation Comparable analgesia Significantly more vomiting with morphine Constipation more common with oxycodone Nightmares only with morphine (n.s.)

a

Opioid consumption ratio of oxycodone/morphine was 2:3 when oxycodone was administered first and 3:4 when oxycodone was administered after morphine. Abbreviation: n.s., not significant.

(Table 11.5).140–143 Between the two drugs, the analgesia was similar in all the studies. Whereas some authors reported lower adverse effects during oxycodone treatment,140,142,143 Bruera et al.141 found that the tolerability was comparable between CR morphine and CR oxycodone. Further studies are necessary to compare the adverse effect profiles of these drugs as well as the dose ratios. In a controlled clinical study, the question of whether prescribed opioids have to be adjusted to account for diurnal variation was tested. Forty-five opioid-responsive patients with advanced cancer on stable doses of analgesics were recruited. Each patient took one placebo and a 24-hour dose of SR morphine daily, 12 hours apart, with the active dose in the morning for 1 week and in the evening for the other week. No significant differences were found in pain control, pain during the day, pain disturbing sleep, or the need for rescue medication.144 Morphine showed induction of apoptosis in human tumor cell lines in vitro.145 Morphine is not recommended in patients with renal impairment because of known accumulation of potentially toxic metabolites. Other routes of morphine administration Subcutaneous (SC), rectal, IV, and spinal (epidural and intrathecal)5,6,146 are the most frequent alternative routes

of morphine administration. Intermittent or frequent SC administration is associated with a “bolus effect” phenomenon characterized by acute toxicity and a brief analgesic efficacy caused by a transient high plasma drug concentration. To avoid a bolus effect as well as painful repeated injections, continuous subcutaneous infusion (CSI) is recommended. A continuous infusion plus an intermittent bolus dose allows a patient to maintain a baseline level of opioid administration plus additional doses for BTP (patient-controlled analgesia [PCA]).147 The blood levels of morphine during CSI are not subject to sudden changes148 and are similar to those during continuous intravenous infusion (CII).149 In a study by Coyle et al.,150 13 of 15 patients undergoing CSI reported adequate pain control and were maintained on this route for 3–76 days. Ventafridda et al.151 showed that the CSI of morphine can be used when nausea and vomiting make oral administration impossible, as well as when analgesia is difficult to obtain with oral morphine or by parenteral injection. In this study, only 16% of the patients preferred CSI, compared with 94% of the patients studied by Bruera et al.152 When switching from oral morphine to SC morphine, a conversion factor of 2:1 or 3:1 should be used153–155 according to the pain relief reported before switching. An initial bolus dose equivalent to 2 hours of infusion is a way to reduce the time necessary to achieve plasmatic steady state. Many different devices are available for CSI. It is important to consider which of the

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203

Table 11.6. Studies comparing different routes of morphine administration Study

Study design

Patients, n

Route

Route

Results

Drexel et al.154

Prospective

36

Morphine, 10–90 mg/ day, intermittent oral or SC

Significantly lower incidence of constipation, nausea, and drowsiness with CSI

McDonald et al.155

Prospective

Oral morphine

Bruera et al.164

Double-blind crossover

164, switched because of drowsiness, nausea, vomiting, uncontrolled pain, difficulty in swallowing 23

Morphine, 5–48 mg/ day, CSI conversion rate 2:1 Bolus SC morphine every 4 hours Conversion rate 2:1

Double-blind crossover

27

SC morphine rectal/parenteral ratio, 2.5:1 CR morphine tablets every 12 hours; conversion rate 1:1

Comparable analgesia and side effects

Babul et al.165

CR morphine sulfate suppository, every 12 hours CR morphine suppository every 12 hours

De Conno et al.166

Double–blind, double– dummy, crossover, single-dose study

34, opioid na¨ıve

Rectal morphine; conversion rate 1:1

Oral morphine

Drexel et al.154

prospective

36

Bruera et al.167

Randomized double–blind crossover

12, 6 evaluable

Morphine, 10–90 mg/ day, intermittent oral or SC CR morphine sulfate suppository every 12 hours

Morphine, 5–48 mg/ day, CSI conversion rate 2:1 CR morphine sulfate suppository every 24 hours

different portable pumps is most suitable for a given patient. PCA devices permit the patient to choose an intermittent (demand) bolus, continuous infusion, or intermittent and continuous modes of administration. Morphine and hydromorphone administered via CSI showed comparable analgesia and tolerability, with a conversion rate of 5:1.156 Patients treated with IV morphine achieved comparable analgesia but had a significantly lower rate of adverse effects (sedation, sleep, mood disturbances) compared with patients treated with IV hydromorphone and sufentanil.157 Tables 11.6 and 11.7 show comparative studies of different routes of morphine administration. In the study of

Significant improvement in pain relief and significantly less nausea and vomiting but not drowsiness with SC

No difference in pain and sedation, small but significant difference in nausea in favor of rectal administration Rectal morphine had a faster onset of action and longer duration of analgesia than an acute dose of oral morphine No significant difference in intensity of sedation, nausea, or number of vomiting episodes between the two routes Significant lower incidence of constipation, nausea, and drowsiness with CSI There was no significant difference between the every-12-hour and every-24-hour treatment groups in symptom (pain, nausea, sedation) intensity, adverse effects, or patient choice

Drexel et al.,154 CSI of morphine produced significantly lower adverse effects compared with oral or SC morphine administered intermittently. In 164 patients who were switched from oral to SC morphine, significant improvements in pain relief, nausea, and vomiting were obtained (Table 11.6).155 The rectal route of administration gives a better bioavailability of opioids subject to first-pass liver metabolism.158,159 Rectal drug vehicles may be liquid or solid. In some countries, preparations of opioids in the form of suppositories are not commercially available. To overcome this situation, microenemas made up of a parenteral formulation of morphine or other opioids may be prepared and then administered rectally as a bolus using

c.i. ripamonti and c. bareggi

204 Table 11.7. Studies on different routes of morphine administration Study

Study design

Patients, n

Route

Route

Results

Vainio & Prospective Tigerstedt172 randomized

30

Oral morphine 151 mg/day (24–480 mg/ day)

Epidural morphine 45 mg/day (2–800 mg/day

Kalso et al.27

10, switched because of adverse effects or uncontrolled pain

Oral morphine every 4 hours, median dose 225 mg

CSI morphine, median dose 327 mg CEI morphine, median dose 106 mg

CNS side effects were less frequent and the KPS was slightly superior in the epidural groups (n.s) Pain relief was similar and adequate in both groups For patients with neuropathic pain, double doses of oral morphine were needed for similar pain relief Pain at rest significantly less during CSI compared with oral morphine Pain when moving significantly less during both CSI and CEI compared with oral morphine No significant difference in pain relief between CSI and CEI Total amount of adverse effects (sum of VAS values) significantly higher during oral compared with CSI Median of the sum of adverse effects during CEI did not differ significantly from oral or CSI

Randomized double– blind crossover

Abbreviations: CEI, continuous epidural infusion; KPS, Karnofsky Performance Status, n.s., not statistical.

a needleless, insulin-type syringe. The advantage of this approach is that absorption of aqueous and alcoholic solutions occurs rapidly.159 The colostomy administration route of opioids is not recommended.160 The rectal route of drug administration may present some disadvantages when used chronically and when feces or diarrhea is present. This alternative route can be administered successfully in patients with BTP (defined as transient flares of severe or excruciating pain in patients already managed with analgesics) and in some clinical situations (Table 11.1). Rectal morphine is safe and effective;161 it is frequently used in Japan for at-home cancer patients.162 Rectal administration of SR morphine tablets is not recommended (EAPC) and not approved by the US Food and Drug Administration (FDA).163 Studies comparing oral or SC morphine with morphine administered rectally (Table 11.6) showed comparable analgesia and adverse effects.164,165 In a single-dose study, De Conno et al.166 found that IR rectal morphine had a faster onset and longer duration of analgesia than oral morphine. Patients who achieve stable pain control with suppositories every 12 hours could undergo a trial of a single daily dose.167 For some time, many reports have described the successful spinal administration of morphine and other opioids to treat cancer pain, especially refractory pain.146,168–170 The

number of cancer patients with cancer pain requiring spinal analgesia has not been clearly defined. According to Zech et al.,171 only 1%–2% of patients need this treatment. There are no trials comparing oral with intrathecal morphine, but two prospective trials have compared the analgesia and tolerability of morphine administered orally with that given epidurally27,172 (Table 11.7). An improvement in pain control as well as in adverse effects was shown by switching from oral to epidural or CSI morphine.27 Of interest, Kalso et al.27 showed no significant benefits, either in efficacy or in adverse effects, by administering epidural morphine compared with the SC route. The authors concluded that the coadministration of local anesthetic agents, ␣2 -adrenergic agonists, or NMDA antagonists may significantly improve the quality of epidural analgesia as compared with the SC route. Further studies are necessary to validate this hypothesis. Adverse effects due to long-term intrathecal morphine – nausea, vomiting, pruritus, urinary retention, constipation, sexual dysfunction and edema – are dose dependent and mediated by opioid receptors.173 IV morphine and oral transmucosal fentanyl are both safe and effective for BTP.174,175 IV and subcutaneous continuous-infusion morphine are equally effective in producing analgesia.176 Morphine mouthwash is a simple and effective treatment for mucositis-associated pain following concomitant

pharmacology of opioid analgesia: clinical principles chemoradiotherapy for head and neck carcinoma.177 The most important side effect of morphine mouthwash is a burning/itching sensation.178 Another possibility for pain control in esophagitis induced by chemoradiotherapy is viscous gel moryephine.179 A single 40-mg dose of nasal morphine gluconate is effective for BTP, with rapid absorption. Side effects were minor and limited to nasal irritation.179 The nasal morphine–chitosan formulation is acceptable and well tolerated in patients with BTP, with an onset of pain relief in 5 minutes.180

Oral methadone Methadone is a synthetic opioid agonist developed more than 50 years ago. Although it has been used mostly as a maintenance drug for opioid addicts, methadone also has proved to be a powerful analgesic and a suitable drug in treating cancer pain.181–190 Methadone is a mu- and delta-opioid receptor agonist with NMDA receptor antagonist affinity.191,192 Thus, methadone may play a positive role in patients experiencing neuropathic pain; however, data from the literature are still controversial.193–197 A double-blind randomized controlled study compared placebo and low-dose methadone in a diverse range of neuropathic pain and demonstrated that methadone has an analgesic effect.198 After 50 years, methadone may still be considered one of the new analgesics because of its resurgence in the analgesic arena, based on impressive study results and clinical successes. It may be an interesting alternative for patients with intolerable opioid side effects.199 Usually, methadone is used as a second-line strong opioid. Methadone has a number of unique characteristics, including excellent oral and rectal absorption, no known active metabolites, high potency, and longer administration intervals, as well as an incomplete cross-tolerance with respect to other mu-opioid receptor agonist drugs.184,189 Methadone has been shown to control pain no longer responsive to morphine, hydromorphone, and fentanyl.200–204 Some data suggest that methadone may be less constipating than other opioids,205–207 but controlled studies have not been done to confirm this hypothesis. For different reasons, methadone has the potential to play a major role in the treatment of cancer pain, as well as chronic nonmalignant pain.208 However, its use is limited by its remarkably long and unpredictable half-life,209 the large interindividual variations in its pharmacokinetics, its potential for delayed toxicity, and, above all, the limited knowledge of its correct

205

administration intervals and equianalgesic ratio with other opioids when administered chronically. The analgesic role of methadone in treating cancer-related pain remains relatively unknown to physicians, nurses, and administrators involved in hospice and palliative care, primarily because of its low cost and consequent nonpromotion by the pharmaceutical industry.210 Different authors have suggested 8-, 12-, or 24-hour dosing intervals for methadone administration to avoid accumulation risk because of its long terminal half-life. Others have suggested titrating the analgesic therapy with an initial loading dose of methadone followed by progressive dose reduction during the first week of treatment. Two prospective randomized trials were carried out to compare the efficacy and tolerability of oral methadone (administered every 8 or 12 hours) with short-release oral morphine in 54 advanced cancer patients treated for 2 weeks and with slow-release oral morphine in 40 patients treated for cancer pain.181,182 In the first study, both drugs significantly reduced the intensity of pain from the first day of treatment. In the methadone group, the mean daily dose was 18 mg, which was maintained for the whole treatment period, whereas, in the morphine group, the mean daily dose was 72.8 mg (± 39 mg) and increased to 119 mg (± 79 mg) by the 14th day. These results show that methadone is about six times more potent than morphine. Patients on morphine presented a significantly higher incidence of xerostomia compared with the methadone group. These data led to the use of methadone as a first-choice opioid in the treatment of moderate to severe pain in patients with head and neck cancer who have radiotherapy-induced xerostomia. In a double-blind study, Bruera et al.211 compared methadone with morphine as first-line opioids in cancer pain. Although the results were interesting, methadone did not evidence superiority above morphine in analgesic properties and tolerability. De Conno et al.212 treated 196 advanced cancer patients with methadone in solution form administered every 8 hours. They analyzed the assessments carried out at T0 and then T7, 15, 30, 45, 60, and 90 days. After 3 months, 43 patients were on methadone again. Compared with T0, a significant reduction in pain score occurred at each time point. The mean dose of oral methadone ranged from 14 mg at T7 to 23.65 mg at T90. Only 11.2% of patients dropped out because of analgesic inefficacy and 6.6% because of methadone-related side effects. Mercadante et al.213 carried out a study of PCA with oral methadone in 24 patients with advanced cancer-related pain. They prescribed a regimen of self-administered

206 methadone with a fixed dose and flexible patient-controlled dosage intervals to achieve appropriate analgesia and to avoid the risk of toxicity from accumulation of methadone. Opioid-na¨ıve patients took a fixed dose of 5 mg of methadone three times daily for 3 days, whereas patients switching from morphine received 50% of the morphine equivalent of methadone for 3 days. From the fourth day, both groups received the fixed night dosage of oral methadone and another dose when the pain reappeared. When methadone was administered more than four times a day, an increase in dosage was prescribed. The methadone escalation index was about 2% a day, with a mean dosage increase of 0.3 mg/day for a mean of 60 days of treatment, with daily dosages ranging from 9 to 80 mg. A mean of 2.4 doses a day was reported (including the fixed night dose). The intensity of side effects was considered acceptable. In a prospective, open trial of PCA with oral methadone, Sawe et al.214 found that 14 patients initially took 30– 80 mg over 24 hours at 3- to 7-hour intervals. After 1 week, these patients prolonged their dosing intervals to a mean of 10 hours, with total oral doses of 10–40 mg/day. In a randomized study by Fisher,215 oral methadone was used to manage 37 episodes of BTP. The onset of pain relief was rapid and the adverse events rare, suggesting that oral methadone could be considered in the treatment of episodic pain. Unlike morphine, which is glucuronidated, methadone is metabolized by the cytochrome P450 group of enzymes and does not produce active metabolites. The main enzyme mediating N-demethylation of methadone in the liver is CYP3A4, with lesser involvement of CYP1A2 and CYP2D6. Therefore, the most important interactions between methadone and other drugs are related to drugs that are able to induce or inhibit CYP3A4. In these circumstances, the methadone plasma concentrations will be reduced or increased, respectively. Moreover, it must be remembered that methadone strongly inhibits CYP2D6; as a result, it can reduce the hepatic biotransformation of drugs metabolized by this enzyme, such as the neuroleptics haloperidol, domperidone, and resperidone or the tricyclic antidepressants.189,216,217 Methadone is recommended for pain relief in patients with impaired renal function.218 In a retrospective study Moryl et al.,219 methadone was effective in the treatment of refractory pain and terminal delirium in advanced cancer patients. Torsades de pointes has been reported with high doses of methadone combined with medications known to increase QTc intervals. Patients with familial cardiac conduction defects or with cardiac disease present the higher risk.220,221

c.i. ripamonti and c. bareggi Other routes of methadone administration Few data are available on the analgesia and tolerability of rectally administered methadone. A study evaluated the analgesic efficacy, tolerability, and absorption profile of 10 mg of methadone hydrochloride administered rectally (as a microenema) in six opioid-na¨ıve cancer patients with pain.222 The pharmacokinetics of rectal methadone showed rapid and extensive distribution phases followed by a slow elimination phase. The plasmatic concentrations presented great intraindividual variability. Pain relief was statistically significant after 30 minutes and continued more than 8 hours after administration. Five patients required an analgesic only 24 hours after the first administration of rectal methadone. In a prospective randomized study, Bruera et al.223 demonstrated that custom-made capsules and suppositories of methadone were safe, effective, and inexpensive in 37 advanced cancer patients with poor pain control receiving high doses of SC hydromorphone (mean daily dose, 276 ± 163 mg). These patients had significant improvement in pain control with minimal toxicity, using doses of oral or rectal methadone higher than those reported in the literature. This study also demonstrated a large interindividual variation between methadone dosage and plasma level. Rectal methadone may be considered an effective, safe, and low-cost therapy for patients with cancer pain in cases in which oral and/or parenteral opioids are not indicated or available. In most patients, continuous SC infusion of different doses of methadone produced inflammatory skin reactions at the injection site, occurring within 24–72 hours.224,225 Mathew and Storey225 confirmed the high incidence of local toxicity connected to the CSI of methadone in six patients. However, they were able to continue the parenteral methadone at a variable dose of 75–280 mg/24 hours, frequently changing the position of the needle. Adding dexamethasone in the same syringe driver allowed the extension of the number of days, averaging 4.9 in the dexamethasone group and 2.6 in the group receiving methadone alone. Intermittent SC methadone was studied by Centeno and Vara226 in 10 patients whose pain was controlled by oral methadone; eight patients tolerated injections over 7 days, and the injection site was changed in only seven of 182 repeat administrations. SC intermittent methadone can be a useful alternative to oral administration in selected patients. The pharmacokinetics of IV methadone showed rapid and extensive distribution phases followed by a slow elimination phase.227 Manfredi et al.201 described the dramatic beneficial effects of IV methadone in four patients in whom

pharmacology of opioid analgesia: clinical principles IV morphine and hydromorphone failed to produce adequate pain relief despite titration to dose-limiting side effects. All the patients had long-lasting pain relief without significant side effects at a methadone dose equal to 20% of the hydromorphone dose. Fitzgibbon and Ready200 described the successful use of large doses of IV methadone administered by PCA and continuous infusion for pain refractory to large doses of IV morphine. Morphine was stopped and treatment with methadone via PCA was initiated (incremental dose, 10 mg every 6 minutes), with a continuous infusion of methadone at a rate of 40 mg/hour. On day 3, the methadone was decreased to 200 mg, with good pain management and no adverse effects. The patient was discharged after 5 days with a dose of 220 mg/day (average daily methadone was approximately one tenth that of morphine). After 6 weeks, the dose was increased to 400 mg/day, with good pain control and no adverse effects. IV methadone administered by PCA was safe and effective in controlling cancer pain, sedation, and confusion in 18 patients previously treated with IV fentanyl. A conversion ratio of 25 mg/hour of fentanyl to 0.1 mg/hour of methadone was used to estimate the initial dose of methadone for all patients (0.25 ratio between fentanyl and methadone).204 Self-administered bolus doses of IV methadone equal to 50%–100% of the hourly infusion rate were allowed every 20 minutes and additional boluses of 100%–200% of the hourly infusion rate every 60 minutes. To control pain, there was a 10% increase in the median hourly infusion dose of methadone from day 1 (64.45 mg) to day 2; after day 2, the median hourly infusion dose of methadone was the same and decreased to 54 mg on day 4. The use of epidural methadone in the treatment of cancer pain is reported to be effective, to be devoid of adverse effects, and to have less tendency to be associated with tolerance.228,229 In another study, methadone doses of 5, 10, and 20 mg administered by the intrathecal route were compared with 0.5 mg of intrathecal morphine after orthopedic surgery in 38 patients. Whereas the intrathecal morphine produced effective and prolonged analgesia, intrathecal methadone at all three doses produced effective analgesia for only 4 hours. Generalized pruritus, nausea, vomiting, and urinary retention were common, both among patients treated with morphine and in those treated with methadone. Respiratory depression occurred in three of eight patients treated with 20 mg of methadone.230 In the pilot study by Hagen et al.,231 seven patients with cancer pain were treated with sublingual methadone at escalating doses ranging from 2 to 18 mg. Patients reported significant pain relief with a median onset of 5 minutes.

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Equianalgesic potency between methadone and other opioids Although morphine and methadone demonstrated approximately the same analgesic potency after single-dose administration,232 these results are not necessarily applicable to the management of patients with multiple repeated doses. A number of authors have reported major differences in the dose of methadone required to control pain in cancer patients as compared with other opioid agonists, such as morphine and hydromorphone. In all the reports, the dose of methadone required for maintaining an analgesic effect was lower (from 2.5 to 14 times) than the dose of the previous opioid agonist.181,186,188,223,233–235 In a prospective study of 38 patients with good pain control, the median oral equivalent daily dose of morphine was 145 mg/day; after the switch to methadone, the median equianalgesic oral methadone dose was 21 mg/day. A median time of 3 days (range, 1–7 days) was necessary to achieve equianalgesia with oral methadone.188 Results of retrospective and prospective studies show that methadone is a potent opioid, with a higher potency than that suggested by single-dose studies. Also, the dose ratio between methadone and morphine and between methadone and hydromorphone is not a fixed number, as proposed in the published equianalgesic tables, but rather changes as a function of the previous dose exposure. This suggests the presence of a partial development of tolerance between methadone and other opioid agonists.187,188,233,234 The results of a cross-sectional prospective study188 carried out in patients who switched from morphine to oral methadone showed that dose ratios ranged from 2.5:1 to 14.3:1 (median, 7.75:1). With respect to the equianalgesic tables, no patient presented a dose ratio of 1:1, whereas the dose ratios of 3:1 and 4:1 approached those obtained only in patients previously treated with low daily doses of morphine (30–90 mg). The dose ratio increased with the increase in the previous morphine dose, with a much higher increase at low morphine doses. These results agree with those of Lawlor et al.,233 who retrospectively evaluated 14 patients with advanced cancer who switched from morphine to oral methadone and were treated with a median morphine daily dose eight times greater than that used in our study.189 The authors reported that the median dose ratio obtained was 11.36, which shows that methadone is much more potent than expected and the dose ratio correlates with the previous administered morphine dose. With respect to the equianalgesic tables mentioned previously,188 Mercadante et al.236 found that when patients

208 with poor pain control and/or adverse effects from treatment with oral morphine were switched to methadone, it was necessary to increase the methadone dose by 20%– 30%. On the basis of a preliminary study, SantiagoPalma et al.204 suggested that when switching patients from IV fentanyl to methadone, a conversion ratio of 25 mg/hour of fentanyl to 0.1 mg/hour of methadone may be safe and effective. If the final mean hourly infusion dose of methadone were used to calculate the initial hourly infusion rate, a conversion of 25 mg/hour of IV fentanyl for 0.125 mg/hour of IV methadone would result. No significant correlation was found between the total dose of fentanyl before the switch and the ratio between the total daily dose of fentanyl before the switch and the total daily dose of methadone on day 4. How to switch to methadone Switching from an opioid agonist to methadone is not always easy and should be carried out by doctors experienced in treating cancer pain. Contrary to expectations, toxicity is more frequent in patients who were previously exposed to high doses of opioids compared with those who received low doses; therefore, more caution is necessary when patients are switched to methadone from higher doses of parenteral opioids. Although some authors have been able to change patients from low opioid doses to methadone in 1 day as outpatients,181,212,234,237 reports on patients on high-dose opioids suggest that the change to methadone should occur in an inpatient setting over 3–6 days. Only Hagen and Wasylenko238 found that cancer patients with advanced disease and severe pain can be safely and effectively switched to methadone in the outpatient setting; however, on average, it took 32 days to successfully switch to methadone in the outpatient setting. Different switching modalities have been reported. Slow switching At the Palliative Care Unit in Edmonton, Canada, and the Symptom Control Division at M. D. Anderson Cancer Center in Houston, Texas, the switching is performed over 3 days.187,233 The common practice consists of decreasing one third of the previous opioid dose over the first 24 hours and replacing it with methadone using an initial equianalgesic dose ratio estimate of 10:1 (i.e., a patient receiving 1000 mg/day of oral morphine would switch to 660 mg of oral morphine plus 33 mg of oral methadone during the first day). Methadone is administered orally every 8 hours. During the second day, if pain control is good, the patient

c.i. ripamonti and c. bareggi undergoes a further 30% decrease in the dose of the previous opioid, but the dose of methadone is increased only if the patient experiences moderate to severe pain. Transient episodes of pain are managed with intermittent rescue doses of short-acting opioids. Finally, during day 3, the final one third of the previous opioid is discontinued and the patient is maintained on regular methadone every 8 hours, plus approximately 10% of the daily methadone dose as an extra dose orally or rectally for BTP. Daily assessment of pain and methadone dose titration is necessary to obtain adequate pain relief. In a report by Benitez-Rosario et al.,239 slow switching was performed from transdermal fentanyl to methadone, with a good efficacy and safe profile. Methadone was initiated 8–24 hours after fentanyl withdrawal, depending on the patient’s previous opioid doses (from ⬍100 ␮g/hour to ⬎300 ␮g/hour). The starting methadone dose was calculated according to a two-step conversion from transdermal therapeutic system fentanyl (TTS-F) to oral morphine (1:100 ratio) and oral morphine to oral methadone (5:1 ratio or 10:1 ratio). The ratio 10:1 was applied when patients on admission were on high-dose fentanyl (400 ␮g/hour); reported the use of aggressive, increasing fentanyl doses (up to 300% in the last 10 days); or had delirium and presented a recent history of questionable use of increasing fentanyl doses to control pain. Opioid rotation was fully effective in 80% of patients; it was partially effective in 20% of patients with somatic pain. Other results were that neuropathic pain was not affected by opioid switching, delirium was reverted in 80% of the patients, and myoclonus was reverted in 100% of the patients after opioid switching. The calculated mean dose ratio between TTS-F doses before rotation and oral methadone doses on day 7 was 1:17 (range, 1:8–1:33). Rapid switching Mercadante et al.234 prospectively studied 24 cancer patients treated with oral morphine who were switched to oral methadone at 20% (dose ratio between morphine and methadone, 1:5) of the previous opioid dose while morphine was completely discontinued. The daily methadone dose was divided into three daily doses and a further dose as needed. Half the patients obtained good pain relief in the first 24 hours, and the others within 3 days after switching. During the 3 days of the study, the methadone dose was reduced in six patients who received higher presetting morphine doses (range, 120–400 mg), increased in 11 patients who had received lower preswitching doses of morphine (range 30–90 mg), and remained stable in

pharmacology of opioid analgesia: clinical principles seven who had received a mean preswitching morphine dose of 107 mg (range, 30–180 mg). No serious complications were found among patients in this study. According to the authors, rapid switching between morphine and methadone also can be used for patients cared for at home if continuous monitoring is performed by an experienced team. It is also our practice to stop morphine and immediately begin treatment with oral methadone every 8 hours using as guidelines the median dose ratios we found in our previous study187 – 4:1 (previous morphine dose of 30–90 mg/day), 8:1 (previous morphine dose of ⬎90–300 mg/day), and 12:1 (previous morphine dose ⬎300 mg/day) – titrating the dose daily according to pain intensity.187 According to Morley and Makin,202 the previous opiate should be stopped and replaced by a fixed dose of methadone that is one tenth the actual or calculated equivalent oral morphine dose when the 24-hour dose is less than 300 mg, or a fixed dose of 30 mg of methadone when the 24-hour dose is greater than 300 mg. This fixed dose should then be administered orally as required, but not more frequently than every 3 hours for 6 days. On day 6, the amount of methadone administered over the previous 2 days is noted and converted into a regular 12-hour regimen. In this case, there is a wide range of doses, up to 300 mg of equivalent oral morphine dose, in which the equianalgesic dose between morphine and methadone is always 10:1. As can be seen in switching to methadone, there is no set standard modality. Mercadante et al.240 reported the experience of a rapid switch from transdermal fentanyl to methadone and vice versa in patients with a fixed conversion ratio of 1:20. This modality was safe and effective. The mean preswitching TTS-F daily dose was 4.2 mg/day (equivalent to 420 mg of oral morphine). According to the initial ratio chosen (1:20), this group of patients received an initial daily dose of oral methadone of 84 mg. Of these patients, 20 were receiving TTS-F doses ≥1.8 mg/day (equivalent to a relatively high dose of oral morphine, about 180 mg/day), and four patients were receiving doses ⬍1.8 mg/day. Seven patients receiving a mean daily dose of oral methadone of 30.8 mg (equivalent to 154 mg of oral morphine) were switched to a mean initial daily dose of TTS-F of 1.54 mg. This clinical improvement was observed in both switching directions. In the patients switching from TTS-F to oral methadone, the mean time to achieve daily dose stabilization after switching was 4.3 days, whereas it was 2 days in patients switched from oral methadone to TTS-F. The number of changes required was 3.4 and 0.7,

209

in the two switching directions, respectively. Hospital discharge after switching was 5.3 and 4.1 days, respectively. The mean number of rescue doses in the two switching directions during hospital admission was 1.8 and 2.1 per day, respectively. There were minimal differences, not statistically relevant, between the initial doses calculated and the daily doses at time of stabilization (15% when switching from fentanyl to methadone and 30% when switching from methadone to fentanyl. The opioid switching between fentanyl and methadone was successful, in both directions, in about 80% of patients (25 of 31 patients), using an initial conversion ratio of 1:20 and a “stop and go” approach, regardless of the dose of the previous opioid, and then modifying the dose of the alternative opioid according to a flexible protocol, depending on the clinical response.

Oral hydromorphone Hydromorphone is an analogue of morphine with similar pharmacokinetic and pharmacodynamic properties. It produces some metabolites, the principal one being hydromorphone-3-glucuronide, and like M3G, it likely is responsible for the neuroexcitatory adverse effects.241,242 Hydromorphone has a key role in the area of chronic and acute pain relief as an alternative to morphine. It is included in clinical practice guidelines for the management of pain secondary to cancer and has been well studied as an analgesic for postoperative pain.243 Hydromorphone can be administered safely to patients with impaired renal function.244 The IR formulation provides useful analgesia for about 4 hours, whereas SR tablets may be administered twice or three times a day. IR hydromorphone administered every 4 hours and ER hydromorphone administered every 24 hours provide comparable analgesia at equivalent total daily doses.245 In a double-blind, crossover, randomized study, comparable analgesia and tolerability were found between CR hydromorphone and CR oxycodone (Table 11.8).246 Wide variations in the equianalgesic dose ratio have been reported between morphine and hydromorphone.187,247,248 No correlation between the previous opioid doses has been found. The ratio may differ depending on whether the switch is from morphine to hydromorphone or from hydromorphone to morphine. A unified ratio of 4.2:1 (4.2 mg of morphine = 1 mg hydromorphone) has been suggested.247 The hydromorphone/methadone ratio is 5–10

c.i. ripamonti and c. bareggi

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Table 11.8. Opioid switching for the treatment of adverse effects due to morphine administration Study

Study design

Patients, n Opioid dose/route

Symptoms

Switching

Results

Katcher & Case report Walsh254

1

Hydromorphone by CII then oral

Itching stopped within 24 hours of starting hydromorphone

Paix et al.256

Retrospective

4

Itching with both routes, nonresponsive to drugs Delirium, hallucinations

Fentanyl

Clinical improvement

de Stoutz et al.257

Retrospective

80

Cognitive failure, hallucinations, myoclonus

Multiple opioids

Clinical improvement in 73% of patients and also pain control

Sjogren et al.258

Retrospective

4

Hyperalgesia, allodynia, myoclonus

Methadone, sufentanil, ketobemidone + benzodiazepines or amitriptyline Oxycodone CSI conversion 0.7:1

Clinical improvement

CR oral morphine 15 mg three times daily + 5 mg every 4 hours, then CII Morphine, 5–120 mg/day oral and CSI Multiple opioids: morphine, hydromorphone, methadone, diamorphine, fentanyl Morphine, 20 mg/day IV, 60–300 mg/day CR, 150–960 mg/ day IM

Maddocks Prospective et al.255

19

Oral or SC morphine Acute delirium

Lawlor et al.259

1

Morphine 14.400 mg/day, IV lorazepam 8 mg/day

Case report

times greater than previously reported249 and varies significantly according to the previously administered dose of hydromorphone.223,247,250

Myoclonus, delirium, hyperalgesia

Methadone

Attenuation of delirium, significant improvement in nausea and vomiting Clinical improvement

less pruritus than did morphine.253 In a case report,254 hydromorphone administered via CII and then orally was able to abolish itching present during oral and IV morphine administration (Table 11.8).247,255–259

Other routes of hydromorphone administration In some countries, hydromorphone is available in rectal as well as injectable formulations for IV, SC, epidural, and intrathecal administration. Hydromorphone administered subcuteneously has some advantages compared with morphine because of its high solubility, the availability of a high-concentration preparation (10 mg/mL), and a bioavailability of about 78%251 and it is at least as effective as morphine when delivered by CSI.252 In a double-blind, crossover study, CII and CSI of hydromorphone for chronic cancer pain were compared. No differences were reported in terms of side effects or analgesia. Plasma concentrations also werecomparable, and after 24 and 48 hours, the two infusion methods showed a stable steady state.251 In a prospective double-blind randomized trial, hydromorphone administered via CSI showed comparable analgesia and adverse effects compared with morphine, with a dose ratio of 5:1.252 By the spinal route in opioid-na¨ıve patients, hydromorphone caused about 33%

Oral oxycodone Oxycodone (dihydroxycodeine) hydrochloride is a semisynthetic opioid that is a derivative of tebaine, with an agonist action at mu and kappa receptors.260 In in vitro binding studies, oxycodone showed a lower affinity for the mu-opioid receptor.142,261 Oxycodone has the same structural relationship to codeine but is nearly 10 times more potent.262 It is metabolized like codeine, that is, demethylated and conjugated in the liver to form oxymorphone in a reaction catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6), and excreted in the urine.263 The bioavailability of oral oxycodone is higher than that of oral morphine (about 87% vs. 37%).264 Different studies show marked interindividual variations in the pharmacokinetics and pharmacodynamics of oxycodone that support the need for individualized dosing regimens.264–269 The role of oxycodone metabolites such as noroxycodone and oxymorphone267,270–273 is not clear. According to Kaiko et al.,271

pharmacology of opioid analgesia: clinical principles

211

Table 11.9. Comparative studies on oxycodone administration Study

Study design

Patients, n

Route

Route

Results

Kaplan et al.276

Randomized double-blind

164

81 patients, CR oxycodone

83 patients, IR oxycodone

Leow et al.264

Open crossover, single dose

12

Oral oxycodone, 9.1 mg

IV oxycodone, 4.6–9.1 mg

Leow et al.265

Open crossover, single dose

12; 11 opioid na¨ıve

Rectal oxycodone, 30 mg

IV oxycodone, 7.9 ± 1.5 mg (mean)

Hagen & Babul246

Double–blind crossover randomized

44; 31 completed the study

Parris et al.277

Randomized double-blind parallelgroup

111; 66 completed the study

CR oxycodone every 12 hours; final dose, 124 ± 22 mg/day CR oxycodone every 12 hours

CR hydromorphone every 12 hours; 30 ± 6 mg/day for 7 days IR oxycodone every 6 hours

No difference in pain intensity Overall, significantly fewer digestive system adverse events for CR compared with IR oxycodone IV oxycodone had a faster onset of pain relief than oxycodone tablets, but the duration of analgesia was the same (4 hours) IV oxycodone had a significantly higher incidence and severity of nausea, drowsiness, and lightheadedness than oral oxycodone IV oxycodone had faster onset of analgesia (5–8 minutes) with respect to the rectal route (0.5–1 hour) but had a shorter analgesic effect (4 hours for IV vs. 8–12 hours for rectal) No difference in incidence or severity of adverse effects Comparable analgesic efficacy and tolerability Two patients had hallucinations on hydromorphone, and no patients on oxycodone No differences in pain scores or tolerability

oxycodone, but not oxymorphone, is primarily responsible for pharmacodynamic and analgesic effects. The half-life of oxycodone does not seem to be modified in patients with renal and hepatic impairment, which is why these patients may benefit from switching to oxycodone if toxicity is present.271 A recent large Chinese study in which 216 cancer patients were treated with CR oxycodone hydrochloride tablets showed that it was safe and effective for moderate to severe pain.274 Adverse events of CR oxycodone hydrochloride – constipation, nausea, vomiting, drowsiness, and dysuria – were most frequent in the first week of treatment. In a controlled study of patients with postherpetic neuralgia,275 CR oxycodone was an effective analgesic for the management of steady pain, paroxysmal spontaneous pain, and allodynia when compared with a placebo. Controlled trials comparing CR and IR oxycodone276–278 showed no difference in pain scores. Parris et al.277 reported that tolerability between the two formulations was the same, but Kaplan et al.276 found significantly fewer adverse effects overall for CR compared with IR oxycodone. Oxycodone CR should be used with extreme caution in patients with

epilepsy or other conditions that may decrease seizure threshold.279 Oxycodone should be used with caution in patients with chronic renal failure.280 Studies comparing orally administered oxycodone and morphine are described in Table 11.5. A recent metaanalysis of four randomized controlled trials attested that oxycodone was as safe and effective as morphine for cancerrelated pain.281 The most interesting result is the absence of hallucinations during oxycodone administration compared with morphine. In one study,143 oxycodone produced constipation more frequently than morphine. The manufacturer and others recommend a conversion ratio of 2:1 from oral morphine to oral oxycodone (2 mg morphine = 1 mg oxycodone).282 In one study,283 patients in therapy with oxycodone ER had lower risk of constipation compared with those prescribed morphine ER. However, clinical experience supports the use of a 1:1 mg conversion ratio.143,284,285 In a recent report by Webster, 286 a new SR gel-cap oxycodone is presented. Table 11.9 reports comparative studies on oxycodone administration.246,264,265,276,277

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Different routes of oxycodone administration Commercially prepared parenteral oxycodone is available in only a few countries. Gagnon et al.285 treated 63 advanced cancer patients with intermittent SC injections of oxycodone. Local tolerance and systemic toxicity were evaluated prospectively. Intolerance at the injection site appeared in two patients who received a concentration of 50 and 60 mg/mL. Most patients were switched to oxycodone because of opioid toxicity, and in 34% of them, delirium was reversed. The conversion ratio used from oral to SC oxycodone was 2:1. The dose ratio between intramuscular (IM) oxycodone and IM morphine is 3:2.270,287 Maddocks et al.288 showed that in patients with morphineinduced delirium, switching to oxycodone produced significant improvement in mental status, nausea, and vomiting (Table 11.9). Oxycodone pectinate suppositories, available in countries such as the United Kingdom, must be given every 8 hours. The single-dose pharmacokinetics and pharmacodynamics of oxycodone administered by IV and rectal routes were determined in 12 cancer patients.265 IV oxycodone was associated with a rapid onset of analgesia (5–8 minutes) compared with the rectal route (0.5–1 hour), but with a shorter analgesic effect (4 hours via the IV route vs. 8– 12 hours via the rectal route) (Table 11.8). A single-dose study compared oral and IV oxycodone.264 Although IV oxycodone produced a faster onset of pain relief, the duration of analgesia was about 4 hours with both routes of oxycodone administration; IV oxycodone produced significantly more adverse effects (Table 11.8). Oxycodone plus lidocaine gel is useful in the management of tenesmus provoked by rectal cancer.289 Absorption of oxycodone is similar after buccal and sublingual instillation in children.290 Absorption of oxycodone after IV injection in children is similar to that in adults. IM oxycodone provides constant drug administration, whereas the buccal and gastric routes have more variation in absorption rate.291

Fentanyl Fentanyl is a semisynthetic opioid and an established IV anesthetic and analgesic drug. It is not used orally because it rapidly undergoes extensive first-pass metabolism. Among analgesic opioid drugs, fentanyl citrate has a very high potency (about 75 times that of morphine) and is skin compatible, having a low molecular weight with good solubility, making it suitable for transdermal administration. Moreover, fentanyl is more lipophilic, a characteristic that

c.i. ripamonti and c. bareggi gives it a faster onset of analgesic properties when administered intravenously. IV fentanyl can be used safely for rapid titration in cancer patients with severe pain.292 Fentanyl may be a valid alternative drug in patients with renal impairment.293,294 Other routes of fentanyl administration The transdermal route of fentanyl administration is the most used in clinical practice. It has become so popular that physicians frequently use transdermal fentanyl as the firstchoice opioid administration for treating moderate to severe pain. Ripamonti et al.295 carried out a study to evaluate if the use of transdermal fentanyl is appropriate according to the WHO guidelines and the EAPC recommendations. The study of cancer patients in Italy reviewed the clinical charts of patients prescribed transdermal fentanyl for the first time in 2002.295 In 29% of outpatients and 53% of inpatients, changing to a fentanyl patch was considered inappropriate according to WHO guidelines and EAPC recommendations. There is a trend toward using this compound even when short-release oral morphine could be used, such as in the titration phase in the presence of instable pain. In June 2005, an “important drug warning” was published by Janssen.296,297 According to this warning, “Duragesic should only be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to Duragesic 25 mcg/h. Patients who are considered opioidtolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromophone daily or an equianalgesic dose of another opioid.” Different studies show that the transdermal fentanyl patch is as effective as oral opioids in relieving cancer-related pain, with a safety and side effect profile equal to or better than that of oral opioids.298–307 In a randomized, open, two-period, crossover study comparing transdermal fentanyl with SR oral morphine, TTS-F was associated with significantly less constipation and less daytime drowsiness but greater sleep disturbance and shorter sleep duration compared with morphine.298 Donner et al.299 evaluated the long-term therapy of 51 patients using transdermal fentanyl. Constipation and the need for laxatives were significantly reduced using TTS compared with SR morphine in the prestudy phase.300 Korte and Morant301 evaluated 20 patients on TTS-F. Constipation was not a major problem; overall, laxatives were needed only during one third of all treatment days. In another study of 38 patients, Korte et al.302 found that TTS-F induced less constipation than

pharmacology of opioid analgesia: clinical principles might be expected. Laxatives were administered continuously in 8% of the patients and intermittently in 79%. Five patients (13%) did not need any laxatives at all. Nine patients on CR morphine and one patient on hydromorphone switched to TTS-F. Constipation, appetite, drowsiness, and concentration were not statistically different between the two treatments.303 Zech et al.304 carried out a pilot study to evaluate the efficacy and side effects of a combination of initial PCA for dose finding with transdermal fentanyl administration in 20 cancer patients. In comparison with the prestudy situation (WHO steps 2 and 3), there was a slight decrease in the visual analogue scale (VAS) scores for constipation, nausea, vomiting, anorexia, and fatigue, whereas other symptoms remained unchanged. In the study of Tawfik et al.,308 cancer patients requiring strong analgesia were treated with transdermal fentanyl for 287 days. Transdermal fentanyl was effective and well tolerated, regardless of previous opioid treatment, so the authors suggest that opioid treatment could be started without titration with short-acting opioids. In an open prospective study, Grond et al.305 evaluated the combination of initial dose titration with PCA and longterm treatment with TTS-F in 50 cancer patients requiring opioids for severe pain. The frequency of moderate or severe constipation was found in 40% of patients before the study, 18% of patients during the titration period (285 days), and 10% of patients during long-term treatment (2979 days). The efficacy and tolerability of a combination of initial PCA for dose finding with TTS-F were evaluated in 70 patients requiring strong opioids for severe cancer pain.307 A respiratory rate below 8/minute during sleep was noted in three patients during the titration period. Comparing the incidence of major symptoms such as constipation, nausea, and vomiting on days 0 and 3, a marked reduction was present during fentanyl treatment, whereas other symptoms, such as sweating, fatigue, dizziness, and pruritus, were unchanged. In a large cross-sectional study, Payne et al.307 compared pain-related treatment satisfaction, side effects, functioning, and well-being in 504 patients with advanced cancer who were receiving TTS-F or SR oral morphine. The fentanyl patients (who were significantly older) had lower functioning scores than did the oral morphine patients; however, despite this lower functioning, they reported fewer side effects than patients treated with oral morphine. The level of analgesia was similar in the two groups. Preclinical evidence supports the relatively low incidence of intestinal side effects observed clinically with the use of fentanyl compared with morphine after both SC and oral administration.309,310

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Some patients switching from oral or SC morphine to transdermal fentanyl may experience acute symptoms of morphine withdrawal despite adequate pain control. It is not understood if this is the cause of reduced constipation when switching to TTS-F. Patients experienced severe abdominal symptoms with diarrhea, abdominal cramps, nausea, sweating, anxiety, and restlessness within 24–48 hours of switching from oral or parenteral morphine to TTS-F. Some patients were converted back to their usual dose of SR morphine or were administered 10 mg of SC morphine successfully, reporting that they fell back to their usual state after 48 hours.298,311–314 It is not known what induces the withdrawal syndrome. It may be the result of different receptors, different receptor subtypes, different secondary messenger systems, different affinities, or different potencies of the two drugs at different receptors. It may be necessary to gradually reduce the dose of morphine to avoid withdrawal symptoms while switching from oral or SC (subacute) morphine to fentanyl. Withdrawal symptoms were reported after discontinuation of transdermal fentanyl, even when using a 25-␮g/hour patch.315,316 For patients refractory to laxatives and general measures, a trial should be considered with a fentanyl patch or continuous SC infusion of morphine. However, TTS-F should be used only in a stable situation in which the patient has been titrated to good pain control using an IR opioid formulation. Further studies should be carried out to evaluate the degree of constipation of one opioid versus another when administered at equianalgesic doses. Oral transmucosal fentanyl citrate (OTFC) is a synthetic opioid agonist manufactured in a matrix of sucrose and liquid glucose base and fitted onto a radiopaque plastic handle. Doses are available in six different strengths (200, 400, 600, 800, 1200, and 1600). Absorption is via the oral mucosa. Administration of a drug through this route avoids the firstpass effect and allows easy and rapid dose titration. From the pharmacokinetic point of view, OTFC is similar to IM and IV fentanyl, whereas the plasmatic concentrations are double those of oral fentanyl and are reached 86 minutes earlier than those of oral fetanyl.317,318 Peak effect occurs in about 20 minutes. Approximately 25% of the fentanyl dose goes directly into the bloodstream through mucosal absorption and accounts for 50% of the dose that reaches the plasma. Total bioavailability is approximately 50%, as duration of action ranges from 2.5–5 hours. The onset of analgesic effect is obtained within 5–15 minutes319 compared with 30–60 minutes with normal-release oral opioids. A total of 76% of patients with incident pain and BTP have experienced favorable results.320

214 In a multicenter, randomized, double-blind, placebocontrolled trial of OTFC for cancer-related breakthrough pain carried out by Farrar et al.,321 OTFC produced significantly larger changes in pain intensity and better pain relief than placebo. In another controlled dose titration study322 in cancer patients treated with OTFC, 74% were successfully titrated. Moreover, OTFC provided significantly greater analgesic effect at 15, 30, and 60 minutes and a more rapid onset of effect than the usual rescue drug. There was no relationship between the total daily dose of the fixedschedule opioid regimen and the dose of OTFC required to manage BTP. Because the optimal dose cannot be predicted, treatment should begin with a dose of 200 mg and increased at 15-minute intervals. It emerged from controlled and uncontrolled studies that the adverse effects of OTFC were similar to those of other opioids, and very few adverse events were severe or serious. OTFC is approved by the FDA solely for the management of BTP in opioid-tolerant cancer patients.323 In a study by Coluzzi et al.,324 IR morphine sulfate was less effective than OTFC for treatment of BTP. OTFC is not recommended for treating acute and/or postoperative pain. Future studies are required to establish the OTFC dose to be used as a rescue dose in patients with BTP compared with the type and dose of opioid taken by the patient. Fentanyl buccal tablets (FBTs) are used as an effervescent drug delivery system to enhance penetration across the buccal mucosa to manage BTP. Bioavailability and absorption are higher for FBTs than OTFC. In a trial,325 a single FBT dose of 100–800 ␮g provided significant pain relief. Intrathecal fentanyl was used in four patients who failed with other analgesic approachs. Safety and tolerability were maintained.326

Diamorphine Diamorphine (diacetylmorphine) is a semisynthetic analogue of morphine and a prodrug that must be biotransformed to 6-acetylmorphine and morphine to produce the analgesic effect.327 It is not widely used for severe cancer pain328 outside Canada and the United Kingdom. Although there does not appear to be any difference between diamorphine and morphine when administered orally, diamorphine is about twice as potent as morphine when administered subcutaneously or intramuscularly.329 Moreover, diamorphine is more soluble than morphine when administered parenterally and has a more rapid onset of analgesia and produces less vomiting but more sedation when administered intravenously.330 Diamorphine also

c.i. ripamonti and c. bareggi may be administered through the spinal331–333 or intranasal route.334

Buprenorphine Buprenorphine is a semisynthetic tebaine derivative. It is a potent partial agonist at the mu receptor. As a mu partial agonist, the drug has a ceiling for its morphine-like effects.335 Sublingual administration allows direct drug absorption into the systemic circulation, thus avoiding the hepatic first-pass metabolism. The peak of morphine-like subjective effects occurs at a dose of approximately 1 mg of SC buprenorphine, which corresponds to 20–30 mg morphine.336 Patients previously treated with buprenorphine required a dose of morphine significantly higher than those treated with other opioids (codeine, oxycodone, DPP, pentazocine) to obtain the same pain relief.337 Like the mixed agonist–antagonists, buprenorphine may precipitate withdrawal in patients who have received repeat doses of a morphine-like agonist and developed physical dependence. Naloxone is relatively ineffective in reversing serious respiratory depression caused by buprenorphine.338 It is necessary for a continuous administration of naloxone to reverse the respiratory effects of buprenorphine. Transdermal buprenorphine achieves good analgesia, with adverse effects similar to those of other opioids; local side effects (erythema, pruritus) are transitory.339 Mercadante et al.340 treated 10 patients who were already receiving transdermal buprenorphine and were no long responsive, with higher doses up to 140 ␮g/hour within 6 days. Six patients achieved effective analgesia. Adverse effects in these patients were no different from those observed before the dosage increase. Transdermal buprenorphine generally is well tolerated and effective for the long-term treatment of chronic cancer or noncancer pain.341 In a recent study by Pace et al.,342 transdermal buprenorphine showed improvement in pain and a positive effect on quality of life compared with oral morphine. A study by Sittl et al.,343 compared different doses of transdermal buprenorphine in a randomized, double-blind, placebo-controlled trial. Buprenorphine was shown to be an effective analgesic against chronic severe pain. Adverse events were mild or moderate (central nervous and gastrointestinal symptoms). Transdermal buprenorphine provides good pain relief; often, patients do not require any analgesic co-medications. It has superior safety with respect to respiratory depression and immunological and renal effects compared with step 3 opioids.344

pharmacology of opioid analgesia: clinical principles Buprenorphine can be administered at normal doses in patients with renal dysfunction because it is excreted mainly through the liver.345,346

Levorphanol Levorphanol is a synthetic potent mu-opioid agonist that also binds delta and kappa receptors.347 It is readily absorbed from the gastrointestinal tract and has a favorable oral-to-parenteral ratio of approximately 1:1.348 When administered parenterally, 2 mg of levorphanol is equianalgesic to 10 mg of morphine.347 It has a half-life of 12–30 hours and a duration of analgesia of 4–6 hours. Levorphanol is considered a useful alternative to morphine, hydromorphone, or fentanyl; however, it must be used cautiously to prevent accumulation.349 The kappa receptor binding may explain its high prevalence of psychotomimetic effects (delirium, hallucinations) compared with other opioids.347 Analgesia produced by levorphanol is mediated by mu-, delta-, and kappa-opioid receptors; it is also an NMDA antagonist and may inhibit uptake of norepinephrine and serotonin. It undergoes glucuronidation in the liver and is then excreted in the kidney. It can be delivered orally, intravenously, and subcutaneously.348 It has a role in patients who are refractory to other opioids.350 In a randomized trial, levorphanol was administered in high- or low-strength capsules for neuropathic pain. Neuropathic pain was reduced by the higher dose, but there were more side effects.351

Oxymorphone Oxymorphone, a semisynthetic mu-opioid agonist considered more potent than morphine, is available in IR and long-acting formulations.352 Oxymorphone is an oral therapeutic option for acute and chronic/severe pain. The safety and efficacy profile is similar to that of commonly used pure opioids.353 The dosage equivalency between ER oxymorphone and CR oxycodone is 2:1.354 A pilot study by Sloan et al.355 reported that cancer patients stabilized on morphine or CR oxymorphone were rapidly and safely converted to ER oxymorphone, with adequate pain relief.

Coadministration of different opioids It is well known that the association of opioid and nonopioid drugs, acting on different receptors, increases the analgesic efficacy through an additive effect.43,356 What is

215

now emerging is that the coadministration of morphine and other opioids, which act on different receptors, not only produce an increase in the analgesic effect of morphine but also reduce CNS adverse effects and opioid tolerance while offering a more balanced analgesia. A preliminary observation by Mercadante et al.357 showed a significant reduction in opioid escalation index (OEI) when another opioid was associated with the previous one. Moreover, the second opioid did not induce significant adverse effects. A review study358 reported the results of in vivo and in vitro studies of cotreatment of morphine plus selective antagonists of a subset of opioid receptors that are coupled to an excitatory second-messenger system. Coadministration of morphine plus very low doses of opioid antagonists, such as naloxone and naltrexone, markedly enhances the intensity and duration of morphine-induced analgesia. At the same time, chronic cotreatment reduces opioid tolerance and dependence through a direct competitive antagonism of Gs-coupled excitatory opioid receptor functions. In clinical studies, low-dose naloxone enhanced pentazocine analgesia359 and morphine analgesia,360 whereas codeine analgesia was increased by low-dose naltrexone.361,362 Low-dose nalmefene, a potent opioid antagonist with a long duration of action, was able to enhance morphine analgesia in both animals and humans.358,363 In preclinical studies, the marked increase in the analgesic effect of morphine through the coadministration of naltrexone did not produce an increase in morphine’s depressant effects on the respiratory system.362 A recent publication by Nielsen et al.364 confirms the hypothesis that oxycodone could act as a kappa(2b)opioid agonist with relatively low affinity for mu receptors. According to the studies of Ross and Smith,365 oxycodone is not a mu-opioid agonist but a kappa-opioid agonist. Ross et al.366 conducted a study to evaluate whether the coadministration of sub-antinociceptive doses of morphine and oxycodone via the intracerebroventricular and/or subacute or intraperitoneal routes produced synergistic pain relief in animals. When the drugs were administered separately, there was no significant difference in pain with respect to basal time or placebo group of rats in both groups. However, a marked analgesic synergy, rapid onset of action (10 minutes), and duration of action lasting approximately 3 hours were observed when the drugs were administered concomitantly. Furthermore, the animals did not present the classic opioid-related CNS adverse effects that appeared when the opioids were administered separately. The combination of SR morphine and SR oxycodone can be a useful alternative to morphine alone, resulting in less emesis.367 There is controversy about oxycodone and morphine.368,369

216 Dextromethorphan (DM) is a low-affinity NMDA receptor antagonist. When administered alone in low doses (90 mg/day or less), it was not able to relieve neuropathic pain;370,371 when administered at higher doses (400 mg/day or more) it was superior to placebo in patients with diabetic neuropathy, but not in those with postherpetic neuralgia.372 Preclinical and clinical studies have been carried out to evaluate the role of DM in the enhancement of analgesia and the prevention of tolerance development when administered in association with morphine. In rats treated with this oral combination of DM and morphine, there was prevention of opiate tolerance and dependence and enhancement of the peak analgesic potency and duration of morphinerelated analgesia without an increase in side effects.373,374 Dudgeon et al.375 compared DM with slow-release morphine for chronic cancer pain in terminal patients. They showed an enhancement of analgesia, which was not statistically significant. Dizziness was greater in the DM group (58% vs. 36%). This toxicity and the limited effect do not support the use of DM to enhance morphine analgesia or modulate opioid tolerance. Future studies are needed to clarify the clinical implications of the coadministration of different opioid analgesics. In particular, we need to know the effects of these preparations in the long term, what doses are required for treating BTP, the cost of these drugs, and their impact on the patient’s quality of life. Oxytrex is a novel drug that combines oxycodone with ultra-low-dose naltrexone, an opioid antagonist. Adding ultra-low-dose naltrexone to oxycodone enhances and prolongs analgesia. Oxytrex twice daily produced a 39% reduction in pain intensity, which was significantly greater than that of placebo (P ⬍ 0.001), oxycodone four times daily (P = 0.006), or Oxytrex four times daily (P = 0.003).376

Role of switching the opioid and/or the route of administration In clinical practice, we can observe patients treated with oral morphine or another opioid who present with an imbalance between analgesia and unwanted effects. In particular, some clinical situations may be present: 1) Pain is controlled, but there are some intolerable adverse effects for the patient. 2) Pain is not adequately controlled, and it is impossible to increase the opioid dose because of adverse effects. 3) Pain is not adequately controlled notwithstanding the continuous increase of the opioid dose, which does not produce adverse effects. Different therapeutic strategies may prevent or treat adverse effects: 1) general measures (reduce the opioid

c.i. ripamonti and c. bareggi dose, hydrate the patient, correct abnormal biochemistry if present, reduce the number of pharmacological associations); 2) administration of symptomatic drugs (adjuvant drugs); 3) administration by an alternative route; 4) administration of an alternative opioid; or 5) switching to an alternative opioid and an alternative route.377 Symptomatic drugs used to prevent or control opioid adverse effects are usually used in clinical practice. Nevertheless, there have been no studies to evaluate their possible toxicity when they are administered in association with opioids (e.g., the increase of sedation when they act on the CNS, as in the case of some antiemetics), their efficacy in a large sample of patients (above all for control of symptoms such as itching, myoclonus, hallucinations, and delirium), and/or the patient’s compliance when more drugs are prescribed. Data are not available to allow to us to compare the advantages and disadvantages of the different therapeutic strategies, such as the use of drugs for symptom control (adjuvant drugs) and the switching of opioids and/or the route of administration. Patients who have poor analgesic efficacy or tolerability with one opioid will frequently tolerate another opioid well, although the mechanisms that underlie this variability in the response to different opioids are not known.14,16,29 According to Bruera et al.,141 the benefits of opioid switching are more likely to be related to subtle differences in pharmacology that emerge when a new opioid is substituted in a patient who has developed toxicity to another opioid than to overt differences in pharmacologic profile in patients with stable pain control. However, much more needs to be understood to answer these questions. Tables 11.8 and 11.10 list a series of positive results from case reports, retrospective studies, and prospective uncontrolled studies on the role of opioid switching for the management of adverse effects resulting from morphine or other opioid administration.247,276,362,363,365,366,370–374,384 Most authors switched the opioid in the presence of adverse CNS effects such as delirium, hallucinations, cognitive failure, myoclonus, seizure, hyperalgesia, and allodynia. Opioid switching often was effective in cases in which the use of symptomatic drugs for symptom control was not effective. The selection of an alternative opioid is largely empirical. A pure opioid agonist such as oxycodone, methadone, hydromorphone, or fentanyl is recommended when morphine fails. Positive results in symptom control and pain relief also were obtained by switching the route of opioid administration. In the prospective study carried out by McDonald et al.155 (Table 11.6), switching from oral to SC morphine produced significant improvement in pain relief

pharmacology of opioid analgesia: clinical principles

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Table 11.10. Opioid switching for the treatment of adverse effects due to opioid administration Patients, n Study

Study design

Opioid, dose/route

Symptoms

Switching

Results

Eisendrath et al.378 Steinberg et al.379

Retrospective

6

Meperidine, 300–1050 mg/day IM Transdermal fentanyl, 125 ␮g/hour

Delirium, seizure (2 patients) Delirium nonresponsive to haloperidol and lorazepam Seizures, myoclonus

Morphine

Clinical improvement Clinical improvement

Case report

1 renal failure

Szeto et al.380

Prospective

14

Meperidine, 75–150 mg every 2–3 hours IM

Kaiko et al.381

Prospective survey

67

Meperidine, 240– 540 mg/day

Parkinson et al.382

Case report

1

Hydromorphone/morphine intrathecal/epidural

MacDonald et al.383

Case report

3

Hydromorphone, 65– 200 ␮g/hour

and nausea and vomiting. Kalso et al.27 (Table 11.7) carried out the only randomized double-blind crossover trial to evaluate the efficacy and tolerability of morphine in patients who switched from oral to epidural or SC administration. The positive results obtained indicate that this practice should be implemented in clinical practice. There is no sound evidence from well-designed clinical trials of the superiority of one opioid over another regarding the side effect profile and/or analgesic profile. However, although conclusions drawn from observational studies and clinical trials must be interpreted with caution, they give some useful information. Theoretically, there may be some benefit in opioid switching in any situation of unacceptable side effects with the initial opioid.236,377,385,386 However, it is not possible to foresee such side effects in any individual. The goal is to personalize the therapy and reassess the patient continuously. Opioid rotation from methadone to another opioid is often complicated by worsening pain and dysphoria.387 In the future, it will be necessary to evaluate the relative roles of adjuvant (symptomatic) drugs compared with opioid and/or route switching when patients suffer persistent adverse effects from an opioid. For each symptom, we must consider the available therapeutic strategies in terms of symptomatic drugs, their efficacy and tolerability, or switching routes and/or opioids. The choice of one strategy over another should take into account the advantages,

48/67 had symptoms of CNS excitation, 8 had myoclonus, 2 had seizures Rhythmic jerking of the legs, spastic contractions of stomach and legs Myoclonus, delirium

Morphine

Morphine, levorphanol, and phenytoin Morphine, diazepam, or anticonvulsant for seizure

Clinical improvement Clinical improvement

IV morphine, IV sufentanil

Clinical improvement

Morphine, methadone

Clinical improvement

disadvantages, evidence, comparison of alternatives, and costs in different care settings. Opioid rotation from high-dose morphine to transdermal buprenorphine was performed in 42 patients because of insufficient analgesia or intolerable adverse effects. Pain relief, overall satisfaction, quality of sleeping, and incidence of adverse effects were recorded. Only 5% reported insufficient relief.388

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12

Opioid side effects and management maxine de la cruz and eduardo d. bruera The University of Texas M. D. Anderson Cancer Center

Introduction The majority of cancer patients (approximately 80%) develop pain before they die.1 Pain in cancer patients is often underdiagnosed, and inadequate treatment with opioid analgesics is well documented.2–4 Many factors influence pain management in this patient group. Inappropriate and suboptimal education of physicians and other health care professionals has been identified as the major barrier to adequate opiate use.5,6 In developing countries, a further issue is reduced availability of opioids due to financial limitations and government regulations. As a result of a major educational effort by a number of organizations, including the World Health Organization, the International Association for the Study of Pain, and the American Society of Clinical Oncology, opioid use has improved very significantly in developed countries during the past two decades.7 The results of such efforts have been quite variable.8 However, in many regions of the world, progress has been made, with opioids being used in higher doses and at earlier stages in palliative care.9 Cancer patients, who now have earlier exposure to opioids and generally have treatment with higher dosages, are better managed than in the past. This highly desirable increase in the use of opioids, combined with increased vigilance, has resulted in increased detection of several side effects, most notably neurotoxicity. With this increase in opioid use and the improvement in identification of adverse effects, management strategies for dealing with these unwanted effects have been developed and augmented.

Opioid side effects Many opioid side effects have been recognized for a long time; however, others have been more clearly identified over the past 10–20 years. The clinical implications of some,

230

such as effects on the immune and endocrine systems, are as yet not clear. Table 12.1 summarizes both well-known and more recently identified opioid side effects. The purpose of this chapter is to discuss traditional and emerging opioid side effects and their management.

Sedation Sedation is a common adverse effect that limits the amount of opioids that can be used to achieve effective pain control. It commonly occurs in patients when opioid analgesics are first initiated or when there is significant dose escalation.10–14 Tolerance to the sedating effect of opioids occurs within 3–7 days, or when opioids are given long enough. In opioid-na¨ıve healthy volunteers, clinical doses of buprenorphine cause alterations in reaction time, muscle coordination, attention, and short-term memory.15,16 However, cancer patients receiving stable opioid doses do not develop significant impairment in psychomotor performance,11 Table 12.1. Opioid side effects Traditional view: r Sedation r Nausea and vomiting r Constipation r Respiratory depression r Less commonly, pruritus, anaphylaxis, sweating, urinary retention r OIN – Severe sedation – Cognitive failure – Hallucinosis/delirium – Myoclonus/grand mal seizures – Hyperalgesia/allodynia Emerging view: r Noncardiogenic pulmonary edema r Immune system effects r Endocrine function effects (hypopituitarism, hypogonadism)

opioid side effects and management reaction times to auditory stimuli,17 postural stability,18 or driving ability.12 Opioid-dependent individuals on methadone maintenance therapy appear to have normal cognitive function and reaction time.19–22 The effects of opioid administration on cognitive performance and psychomotor skills such as driving ability are further discussed and recommendations are made later in this chapter. In some patients with severe pain, somnolence during the first days of treatment or after an increase in dose may simply reflect increased comfort after days of pain-induced insomnia rather than true somnolence. There are many other possible causes of sedation in patients who are taking opioid medication. However, the exact mechanism by which they cause sedation remains unclear. Fig. 12.1 summarizes the contributors to sedation in cancer patients. Accumulation of active metabolites of opioids causes sedation and may occur quite rapidly in a number of situations. It is more likely to occur in patients on high doses of opioids and in those with renal insufficiency. Renal impairment developing as a result of administration of nonsteroidal anti-inflammatory drugs (NSAIDs) or some antihypertensives may also cause buildup of active opioid metabolites.23,24 Other medications that have centrally acting sedative effects, such as hypnotics, tricyclic antidepressants, and centrally acting antiemetics, may add to sedation if used with opioids. Consideration of the use of hypnotics is particularly important in cancer patients because they frequently are prescribed to these patients for significant periods of time.25,26 Alcohol may have a similar sedative-

231 enhancing effect. It is important to consider that rapidly progressing sedation may be the result of other complications, including metabolic alterations such as hypercalcemia or hyponatremia, sepsis, or progressive brain metastases.25 Assessment of sedation is necessary in total management of pain. It can be argued that excessive sleepiness affects the quality of life of both patients and families. Patients may forego adequate analgesia to be more alert. Safety and social aspects of the patient’s life also are affected. Also, sedation may be an early sign of unrecognized delirium.27,28 Validated tools such as the Epworth Sleepiness Scale (ESS) and Stanford Sleepiness Scale are available for clinicians to use. Management Patients with sedation should be carefully assessed to look at potential causes. Underlying factors, such as those in Fig. 12.1, should be addressed where possible. Naloxone is not indicated for use in patients presenting with opioidinduced sedation in the absence of signs of respiratory depression, as this may precipitate an unnecessary opioid withdrawal syndrome and severe pain.29 When somnolence is encountered in the presence of residual pain, it is necessary to reexamine the possibility that previously unsuspected anxiety, depression, or other unresolved psychological distress is augmenting the patient’s expression of pain, and that the opioid dose is excessive in relation to the nociceptive component of the

Opioids and active metabolites Other drugs e.g. NSAIDS causing renal impairment

Infection

CNS sedatives e.g. tricyclic antidepressants, benzodiazepines, alcohol

SEDATION

Metabolic abnormalities e.g. hypercalcemia, hyponatremia

Renal or hepatic impairment

CNS involvement

Dehydration Fig. 12.1. Contributors to sedation in cancer patients.

232 pain. Somatization of psychosocial suffering has been identified as an independent predictor of cancer pain control in cancer patients.30 In these cases, the opioid dose should be reduced and other symptoms should be appropriately treated. In patients in whom there is persistent sedation at opioid doses necessary to achieve pain control, adjuvant opioidsparing measures should be considered, as these may allow reduction in the opioid dose. These include the use of NSAIDs, bisphosphonates, and corticosteroids. Neuropathic pain may be treated with different classes of antidepressants (tricyclics, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors) or anticonvulsants (gabapentin, pregabalin, carbamazepine). Concurrent use of adjuvants may be more effective, especially if the patient presents with other symptoms, such as depression, anorexia, and bone pain, to name a few. Nonpharmacological measures such as radiation therapy or nerve blocks also may be useful. Finally, a trial of psychostimulants may be useful in patients who are sedated at opioid doses needed for adequate pain control. Psychostimulants have multiple effects as adjuvant drugs in pain management. They potentiate opioid-induced analgesia, counteract opioid-related sedation and cognitive dysfunction, and allow an escalation of opioid dose in patients with pain syndromes that are difficult to treat.31 Dextroamphetamine was found to antagonize opioidinduced sedation in a single-dose study involving postsurgical patients.32 Controlled clinical trials show conflicting results. A number of investigators have found that the use of methylphenidate resulted in a significant improvement in the visual analogue scale for drowsiness and confusion.4,33,34 Wilwerding et al.35 were unable to demonstrate a statistically significant benefit for methylphenidate in reducing opioid-induced drowsiness; however, a trend toward decreased drowsiness after methylphenidate was observed. Methylphenidate significantly improved cognitive function (measured by finger-tapping speed, arithmetic, digit memory, and visual memory) in patients being treated with high doses of opioids. Fernandez et al.36 reported an uncontrolled trial involving 19 cognitively impaired patients with AIDS-related complex who demonstrated improvements in neuropsychological tests when treated with methylphenidate and dextroamphetamine. Psychostimulants can produce adverse effects such as hallucinations, delirium, and psychosis (which can be treated with haloperidol or discontinuation of the drug). Amphetamine derivatives have other adverse effects, such

m. de la cruz and e.d. bruera as decreased appetite, and tolerance to their effects may develop. Another concern regarding this class of medication is the high potential for abuse that may result in underusage.37,38 Before prescribing psychostimulants, a careful medical history must be taken to exclude any psychiatric disorder. This is important as stimulants are contraindicated in patients with a history of hallucinations, delirium, or paranoid disorders. They are also relatively contraindicated in patients with a history of substance abuse or hypertension. In clinical practice, the usual starting doses of psychostimulants are as follows: methylphenidate, 10 mg/day; dextroamphetamine, 2.5 mg/day; pemoline, 20 mg/day. The drug dose can be increased if no adverse effects are observed. The therapeutic effect is evident within 2 days of treatment. Morning and noon administration are advised so as not to disturb sleep.39 Concerns regarding the use of psychostimulants have prompted investigation of new drugs to address the problem of opioid-induced sedation. Modafinil (Provigil) and donepezil have both been studied for this purpose. Modafinil is a wake-promoting agent indicated for use in patients with daytime sleepiness resulting from narcolepsy,40,41 shift work sleep disorder,42 or obstructive sleep apnea.43 Donepezil is an acetylcholine esterase (AChE) inhibitor that is used in the United States for the treatment of Alzheimer’s dementia. Although both drugs have shown promise, most studies that have been conducted have primarily been open-label trials with small sample sizes and limited time to follow-up. A retrospective chart review study by Webster et al.37 that included 11 patients with opioid-induced sedation receiving modafenil showed significant improvement in the ESS at an average dose of 427 mg/patient/day. However, the study had several limitations:1 the duration of the study was not factored in the analysis, so improvement in sedation could not be completely attributed to modafenil;2 time to follow-up was not standardized, so measurement of final ESS varied;3 and ESS was measured only twice in each patient. The cholinergic pathways have been shown to modulate arousal and memory.44 It is also believed that the cholinergic system plays a role in opioid-induced sedation, and previous studies have suggested that these drugs inhibit cholinergic activity in multiple regions of the brain, resulting in decreased arousal and increased sleepiness.45,46 Several approaches to counteract this effect have resulted in trials with donepezil, a centrally selective AChE inhibitor shown to be effective in cognition and behavior disorders associated with Alzheimer’s disease. A number of case reports demonstrated moderate improvement in sedation as well

opioid side effects and management as improved nighttime sleep in 22 patients who received at least 200 mg of morphine equivalent dose per day. Two patients showed tolerance, with response improved after an increase in donepezil dose.47,48 In an open-label trial of 20 patients, donepezil was shown to improve opioid-induced sedation and fatigue.49 A retrospective study involving 40 patients with opiate-related daytime sleepiness receiving donepezil reported that about 73% had moderate treatment benefit.50 It was noted, however, that benefits declined over time – with 38% of responders losing benefit over the average period of 83 days. Tolerance to donepezil appeared on average about 116 days post initiation.

Constipation Constipation occurs in approximately 90% of patients treated with opioids.51 Opioid-induced constipation occurs as a dose-related phenomenon with wide individual variability. Tolerance to this symptom develops very slowly, and many patients require laxative therapy for as long as they take opioids. There is evidence of a difference among individual opioids in their constipation-inducing potential. Hunt et al.52 performed a crossover trial of equianalgesic doses of subcutaneous fentanyl and morphine in 23 hospice cancer patients and found that patients had more frequent bowel motions while on fentanyl. Measures for nausea, delirium, and cognitive function showed no differences between the two drugs. In a retrospective study of 49 patients, the amount of laxatives needed to achieve at least one bowel movement

233 every 3 days was compared with the median equivalent daily dose of parenteral morphine for each opioid. Laxative doses for methadone were significantly lower than for morphine and hydromorphone. Abdominal involvement, female gender, and older age also resulted in greater need for laxatives.53 Further studies are needed in this area to prospectively look at which opioids have more favorable side effect profiles with respect to constipation. Opioid-induced constipation is believed to be mediated by gastrointestinal ␮ receptors.54 They cause constipation through one of three mechanisms: reduction in motility, reduction in secretion (pancreatic, biliary, electrolyte, and fluid), and increase in intestinal fluid absorption and blood flow.48–50 Exogenous opioid administration extends the transit time and desiccates the intraluminal content. There is some evidence that morphine stimulates mucosal sensory receptors, which in turn activate a reflex arc to further increase fluid absorption.55 Many factors can contribute to constipation in cancer patients, and Fig. 12.2 summarizes the main causes in this population. Constipation may result in a number of clinical presentations and complications that are not normally associated with absence of bowel movements; these are summarized in Table 12.2.56–58 Management Patients who are initiated on opioid medication need to be advised of the likelihood of developing constipation and should be started on laxatives with the dose titrated to effect.

Opioids

Abdominal surgery or involvement

Dehydration

Immobility

CONSTIPATION

Reduced oral intake

Electrolyte abnormalities e.g. hypokalemia, hypercalcemia

Autonomic failure

Other medications e.g. tricyclic antidepressants Fig. 12.2. Causes of constipation in advanced cancer patients.

234 Table 12.2. Clinical presentations and complications of constipation Clinical presentations r Abdominal pain r Distention r Anorexia r Nausea and vomiting r Urinary retention r Increased liver or retroperitoneal pain r Confusion r Diarrhea Complications of untreated constipation r Fecal impaction r Rectal tears, fissures, and hemorrhoids r Bowel obstruction r Intestinal perforation r Inadequate absorption of oral medication

Even patients with poor oral intake should be advised that constipation may occur and of the benefits of laxative use. All patients taking opioids should be assessed for constipation because of its prevalence in this group. Assessment of constipation was found to be insufficient, even in patients at high risk for constipation, in a palliative care center. Patient location (home or hospital) did not predict the degree of constipation on admission.59 Assessment included at least a history of the frequency and difficulty of defecation and symptoms attributed to constipation, and a physical and rectal examination. If the history is unclear, an abdominal radiograph may be helpful.60–62 The use of a radiological constipation score may be necessary for adequate diagnosis in some patients, particularly those with cognitive failure. On a plain abdominal radiograph, the abdomen is divided into four quadrants. Each quadrant is assessed for constipation score: 0 = no stool, 1 = stool occupying ⬍50% of the lumen, 2 = stool occupying ⬎50% of the lumen, 3 = stool completely occupying the whole lumen of the colon. The total score for all quadrants is calculated and ranges from 0 to 12. A score of 7–12 indicates severe constipation that requires immediate treatment.59,60,62 In addition to opioid therapy, the majority of cancer patients also have at least one or two more of the precipitating factors described in Fig. 12.2. Therefore, the management of constipation in these patients frequently requires a multimodal approach, which can be divided into general and therapeutic approaches. General interventions involve the elimination of medical factors that may be contributing to constipation (e.g., treatment of electrolyte abnormalities, discontinuation of all nonessential constipating drugs), increase in fluid intake and fiber consumption, and, if possible, the availability of comfort, privacy, and convenience during defecation. Increased fiber intake may not be

m. de la cruz and e.d. bruera desirable in patients who have poor caloric intake or are cachectic, as it may result in early satiety and prevent the ingestion of more nutritious foods. Therapeutic interventions involve the use of laxatives, rectal suppositories, enemas, and manual disimpaction. Oral laxatives include bulk agents, osmotic agents, contact cathartics, lubricants, prokinetic drugs, opioid antagonists such as oral naloxone, and a newer agent, methylnaltrexone. Bulk agents such as cellulose and psyllium seeds are used as a fiber supplement to increase stool bulk. They typically work after 2–4 days of regular use. They may cause distention, bloating, and abdominal pain and are unsuitable for patients with advanced cancer as they require adequate oral fluid intake and may result in satiety, which may result in reduced oral intake of nutritious foods. Saline laxatives such as magnesium and sodium salts act as osmotically active particles and draw fluid into the intestinal lumen, resulting in a semiliquid stool that has a reduced transit time. They usually work in 3–6 hours; long-term use should be avoided, as the action is not physiological. Sodium salts should be avoided in patients with cardiac failure or renal insufficiency because these agents can cause water and sodium retention. Lactulose and sorbitol also act as osmotic laxatives and are not absorbed by the bowel, resulting in water retention in the lumen. Their onset of action is usually 24–48 hours. Use may be limited as they cause flatulence and nausea in some patients sensitive to the sweet taste. Contact cathartics (senna, cascara, danthron, phenolphthalein, bisacodyl, docusates, and castor oil) are the most commonly administered laxatives for opioid-induced constipation. They exert their effect by increasing peristalsis and reducing absorption of water and electrolytes from the bowel lumen.63 Onset of action varies among individual agents in this group: castor oil, 2–6 hours; docusate, 24–72 hours; and the others, in the region of 6–10 hours. Shortterm use is safe; however, overuse may cause dehydration, and long-term ingestion may result in dependence on laxatives for bowel function.64 Lubricant laxatives (mineral oils) soften the stool and lubricate the stool surface and usually are effective in 6–8 hours of administration. These are not recommended for chronic laxation because long-term use is associated with perianal irritation, malabsorption of fat-soluble proteins, and risk for lipoid pneumonia.64 A prokinetic agent such as metoclopramide or domperidone is considered for cases that have not responded to conventional measures. A continuous infusion of metoclopramide has been used to treat severe narcotic bowel obstruction.65

opioid side effects and management Two types of opioid antagonists have been shown to have a beneficial effect on opioid-induced constipation but have limited use because of the risk for opioid withdrawal. Oral naloxone, a ␮-opioid antagonist, can reverse opioidinduced constipation.66,67 It has been shown that the oral administration of naloxone at a daily dose of 20% or more of the prevailing 24-hour morphine dose can provide a clinical laxative effect without antagonizing opioid analgesia.68 However, some patients in this study experienced opioid withdrawal. In another prospective study, oral naloxone was shown to improve symptoms of opioid-induced constipation and reduce laxative use in chronic pain patients. Opioid withdrawal symptoms such yawning, sweating, and shivering were seen in four of 22 patients for a short duration. One patient withdrew from the study because of opioid withdrawal, the other three continued without problems after a slight reduction in dose. In this study, oral naloxone was started and titrated individually between 3 × 3 mg to 3 × 12 mg/day, depending on laxation and withdrawal symptoms.69 Methylnaltrexone is the first peripheral opioid receptor antagonist. Because it does not cross the blood–brain barrier, it confers an advantage over naloxone in terms of its ability to block peripheral opioid receptors while sparing actions mediated by centrally located receptors.70 In studies of healthy subjects, methylnaltrexone was reported to effectively reduce the delay in gastric emptying and transit time without affecting the analgesic effects of opioids.71,72 In a randomized placebo-controlled study conducted by Thomas et al.73 involving 133 patients with opioid-induced constipation, subcutaneous methylnaloxone at a dose of 0.15 mg/kg body weight was effective in inducing laxation within 4 hours of administration when compared with placebo and did not trigger pain or other symptoms of opioid withdrawal. There was also note of more patients reporting ease with laxation and reduced distress associated with constipation. Intravenous methylnaltrexone also was shown to induce laxation in a double-blind placebo-controlled trial of 22 patients in a methadone maintenance program who had methadone-induced constipation. No opioid withdrawal was observed, and no significant adverse effects were reported.74 A follow-up study using oral methylnaltrexone showed dose-related laxation in 12 patients on a methadone maintenance program, again with no withdrawal and no adverse effects reported.75 Portenoy et al.76 conducted a multicenter randomized parallel-group doseranging trial consisting of 33 adult patients. They concluded that subcutaneous methylnaloxone at a dose of 5 mg and above, with no dose–response relationship above 5 mg/day. In April 2008, methylnaltrexone was approved by the US

235 Food and Drug Administration for opioid-induced constipation when response to laxative therapy is insufficient.77 Combined laxative treatment is not universally effective; 40% of advanced cancer patients also require the use of enemas and/or rectal manipulation.51 For most cancer patients, the use of enemas and rectal suppositories is limited to the acute, short-term management of more severe episodes of constipation. Some patients who cannot tolerate oral laxatives may be able to use long-term rectal laxatives or enemas effectively.64 Suppositories may be inert or active. Inert suppositories usually contain glycerine and draw fluid into the rectum and act as a stimulus for defecation. Active suppositories contain a cathartic. In cases in which suppositories are ineffective, enemas may be used. Microenemas are useful as their small fluid volume makes them less distressing for the patient. Docusate and bisacodyl are also available in enema form. Sodium phosphate enemas may cause fluid and electrolyte imbalances, particularly in dehydrated patients. Soap and water enemas may cause fluid overload and may irritate the rectal mucosa. Another approach in patients with severe refractory constipation is to consider opioid rotation to methadone, which appears to be less constipating than other opioids.53 Opioid rotation is dealt with in more detail later in this chapter under “Opioid-Induced Neurotoxicity: Management.” Other novel approaches have been described, including use of fresh baker’s yeast or NSAIDs. A small recently published preliminary study of cancer patients who concurrently initiated opioid therapy and fresh baker’s yeast showed it had an effect on prevention of constipation in the short term.78 Ketorolac infusion also was shown in a small study to relieve opioid bowel syndrome, probably in part by its morphine-sparing effect, but also possibly by a prostaglandin inhibitory effect.79 Prostaglandins inhibit intestinal motility, which has been shown to be reversed by indomethacin.80,81

Nausea and vomiting Opioid analgesia can cause nausea and vomiting in patients after initiation or increase in dose; this usually responds well to antiemetics and disappears spontaneously within the first 3 or 4 days of treatment.82,83 Nausea has been reported to be present in 8%–35% of patients receiving opioids, and vomiting in about 14%–40%.84 Some patients, particularly those receiving high doses of opioids, experience chronic and severe nausea, which may be accompanied by abdominal pain, constipation, and gas distention of the large bowel and occasionally of the small bowel. As with other

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236

Opioids and active metabolites Raised Intracranial Pressure

Metabolic Abnormalities

Chemotherapy/ Radiotherapy

Other Drugs

NAUSEA

Constipation

Autonomic Failure

Peptic Ulcer Disease

Bowel Obstruction

Fig. 12.3. Contributors to nausea in advanced cancer patients.

symptoms in cancer patients, there often are many potential causes of nausea and vomiting, and in many patients, the etiology is multifactorial. Fig. 12.3 summarizes the main contributors to nausea in cancer patients. Opioids cause chronic nausea by a number of mechanisms, including stimulation of the chemoreceptor trigger zone in the area postrema of the medulla, stimulation of the vomiting center, vertigo because of stimulation of the eighth cranial nerve, gastroparesis, and constipation. Chronic nausea has been associated with accumulation of active morphine metabolites such as morphine-6-glucuronide (M6G).85 The frequency of nausea and vomiting is comparatively higher in ambulatory patients as compared with those confined to bed, which suggests that these drugs also act by altering the sensitivity of the vestibular center. Management Those exposed to opioids for the first time, or those who undergo a significant dose increase, should have universal access to antiemetics. Opioid-induced nausea and vomiting are most likely to be effectively treated with prokinetic agents such as metoclopramide.86–88 However, there have been no randomized controlled trials comparing different agents in the management of opioid-induced emesis. Methylnaltrexone likewise has shown promise in the treatment of nausea, most notably in patients who have undergone colonic type surgery and are at risk for developing postoperative ileus. At total of 65 patients were randomly

assigned to receive methylnaltrexone versus placebo as an intravenous infusion every 6 hours post surgery. Those who received methylnaltrexone had earlier recovery of their bowel function.89 Drugs with central nervous system (CNS) effects also can be helpful; for example, because the vestibular center has a high concentration of muscarinic cholinergic90 and histamine H1 receptors,91 the use of anticholinergic and antihistaminic drugs might be beneficial in the specific cases of nausea related to movement. Antiemetic agents that act centrally on the CNS have the potential to cause troublesome side effects, such as sedation, which can add to opioid toxicity in some patients. In patients who do not initially respond to antiemetics, the addition of corticosteroids can dramatically improve the effects of prokinetic drugs;92 the mechanism of this effect of corticosteroids is not well understood. The etiology of nausea and vomiting is often multifactorial, and if possible underlying causes should be identified and corrected; constipation, which frequently coexists in these patients, should be treated, metabolic abnormalities should be corrected, and other medications that might contribute should be discontinued.

Respiratory depression Respiratory depression as a side effect of opioid use is dose dependent and is a rare occurrence. In fact, the incidence of clinically recognized and relevant respiratory depression is about 1.1% in postoperative patients93 and 1.2%

opioid side effects and management in postoperative patients receiving epidural morphine.94 In clinical practice, however, the true incidence of respiratory depression cannot be fully characterized, in part because of institutional guidelines put in place to safeguard the safety of patients. Different receptor mechanisms are responsible for opioid-induced analgesia and respiratory depression. Opioids have a direct effect on the pontine and bulbar brainstem respiratory centers, reducing respiratory drive.95 Respiratory depression generally occurs after short-term administration of high doses of opioids in opioid-na¨ıve individuals. In cancer patients who are on long-term opioid treatment, tolerance develops to the respiratory depressant effects with repeated administration of the drugs.96 Respiratory depression will not occur in the absence of other concurrent side effects, such as sedation. Patients who ignore sedation and continue to take regular opioid medication may develop respiratory depression. Simultaneous administration of other CNS depressants increases the risk for opioid-induced respiratory depression as a result of excessive sedation.97–99 In renal impairment, the buildup of renally excreted morphine metabolites such as M6G can lead to respiratory depression.100 Another area where there is risk of respiratory depression in patients on long-term opioids is following the rotation from another opioid to methadone; problems with dose ratios and reduced cross-tolerance result in a significant risk of respiratory depression.101,102 Pain is an effective antagonist to the respiratory depressant effects of opioids. In a study of normal subjects, respiratory responses to noxious stimuli were measured. Borgbjerg et al.103 concluded that pain stimulates respiration and attenuates the respiratory depressant effect of morphine in an intensity-dependent manner. In a study by Walsh et al.104 in 20 hospice patients on oral morphine receiving doses ⬎100 mg/24 hours, the investigators found no evidence of ventilatory failure. The study results showed that even in such medically compromised patients, if the opioid is titrated for pain, the risk for respiratory depression is not significant. They also demonstrated that opioid use does not result in clinically significant respiratory depression or other adverse respiratory effects in cancer patients when dose escalation is titrated appropriately for pain control; therefore, they recommended that fear of respiratory depression, even in such vulnerable patients, should not limit their use for optimizing pain management. Cases of respiratory depression are observed more frequently in patients who have unexpected sudden relief of their pain. Abolition of pain by cervical cordotomy and neurolytic blocks in patients on opioid medication has resulted in respiratory depression.105,106

237

Management In patients with respiratory depression, dose reduction, discontinuation, or opioid rotation is recommended. Naloxone should be administered immediately in a diluted solution in small increments to avoid withdrawal symptoms. It is usually administered as 0.1 mg every 3–5 minutes until reversal of the symptoms occurs. The patient should be monitored as naloxone has an elimination half-life of 30 minutes and respiratory depression may recur when the effect of the naloxone becomes attenuated by its elimination; repeat administration or a continuous intravenous or subcutaneous infusion may be required. If naloxone is not given in small doses, opioid withdrawal and pain crisis may occur.

Pruritus Some side effects vary with route of administration of the opioid; pruritus, nausea and vomiting, respiratory depression, and urinary retention are more common with neuraxial (epidural and intrathecal) administration.107 Pruritus is uncommon in patients receiving systemic opioids but is reported to occur in 8.5% and 46% of patients receiving epidural and intrathecal opioids, respectively.108 The exact etiology is not clear but is thought to be related to degranulation of mast cells and histamine release.109,110 Management Conventional antihistamine agents have limited use because of their anticholinergic effect, which may be additive to the other effects of opiods, such as sedation, dry mouth, and constipation. In the management of patients with pruritus associated with neuraxial administration of opioids, a variety of medications have shown potential, but none is universally effective. Epidural administration of droperidol,111 butorphanol,112 and naloxone113 has been reported to be useful, as has intravenous prophylactic ondansetron.114 Antihistamines, intravenous propofol, low-dose intravenous naloxone,115 and transnasal butorphanol116 have also been used with reported success. Change of opioid from morphine to hydromorphone also has been reported to be effective.117,118

Urinary retention Urinary retention, like pruritus, is also more common with neuraxial administration of opioids.107 It is more likely to occur in opioid-na¨ıve patients and in the first days of

m. de la cruz and e.d. bruera

238 treatment with opioids. Low-dose intravenous naloxone may be useful, but care must be taken not to induce withdrawal. Alternatively, a program of intermittent catheterization may be used but is rarely needed.

Noncardiogenic pulmonary edema Noncardiogenic pulmonary edema was first described by Osler more than 100 years ago.119 This side effect of opioid use has been well documented with street use of narcotics and in cases of opioid overdosage. It also has been reported after the administration of naloxone.120 In recent years, with use of high doses of opioids for management of cancer pain, this phenomenon has been described in cancer patients.121 Cancer patients who develop this problem generally have had a large increase in their opioid dose for pain relief in the previous days. In cancer patients with a nonintensive management approach, there is a high mortality associated with opioid-induced noncardiogenic pulmonary edema; whereas in drug addicts, the incidence has been described as less than 1%.119 There are several hypotheses for the mechanism of this phenomenon, including increased capillary permeability, immune complex deposition in the lung, endothelial damage from hypoxia, and an effect of opioids in an area of the brainstem that may control capillary permeability.121 Management The apparent relationship between recent large increases in opioid dose and the development of noncardiogenic pulmonary edema indicates that it should be anticipated in patients who have required massive dose increases of their opioids. Approximately 15% of patients receiving parenteral opioids require rapid increases in daily dose.122 In these patients, consideration should be given to the use of adjuvant analgesic measures with other pharmacologic and nonpharmacologic agents to try to prevent the need for rapid dose escalation. Opioid rotation may be helpful in reducing dose increases because of incomplete cross-tolerance among different opioids.123 Other potential precipitating factors, such as excessive hydration, oxygen therapy, or corticosteroids, should be limited in these patients.

Opioid-induced neurotoxicity Opioid-induced neurotoxicity (OIN) is a syndrome of neuropsychiatric consequences of opioid administration.124 The features of OIN include cognitive impairment, severe sedation, hallucinosis, delirium, myoclonus, seizures,

Table 12.3. Risk factors for OIN

r r r r r r

High opioid dose Prolonged opioid exposure Preexisting borderline cognition/delirium Dehydration Renal failure Opioids with mixed agonist/antagonist activity (e.g., pentazocine, butorphanol, and nalbuphine) r Other psychoactive drugs

hyperalgesia, and allodynia. Patients exhibiting some or all of these features are suffering from OIN. OIN is seen in patients receiving high doses of opioid analgesics for prolonged periods, often in association with psychoactive medications. Often, fluid depletion and renal failure also are present. Risk factors for OIN are summarized in Table 12.3. Sedation, cognitive failure, hallucinosis, and delirium Sedation was described earlier in this chapter. In cases of OIN, it is often seen in association with other features of OIN, such as cognitive failure, and may be a feature of delirium. Cognitive failure is often seen in patients with advanced cancer.125 Although it has multiple causes, opioid treatment plays a major role.125–131 Fig. 12.4 outlines the main causes of cognitive failure and delirium in cancer patients. Cognitive changes may be seen in patients with recent significant increase in opioid dose, but these usually subside within approximately 1 week of being maintained on the opioid.12,132,133 Cognitive dysfunction may be more severe in patients receiving higher doses or opioids having agonist/antagonist activity compared with pure agonists, in patients receiving other psychoactive medications, and in those with borderline cognitive impairment before initiation of treatment.129–131 The impairment usually is a slowing of cognitive abilities rather than an increase in the number of errors or major lapses in judgment.134,135 In cancer patients on long-term opioid treatment, other factors related to the cancer also influence the level of cognitive functioning, and the picture at present is not entirely clear. Advanced cancer patients on stable doses of oral morphine have been compared with advanced cancer patients not on opioids and to healthy age-matched controls. Cancer patients performed less well than healthy controls on all assessments, and those on morphine had poorer grammatical reasoning, alertness, and cognitive function than both other groups.135 In another study that attempted to separate the impact of performance status, pain, and oral opioids

opioid side effects and management

239

Opioids and active metabolites Psychoactive drugs e.g. tricyclic antidepressants, benzodiazepines, alcohol

Thyroid or adrenal dysfunction

Vitamin deficiencies

Metabolic abnormalities e.g. hypercalcemia, hyponatremia COGNITIVE IMPAIRMENT/ DELIRIUM

Paraneoplastic syndromes

Renal or hepatic failure

CNS involvement

Hypoxia

Dehydration

Infection

Other drugs e.g. corticosteroids or NSAIDS causing rena impairment Fig. 12.4. Contributors to cognitive impairment and delirium in cancer patients.

on neuropsychological functioning in cancer patients, the use of long-term oral opioids did not affect any of the neuropsychological tests used. The control group consisted of cancer patients with Karnofsky Performance Status A (able to carry on normal activity and work with no special care needed) who had no pain and received no opioid medication. Those with lower performance status had slower continuous reaction times, and pain was possibly responsible for more deterioration in serial addition task than opioid treatment.136 In an observational study involving only patients with cancer pain receiving opioids, the majority had mental status impairment, with only 23% (8 of 35) retaining full cognitive function.132 In a series of papers studying cognition and reaction time in cancer patients treated for pain, those on opioid analgesics had significant retardation in reaction time when compared with healthy controls14,17 and cancer patients not on opioids.13 Impairment of alertness and cognitive function has major implications in driving ability. In patients with advanced cancer, the presence of malignancy itself aggravates cognitive impairment. The effects of cancer and opioid medication on driving ability have been looked at in a few studies. Cancer patients on regular morphine undergoing a series of psychologic and neurologic tests for assessment of driving ability were compared with those not on opioids.

No significant difference was noted in driving ability, but there was a slight and selective effect on functions related to driving in the patients on long-term morphine.12 Overall, this study suggests cancer patients, both those receiving and not receiving opioids, have significant impairment in driving ability compared with healthy controls. A pilot study looked at pre-driver evaluation and simulator driving evaluation in patients with nonmalignant pain using stable chronic opioid analgesic therapy and compared them to cerebrally compromised patients who had the same evaluations and subsequent behind-wheel driving tests. The comprehensive off-road driving evaluation used measures that have been shown to be sensitive in predicting on-road driving performance. The study generally supported the notion that chronic opioid analgesic therapy did not significantly impair the perception, cognition, coordination, and behavior measured in off-road tests, but the authors commented that methodological problems may limit the generalizability of results and recommended further research.137 In general, patients should be advised to refrain from driving, operating machines, and performing tasks that require significant concentration and psychomotor skills for a period of 3–4 days after initiation of opioid therapy and after significant increases (30%–50%) in their daily dose of opioid. In cases of doubt about driving ability in patients receiving opioids, an appropriate approach would

240 be to ask the patient to take a driving test with the local driving authority or a skilled occupational therapist. Hallucinations have been described in patients receiving opioid analgesia.138–142 Most of the reports have described visual hallucinations. However, tactile hallucinations have been suggested to occur more frequently.143 Occasionally, patients may have hallucinations without obvious cognitive failure,144 and their fear of being considered psychiatrically ill may cause reluctance to reveal the situation to caregivers. In some cases, an abrupt change in the patient’s mood (anxiety or depression) may be the only sign of the development of organic hallucinosis.145 During recent years, a number of authors have documented that delirium is one of the most frequent neuropsychiatric complications in patients with advanced cancer.96,146,147 It is reported that about 80% of cancer patients have delirium near death.147,148 In a prospective series of 131 patients with advanced cancer consecutively admitted to a tertiary palliative care unit, delirium was present in 42% on admission and developed in 45% of the remaining patients. Eighty-eight percent of patients who died had a diagnosis of delirium, and these patients subsequently were shown to have poorer survival rates than controls.147 Patients with delirium present with combinations of cognitive failure, fluctuating levels of consciousness, changes in the sleep–wake cycle, and variable severity of psychomotor agitation, hallucinations, delusions, and other perception abnormalities.149 Psychomotor presentation varies from hyperactive, agitated, and hyperalert features to a hypoactive, withdrawn state; however, a mixed type with features of hyperactivity and hypoactivity is more common.143 Nonagitated delirium is frequently underdiagnosed.150 Myoclonus and seizures Morphine at high doses has been found to induce myoclonus in animals and humans. The term myoclonus is applied to a sudden, brief, shock-like involuntary movement caused by active muscular contractions that may involve a whole muscle or may be limited to a small number of muscle fibers.151 It has been described as being a type of tonic–clonic seizure, representing a continuum of neural effects.152,153 On the other hand, it may represent a pre-epileptiform phenomenon that, if left untreated, may progress to tonic–clonic seizures. In animals, morphine, hydromorphone, and fentanyl have been found to be capable of causing agitation, myoclonus, hyperalgesia, and seizures when administered systemically or intrathecally.154 In humans, myoclonus has been described after the administration of morphine,105,155–157

m. de la cruz and e.d. bruera hydromorphone,158,159 meperidine,160–162 fentanyl and its derivatives,163–165 and diamorphine.166 Studies have shown that high concentrations of these opioids and their metabolites in cerebrospinal fluid may cause myoclonus.167–170 Renal impairment causes metabolite accumulation, which is responsible for myoclonus.155,163,171 In a small prospective trial, 12 of 19 patients treated with oral or parenteral morphine developed myoclonus, and one patient developed hyperalgesia.172 The frequency of patients developing myoclonus was not linked to the plasma concentration of morphine but was associated with the concomitant use of antidepressants, antipsychotics, and NSAIDs. Myoclonus was less likely in patients on steroids. Grand mal seizures may be more likely in patients who have other risk factors, such as a history of seizures, brain metastases, or other metabolic abnormalities. Hyperalgesia and tolerance Hyperalgesia and allodynia are two of the most distressing presentations of opioid toxicity. Hyperalgesia is an exaggerated nociceptive response to noxious stimuli, whereas allodynia is an exaggerated nociceptive response to innocuous stimuli.170 Hyperalgesia and allodynia have been observed following high doses of morphine (both parenteral and intrathecal) in humans.141,156 Sjogren et al.157,171 described this toxicity well. They reported that eight patients demonstrated hyperalgesia and myoclonus after receiving high doses of intravenous morphine and described another series of four patients who developed hyperalgesia during systemic morphine administration. Hyperalgesia may have one of two presentations: 1) an exaggerated nociceptive response – for example, to cutaneous stimulation such as a pinprick – or 2) a worsening of the underlying pain syndrome. The latter type of hyperalgesia has also been described clinically as the development of paradoxical pain.172 Opioid tolerance is described as a reduced sensitivity to the analgesic effects of the drug over time that can be addressed by increasing the dose of opioids. This is of clinical relevance because clinicians may misinterpret this phenomenon by not recognizing it as a neurotoxic adverse effect, and respond by further increasing the opioid dose in an attempt to control the pain. It is important to consider the possibility of OIN in patients with rapid opioid dose escalation. Both phenomena are thought to occur with the activation of neuroexcitatory N-methyl-d-aspartate (NMDA) receptors located in the CNS that initiate intracellular processes resulting in an imbalance between excitatory and inhibitory neurons, causing aberrant nerve activity (hyperalgesia) and

opioid side effects and management opioid receptor downregulation, presumably causing tolerance.173 Another mechanism described in the literature involves neuronal circuits in the brainstem and spinal cord mediated by cholecystokinin and dynorphin, respectively, which with increasing activity, cause amplification of pain signals.174,175 Bowsher176 likewise proposed that the inactive metabolite of morphine-3-glucoronide may result in hyperalgesia. Investigators are only beginning to understand these phenomena. It is still unclear why, how, and when these occur. A number of compounds have been identified as being involved in the mechanism of allodynia in animal studies, including morphine, morphine-3-glucuronide (M3G), normorphine, and hydromorphone. All are capable of causing allodynia in rats after intrathecal administration.173,174 Several experimental models have been proposed to try to explain both tolerance and hyperalgesia. Management of opioid-induced neurotoxicity As is the case with many symptoms in advanced cancer patients, sedation, cognitive impairment, hallucinations, and delirium with agitation or withdrawal have several potential underlying causes. In a previously mentioned prospective study of delirium in advanced cancer patients, a median (range) of three1–6 precipitating factors were identified for each episode of delirium.146 In individuals presenting with possible opioid side effects or toxicity, a detailed assessment is necessary to identify treatable causes. This includes a history (and collateral history if the patient is confused) with particular attention to medications and history of alcohol or substance abuse, a physical examination, and assessment of mental status. When any feature of OIN is present, blood tests to look at complete blood count, electrolytes, renal function, hepatic function, and calcium should be undertaken, along with urinalysis and possibly a chest radiograph if sepsis is considered. Identified possible contributing factors should be treated as appropriate. As approximately 80% of patients have delirium near death, in delirious patients in whom the illness trajectory suggests that death is imminent and further treatment is not planned, it is not appropriate to assess them in this degree of detail. Management of sedation was described earlier. Impaired cognitive function may also respond to a similar management strategy with treatment of underlying contributors, opioid dose reduction where possible, and a trial of psychostimulants in selected patients. Care must be taken to exclude a history of psychiatric disorders in particular hallucinations, delirium, or paranoid ideation, as these may be precipitated or exacerbated by the use of psychostimulants.

241 Table 12.4. Approaches to management of acute episodes of OIN

r r r r

Hydration Opioid rotation Opioid dose reduction or discontinuation Discontinuation of other contributing drugs (e.g., hypnotics, NSAIDs) r Circadian modulation r Symptomatic treatment with haloperidol or other medications

Hallucinations, agitation, or withdrawal in a patient treated with opioids should alert the clinician to the possibility of opioid toxicity. A high index of suspicion is needed in these cases. Simple and reliable instruments, such as the Mini Mental State Examination175 and the Memorial Delirium Assessment Scale,176 are available for the screening, monitoring, and diagnosis of delirium in advanced cancer patients. Lawlor et al.,146 following careful assessment and management, had an overall delirium reversibility rate of 49%; they clearly identified opioid and nonopioid psychoactive medications as precipitating factors independently associated with delirium reversibility. Several strategies have been proposed and successfully used in the management of OIN. Table 12.4 summarizes these approaches. Opioid rotation It is well documented that several of the opioids, as well as their active metabolites, can cause effects considered part of the syndrome of OIN. Morphine has three active metabolites, M3G, M6G, and normorphine. Morphine and its metabolites have all been shown to cause central excitation, which is mediated by receptors that seem to be distinct from the receptors involved in analgesia.169 In animal models, M3G has been shown to antagonize the analgesic effects of morphine and M6G and to induce hyperalgesia, myoclonus, and convulsions.169,177 Normorphone also may cause significant hyperexcitability.178 A recent analysis in patients on long-term morphine treatment indicates that elevated concentrations of M3G in plasma, as well as plasma and cerebrospinal fluid M3G/M6G ratios, may have a pathological role in the development of hyperalgesia, allodynia, and/or myoclonus.178 Morphine, hydromorphone, and fentanyl are capable of causing agitation, myoclonus, hyperalgesia, and tonic−clonic seizures in animals when administered systemically or intrathecally.153,157,179,180,181 If neurotoxicity is thought to be secondary to accumulation of the parent opioid or its active metabolites, switching opioids has been shown to be effective in reversing the symptoms. Several studies have shown that opioid rotation is a safe and effective method for reducing neurotoxicity

242 while retaining analgesia.142,157,158,160,167,171,182–189 Despite the fact that these studies were small and uncontrolled, all patients had evidence of OIN and all were observed to have significant improvement following the opioid rotation. Differences in analgesic or adverse effects following opioid rotation are thought to be the result of a number of mechanisms, including receptor activity, asymmetry in cross-tolerance among different opioids, different opioid efficacies, and accumulation of toxic metabolites.190 A retrospective review of the prevalence of OIN has shown a dramatic decrease in agitated delirium after the institution of hydration and opioid rotation.191 These results justify the use of opioid rotation in the management of OIN and should be the focus of future randomized controlled trials. The ideal alternative opioid has not yet been determined. In patients who develop OIN while on morphine, a trial of hydromorphone or oxycodone is usually effective. The reverse (hydromorphone or oxycodone to morphine) is also effective. If OIN develops after rotation among the first-line agonists, a second-line opioid such as methadone or parenteral fentanyl may be used. Methadone has the advantages of extremely low cost and no known active metabolites but the disadvantages of a long and variable half-life and poorly defined equianalgesic dose as compared with morphine or hydromorphone.192–194 Recent research suggests the benefit of methadone in NMDA receptor antagonism.195–197 Methadone is commonly administered orally or rectally, with good absorption. Cross-tolerance appears to be less than with other opioids, and equianalgesic doses are relatively lower in patients previously exposed to high doses of opioid agonists as compared with patients previously exposed to low doses.198–200 Rotation to methadone can be achieved safely over a 3–4 day period by gradually increasing the dose while decreasing the offending opioid by similar proportions.194 However, rotation to methadone should be attempted only by experienced specialists because of the problem with poorly defined equianalgesic ratios. The management of patients on methadone once the rotation has been completed is no different from other opioid agonists.201 Dose reduction or discontinuation Reduction in dosage or discontinuation of opioids has been shown in several reports to reverse OIN.141,155,202,203 This intervention is clear proof that opioids are causative agents in the neurotoxicity syndrome. The use of adjuvant opioidsparing treatments was mentioned earlier in this chapter.

m. de la cruz and e.d. bruera However, reduction or discontinuation of opioids is rarely possible in patients with advanced cancer pain syndromes. Aggressive opioid rotation may result in lower doses being used in individual patients as well as in programs as a whole,186,204 and this can contribute to a lower overall incidence of OIN in a palliative care program.186,191,204 Circadian modulation Pain and its perception vary from patient to patient, and some studies have demonstrated that the pain intensity can change according to the time of day. A circadian pattern of pain can be demonstrated in patients whose pain is caused by a variety of different diseases,205 and animal experiments have shown that reactions to induced pain also follow circadian rhythmicity.206 Evidence of circadian cycling in patients with advanced cancer pain has been observed only recently. A prospective study measuring the temporal variation of pain in cancer patients found that peak pain consistently occurred in the late afternoon, at around 6:00.207 This has been supported by our group and others who found the peak use of rescue opioids occurred between 6:00 pm and 10:00 pm, whereas the lowest doses were given between 2:00 am and 6:00 am.193,208–212 Further prospective studies should evaluate whether pain management regimes targeted to the circadian variation in pain intensity might reduce overall opioid requirements and the consequent development of OIN or tolerance without jeopardizing effective analgesia. Opioids with a short and predictable half-life, such as fentanyl and its derivatives, might be ideally suited to such studies. Hydration The active metabolites of opioid agonists are water soluble and are likely to accumulate in patients with renal failure or volume depletion. Ensuring patients receive adequate hydration orally or parenterally will decrease the severity and duration of OIN. In the advanced cancer patient, hydration is most easily administered intravenously or subcutaneously.213 If the decision is made not to hydrate a terminally ill patient who is receiving opioid analgesics, it is likely that active opioid metabolites will accumulate as the patient becomes progressively volume contracted and urine output decreases. Under these conditions, patients will require careful reduction in opioid dose and ongoing assessment for signs of OIN. Should the latter develop, opioid rotation may be required. Renal failure in patients with advanced cancer has been associated with an increase in the serum levels of M3G and M6G. These patients also developed signs of OIN.214

opioid side effects and management Although volume status was not noted, the accumulation of toxic metabolites in association with renal failure emphasizes the importance of proper hydration to prevent OIN. In at least one study, the introduction of a policy of hydration resulted in a dramatic and significant decrease in agitated delirium.191 Unfortunately, no determinations of serum levels of opioids or metabolites were made before or after the establishment of hydration. Most effects of OIN resolve within 3−5 days of introduction of opioid rotation and hydration. Other medications The administration of naloxone may be useful in cases of massive acute opioid overdose.124 However, in cancer patients who have been on long-term opioid therapy for ongoing cancer pain, naloxone can precipitate severe pain aggravation, opioid withdrawal syndrome, or toxic−clonic seizures and thus should be used only in exceptional circumstances and with extreme caution.27 Hyperactive delirium caused by opioid therapy is best treated symptomatically with haloperidol to control symptoms until other measures, such as hydration and opioid rotation, start to have an effect.23,215,216 However, it may be difficult to determine whether the cause of delirium is opioid induced or pain related. Increased agitation is often interpreted by families and staff as increased pain, and if the cause is opioid related, increasing the opioid medication may result in significant aggravation of delirium and agitation.217 In most patients, hallucinations, delusions, or agitation will respond rapidly to haloperidol given orally or subcutaneously. If this is not effective, a more sedating alternative, such as chlorpromazine, may be needed. In a very small number of patients whose symptoms cannot be controlled using the aforementioned measures, a continuous subcutaneous infusion of midazolam may be required, usually 25–50 mg in a total volume of 50 mL dextrose 5%, starting at 1 mL/hour and titrating until there is control of symptoms. This treatment results in significant sedation. An array of other medications, such as baclofen, barbiturates, clonazepam and other benzodiazepines, and clonidine, have been used to manage various symptoms of OIN.156,203,218–220 There are few controlled trials addressing the role of these drugs, and the efficacies reported by different groups are sometimes contradictory, as in the cases of baclofen155,202 and diazepam.105 In addition, most of these drugs can cause various forms of neurotoxicity, and recent evidence suggests benzodiazepines may antagonize opioid analgesia.221 Although other medications may improve OIN symptoms, they do not address the underlying cause.

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Table 12.5. Risk factors for opioid dose escalation in cancer patients

r r r r r

Neuropathic pain Incidental pain Tolerance Somatization Substance abuse

Prevention of OIN Prevention and early recognition and treatment of OIN may lead to better quality of life for patients with advanced cancer. Strategies have been developed to ensure good pain control in cancer patients while minimizing the risk of OIN. Prevention is best achieved by individual assessment of risk factors in each patient and by prevention of opioid dose escalation. The main risk factors for OIN are summarized in Table 12.3. These factors should be identified and, if possible, managed rapidly for the prevention of OIN. Prevention of dose escalation Table 12.5 summarizes the main risk factors for opioid dose escalation in cancer patients. Some of them, such as neuropathic pain, tolerance, and incidental pain, are independent predictors of poor pain control. The following paragraphs address the two most frequently unrecognized reasons for dose escalation: psychological distress and somatization and substance abuse. Psychological distress and somatization Patients with advanced cancer have a variety of ways of coping with their diagnosis and disease. Often, the perception of pain or other symptoms may be accentuated by the emotional state or by psychological distress in the patient. This condition of psychological distress, also known as somatization, may lead to excessive somatic complaints that may have no identifiable etiologic or organic basis or may be grossly in excess of expectations based on clinical findings.222–224 Depression is closely related to somatization225,226 and may be the most common cause. Somatization has been associated with neurological227 and cardiovascular diseases,228 but few studies have documented an association in cancer patients.229–231 In one series, 28% of cancer patients referred for psychiatric evaluation were found to have evidence of somatization.232 The psychiatric diagnoses of these patients included depression, anxiety, and atypical somatoform disorder. Because perception of cancer pain is affected by multiple factors, including psychosocial and emotional stressors,233,234 patients who somatize will have a tendency to express pain intensity as higher and will derive

244 little benefit (but often toxicity) from pharmacologic treatment of their pain. In addition to a history of affective disorder, previous somatization associated with stressors (e.g., back pain, headache) and the presence of high intensity for multiple symptoms simultaneously are signs suggestive of somatization. Because of the absence of a gold standard, the diagnosis of somatization is made based on a number of repeated observations, and after extensive discussion with the patient and family. Psychological distress (somatization) has been identified as an independent risk factor for poor pain management in studies evaluating a staging system for cancer pain.28,235–237 These patients are often seen as “suffering” by primary care physicians as well as specialists, who in escalating opioid analgesics often precipitate OIN. In such situations, unidimensional pain assessment (“Pain is what the patient calls pain and has the intensity the patient reports”) is not useful, and multidimensional assessment and treatment strategies must be used.152,238,239 Acknowledgment of the existing underlying pain syndrome and physician support are important, but psychological and spiritual counseling can alleviate some of the emotional suffering, with a subsequent decrease in pain perception and opioid requirements.239,240 Obtaining a detailed psychosocial history from the patient, family members, and/or primary physician can help in identifying maladaptive coping mechanisms and, with careful multidimensional pain assessment, may allow for pain analgesia without OIN.239,241 Substance abuse In a similar vein, cancer patients who have a past or active history of substance abuse present a special pain control problem. Their history of abuse reflects maladaptive coping strategies that frequently lead to excessive expression of symptoms. This often is misinterpreted as nociception, leading to an escalation of opioids and OIN.152,238,242 Recent studies have found that approximately 4%–9% of North Americans have some form of alcohol dependence.243,244 The incidence of addictive disorders in the United States (and likely similar in developed countries) ranges from 3% to 16%.245,246 It has been well documented that persons with one addictive disorder are at increased risk for other forms of substance abuse.245,247 The rates of substance abuse may be higher in medical settings, especially as abusive behavior often leads to medical diseases.248 The rates of addiction in cancer patients also may be higher, as alcohol use and abuse may play an etiologic role in several types of malignant disease (e.g., head and neck, esophageal, hepatocellular carcinoma). Patients with newly diagnosed lung cancer were questioned with respect to psychiatric symptomatology and substance abuse; 46%

m. de la cruz and e.d. bruera of the patients had abused alcohol sometime in their lives, and 13% were currently abusing alcohol.249 In two hundred patients admitted to a tertiary palliative care program, the prevalence of alcoholism was 27%.250 Opioid abuse and misuse are more likely to be seen in cancer patients with a history of drug or alcohol abuse,251,252 and substance abuse has been identified as an independent risk factor for poor pain management.28,199–201 Screening for substance abuse is an important first step in the prevention of escalation of opioids and subsequent development of OIN. The CAGE (cut down, annoy, guilt, eye opener) questionnaire253 has a sensitivity ⬎85% to diagnose alcohol dependence243 and may be done as part of the routine history taking. A positive response to two of the four questions (cut down, annoyed by criticism, experiencing guilt, eye-opener drink in the morning) is indicative of alcohol dependence and may also indicate abuse of other substances.244 Patients should be questioned about their lifelong alcohol intake, as addictive behavior may indicate maladaptive coping strategies that are seldom if ever changed throughout life. Also, it is important to inquire about the desired effects of any substances abused, which can bring out valuable information about comorbid psychiatric or behavioral problems (e.g., anxiety, somatization, depression, personality disorders) or unrelieved symptoms that the patient may find particularly noxious.252 As indicated previously, multidimensional assessment and treatment strategies can be effective in identifying the maladaptive coping (“coping chemically”) of these patients. A retrospective study found that after the institution of routine alcohol screening (using the CAGE questionnaire) and multidimensional assessment, patients could be identified as alcoholics and their pain treatments adapted accordingly. Alcoholic patients had higher doses of opioids on admission, but maximal dose of opioid and pain intensity during inpatient treatment were not significantly different from those in nonalcoholics.250 This is in contrast to earlier studies that found that alcoholics not treated with a multidisciplinary strategy had significantly worse prognosis and pain management problems.251,254 Such treatment strategies can alert the physician to the potential risk of rapid escalation of opioids in substance abusers and help in the prevention of OIN.152,238,239 Overall management Cancer patients receiving opioids for pain likely will always be at some risk for the development of OIN. Prevention and early recognition and treatment of OIN will reduce morbidity in these patients. Strategies for prevention of OIN

opioid side effects and management Table 12.6. Prevention of further episodes of OIN

r Identify and manage risk factors for OIN (Tables 12.3, 12.4) r Identify reasons for opioid dose escalation (Table 12.5) r Carefully monitor for early signs of OIN (included in Table 12.1)

r Educate patient and family about risk factors and early signs of OIN

r Educate primary care physician about risk factors and early signs of OIN

are summarized in Table 12.6. Physicians treating these patients should become familiar with the components of the syndrome to ensure early diagnosis. When faced with a patient exhibiting any or all components of OIN, the physician should ask why the individual is toxic. Is it the presence of one or several risk factors, multiple drug treatments, or opioid dose escalation, or are the patient’s toxic symptoms the result of another reversible cause, such as infection or metabolic abnormalities? Use of a multidisciplinary assessment and treatment approach will motivate the health care team to have a high index of suspicion and ensure the same standard of care is provided to all patients. If symptoms of OIN develop, rapid identification can lead to swift treatment and reversal of toxicity. Once a patient has had an episode of OIN, the risk for subsequent episodes rises. Increased vigilance of this subgroup of patients should be undertaken; if toxicity recurs, treatment using opioid rotation, hydration, or other methods should commence immediately. The authors have found that patients with several risk factors for OIN may require multiple opioid rotations, and the interval between rotations decreases as the patient approaches death. Further preventive strategies, such as psychological counseling for addiction or somatization, should be instituted early as these advanced cancer patients have short life spans and toxicity has major implications for the quality of their remaining life.

Immune system effects There is substantial evidence to support the theory that opiates have an effect on host defenses and are associated with the pathogenesis of infection among intravenous drug users.255 Morphine in vivo has been shown to suppress a variety of immune responses that involve the major cell types in the immune system, including natural killer cells, T cells, B cells, macrophages, and polymorphonuclear leukocytes (PMNs). There is evidence that some of this effect is by direct depression of macrophage and PMN function, but it also appears that there may be an indirect effect on the

245 immune system, possibly through an in vivo neural-immune circuit through which morphine acts to depress the function of all cells in the immune system.256 In a study of postoperative patients receiving opioids, Yardeni et al. demonstrated that patients who received large (70–100 ␮g/kg) or intermediate (23–30 ␮g/kg) doses of fentanyl had diminished proinflammatory cytokine response (interleukin [IL]1␤, IL-6, IL-2, and NKCC [sodium, potassium, chloride cotransporter]) compared with those who received low-dose fentanyl (2–4 ␮g/kg).272 The importance of these findings for cancer patients, especially those with advanced cancer and short life expectancy receiving opioid analgesia, is as yet unknown. It is possible that some of the immune changes ascribed to chemotherapy and advanced cancer may be partly opioid related in some patients. At present, opioid use is not contraindicated in immunosuppressed patients. Knowing whether individual opioids have different effects in these patient populations might help identify better therapies for various groups of patients.

Endocrine effects of opioids Several studies have shown that opioids inhibit the production of multiple hypothalamic, pituitary, adrenal, and gonadal hormones. Opioid administration has been shown to inhibit adrenocorticotropic hormone (ACTH)257 and cortisol levels, and naloxone stimulates the release of ACTH.258–260 Opioids also have been shown to inhibit vasopressin and oxytocin release at the posterior pituitary level, elevate insulin and glucagon, and inhibit somatostatin.261 A series of reports and investigations have described the occurrence of hypogonadism in patients receiving chronic opioid therapy for pain. A retrospective study by Abs et al.262 that looked at 73 patients receiving long-term (range, 3–61 months) intrathecal opioid administration for intractable nonmalignant pain showed hypogonadotrophic hypogonadism in a large majority of patients. There was significant suppression of luteinizing hormone and testosterone in males and a similar decrease in females, with resultant disruption in the menstrual cycle of premenopausal women. Sexual dysfunction was reported in about 95% of the patients taking opioids as compared with controls. Subsequent sex steroid replacement resulted in restored libido but not overall well-being. In addition, 15% were shown to have developed hypocorticism, and approximately the same percentage had developed growth hormone deficiency. A control group of patients who had a comparable pain syndrome but were not treated with opioids was used. There are several implications to this observation as

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246 it has been reported that hypogonadism causes a decrease in bone mass, increased muscle wasting, anemia, and cognitive changes.263 Similarly, chronic deficiency in growth hormone has been shown to result in alteration in body composition (reduced lean body mass and increased fat) and reduced quality of life, described as having poor concentration, social isolation, and lower physical activity.264–266 It has been hypothesized that pain and not opioids causes the sexual dysfunction.267,268 However, there is increasing evidence that opioids are associated with central hypogonadism. The exact mechanism remains unclear. Rajagopal et al.269 analyzed 20 cancer survivor patients receiving chronic opioid therapy and showed that 90% of the patients exhibited central hypogonadism as well as symptoms including fatigue, depression, and sexual dysfunction. The same findings have been reported by similar investigators for patients treated with opioids for noncancer pain.270,271 Daniell,273 in a study of 54 community-dwelling males on chronic opioid therapy, reported that 89% of subjects had low free testosterone and 85% of those who reported a decrease in libido with opioid use had prior normal sexual function. Because of its potential impact on patients’ quality of life, further studies are needed to look at the effect of opioid use on endocrine function in cancer patients. The possibility exists that some of the symptoms we ascribe to cancer may be related at least partly to endocrine dysfunction secondary to opioid administration. In a study of 48 advanced cancer patients, Strasser et al.274 reported that hypogonadism was associated with opioid use. There was note of a trend similar to those seen in other studies of hypogonadism at higher opioid doses. Most endocrine abnormalities are relatively easy to diagnose with blood tests. If some of the symptoms we currently associate with the presence of cancer, such as profound fatigue, reduced libido, and loss of muscle mass, are related to endocrine changes, hormonal supplementation may offer treatment options in patients with these problems.

Conclusion Opioid side effects are relatively frequent but minor in severity. When appropriately diagnosed and managed, these side effects are rarely a cause for drug discontinuation. Increased opioid use has resulted in more frequent observation of opioid-induced toxicity. The main challenges are to make an early and appropriate diagnosis in patients with multiple other possible causes of neuropsychiatric changes. This syndrome can be controlled effectively with simple measures. The potentially important effects of opioids

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213. Fainsinger RL, MacEachern T, Miller MJ, et al. The use of hypodermoclysis for rehydration in terminally ill cancer patients. J Pain Symptom Manage 9:298–302, 1994. 214. Ashby M, Fleming B, Wood M, Somogyi A. Plasma morphine and glucuronide (M3G and M6G) concentrations in hospice inpatients. J Pain Symptom Manage 14:157–67, 1997. 215. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 153:231–7, 1996. 216. Settle EC Jr, Ayd FJ Jr. Haloperidol: a quarter century of experience. J Clin Psychiatry 44:440–8, 1983. 217. Coyle N, Breitbart W, Weaver S, Portenoy R. Delirium as a contributing factor to “crescendo” pain: three case reports. J Pain Symptom Manage 9:44–7, 1994. 218. Fromm GH. Baclofen as an adjuvant analgesic. J Pain Symptom Manage 9:500–9, 1994. 219. Luo L, Puke MJ, Wiesenfeld-Hallin Z. The effects of intrathecal morphine and clonidine on the prevention and reversal of spinal cord hyperexcitability following sciatic nerve section in the rat. Pain 58:245–52, 1994. 220. Waldman HJ. Centrally acting skeletal muscle relaxants and associated drugs. J Pain Symptom Manage 9:434–41, 1994. 221. Gear RW, Miaskowski C, Heller PH, et al. Benzodiazepine mediated antagonism of opioid analgesia. Pain 71:25–9, 1997. 222. Lipowski ZJ. Somatization: the concept and its clinical application. Am J Psychiatry 145:1358–68, 1988. 223. Massie MJ. Somatoform disorder and cancer. In: Holland JC, Rowlands JH, eds. Handbook of psychooncology. Oxford: Oxford University Press, 1989, pp 317–19. 224. Wickramasekera IE. Somatization. Concepts, data, and predictions from the high risk model of threat perception. J Nerv Ment Dis 183:15–23, 1995. 225. Katon W. Depression: relationship to somatization and chronic medical illness. J Clin Psychiatry 45(3 Pt 2):4–12, 1984. 226. Katon W, Kleinman A, Rosen G. Depression and somatization: a review. Part II. Am J Med 72:241–7, 1982. 227. Marsden CD. Hysteria – a neurologist’s view. Psychol Med 16:277–88, 1986. 228. Bass C, Wade C, Hand D, Jackson G. Patients with angina with normal and near normal coronary arteries: clinical and psychosocial state 12 months after angiography. Br Med J (Clin Res Ed) 287:1505–8, 1983. 229. Fobair P, Hoppe RT, Bloom J, et al. Psychosocial problems among survivors of Hodgkin’s disease. J Clin Oncol 4:805–14, 1986. 230. Devlen J, Maguire P, Phillips P, Crowther D. Psychological problems associated with diagnosis and treatment of lymphomas. II: Prospective study. Br Med J (Clin Res Ed) 295:955–7, 1987. 231. Loge JH, Abrahamsen AF, Ekeberg O, et al. Psychological distress after cancer cure: a survey of 459 Hodgkin’s disease survivors. Br J Cancer 76:791–6, 1997. 232. Chaturvedi SK, Hopwood P, Maguire P. Non-organic somatic symptoms in cancer. Eur J Cancer 29A:1006–8, 1993.

opioid side effects and management 233. Cherny NI, Coyle N, Foley KM. Suffering in the advanced cancer patient: a definition and taxonomy. J Palliat Care 10:57–70, 1994. 234. Breitbart W. Cancer pain management guidelines: implications for psycho-oncology [abstract]. Psychooncology 3:103– 8, 1994. 235. Bruera E, Watanabe S. New developments in the assessment of pain in cancer patients. Supportive Care Cancer 2:312–18, 1994. 236. Bruera E, Macmillan K, Hanson J, MacDonald RN. The Edmonton staging system for cancer pain: preliminary report. Pain 37:203–9, 1989. 237. Vigano A, Watanabe S, Bruera E. Methylphenidate for the management of somatization in terminal cancer patients. J Pain Symptom Manage 10:167–70, 1995. 238. Watanabe S, Carmody D, Bruera E. Successful multidimensional intervention in a patient with intractable neuropathic cancer pain. J Palliat Care 13:52–4, 1997. 239. Robinson K, Bruera E. The management of pain in patients with advanced cancer: the importance of multidimensional assessments. J Palliat Care 11:51–3, 1995. 240. Dalton JA, Feuerstein M. Fear, alexithymia and cancer pain. Pain 38:159–70, 1989. 241. Turk DC, Sist TC, Okifuji A, et al. Adaptation to metastatic cancer pain, regional/local cancer pain and non-cancer pain: role of psychological and behavioral factors. Pain 74:247–56, 1998. 242. Chapman CR, Gavrin J. Suffering and its relationship to pain [see comments]. J Palliat Care 9:5–13, 1993. 243. Poulin C, Webster I, Single E. Alcohol disorders in Canada as indicated by the CAGE questionnaire [see comments]. CMAJ 157:1529–35, 1997. 244. O’Connor PG, Schottenfeld RS. Patients with alcohol problems [see comments]. N Engl J Med 338:592–602, 1998. 245. Regier DA, Myers JK, Kramer M, et al. The NIMH Epidemiologic Catchment Area program. Historical context, major objectives, and study population characteristics. Arch Gen Psychiatry 41:934–41, 1984. 246. Savage SR. Long-term opioid therapy: assessment of consequences and risks. J Pain Symptom Manage 11:274–86, 1996. 247. Lehman WE, Barrett ME, Simpson DD. Alcohol use by heroin addicts 12 years after drug abuse treatment. J Stud Alcohol 51:233–44, 1990. 248. Moore RD, Bone LR, Geller G, et al. Prevalence, detection, and treatment of alcoholism in hospitalized patients [see comments]. JAMA 261:403–7, 1989. 249. Ginsburg ML, Quirt C, Ginsburg AD, MacKillop WJ. Psychiatric illness and psychosocial concerns of patients with newly diagnosed lung cancer [see comments]. CMAJ 152:701–8, 1995. 250. Bruera E, Moyano J, Seifert L, et al. The frequency of alcoholism among patients with pain due to terminal cancer. J Pain Symptom Manage 10:599–603, 1995. 251. McCorquodale S, De Faye B, Bruera E. Pain control in an alcoholic cancer patient. J Pain Symptom Manage 8:177–80, 1993.

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252. Passik SD, Portenoy RK, Ricketts PL. Substance abuse issues in cancer patients. Part 2: evaluation and treatment. Oncology (Huntingt) 12:729–34, 1998. 253. Ewing JA. Detecting alcoholism. The CAGE questionnaire. JAMA 252:1905–7, 1984. 254. Bruera E, MacDonald S. Audit methods: the Edmonton Symptom Assessment System. In: Higginson I, ed. Clinical audit in palliative care. Oxford: Radcliffe Medical Press, 1993, pp 61–77. 255. Risdahl JM, Khanna KV, Peterson PK, Molitor TW. Opiates and infection. J Neuroimmunol 83:4–18, 1998. 256. Eisenstein TK, Hilburger ME. Opioid modulation of immune responses: effects on phagocyte and lymphoid cell populations. J Neuroimmunol 83:36–44, 1998. 257. Grossman A, Besser GM. Opiates control ACTH through a noradrenergic mechanism. Clin Endocrinol 17:287–90, 1982. 258. Volavka J, Bauman J, Pevnick J, et al. Short-term hormonal effects of naloxone in man. Psychoneuroendocrinology 5:225–34, 1980. 259. Morley JE, Baranetsky NG, Wingert TD, et al. Endocrine effects of naloxone-induced opiate receptor blockade. J Clin Endocrinol Metab 50:251–7, 1980. 260. Allolio B, Winkelmann W, Hipp FX, et al. Effects of a metenkephalin analog on adrenocorticotropin (ACTH), growth hormone, and prolactin in patients with ACTH hypersecretion. J Clin Endocrinol Metab 55:1–7, 1982. 261. Pfeiffer A, Herz A. Endocrine actions of opioids. Horm Metab Res 16:386–97, 1984. 262. Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 85:2215–22, 2000. 263. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol 161:73–88, 2000. 264. Cuneo RC, et al. The growth hormone deficiency syndrome in adults. Clin Endocrinol (Oxf) 37:387–97, 1992. 265. McGauley GA. Quality of life assessment before and after growth hormone treatment in adults with growth hormone deficiency. Acta Paediatr Scand Suppl 356:70–2, 1989; discussion 73–4. 266. McGauley G. The psychological consequences and quality of life in adults with growth hormone deficiency. Growth Horm IGF Res 10(Suppl B):S63–8, 2000. 267. Bair MJ, et al. Depression and pain comorbidity: a literature review. Arch Intern Med 163:2433–45, 2003. 268. Ambler N, et al. Sexual difficulties of chronic pain patients. Clin J Pain 17:138–45, 2001. 269. Rajagopal A, et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer 100:851–8, 2004. 270. Schneider J. Hypogonadism in men treated with chronic opioids. Arch Phys Med Rehabil 89:1414, 2008; author reply 1414. 271. Fraser LA, Morrison D, Morley-Forster P, et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes 2008 [Epub ahead of print].

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272. Yardeni IZ, Beilin B, Mayburd E, et al. Relationship between fentanyl dosage and immune function in the post-operative period. J Opioid Manag 4:27–33, 2008. 273. Daniell HW. Hypogonadism in men consuming sustain-action oral opioids. J Pain 3:377–84, 2002.

m. de la cruz and e.d. bruera 274. Strasser F, et al. The impact of hypogonadism and autonomic dysfunction on fatigue, emotional function, and sexual desire in male patients with advanced cancer: a pilot study. Cancer 107:2949–57, 2006.

13

Antipyretic analgesics burkhard hinz a and kay brune b a b

University of Rostock and Friedrich-Alexander University, Erlangen

Introduction Antipyretic (or nonopioid) analgesics are a group of heterogenous substances including acidic (nonsteroidal anti-inflammatory drugs [NSAIDs]) and nonacidic (acetaminophen, pyrazolinones) drugs. Moreover, various selective cyclooxygenase-2 (COX-2) inhibitors with improved gastrointestinal tolerability compared with conventional NSAIDs have been established for symptomatic pain treatment in recent years. This chapter summarizes the pharmacology of all these drugs, with particular emphasis on their rational use based on their diverse pharmacokinetic characteristics and adverse drug reaction profiles. Moreover, the mechanisms underlying their antihyperalgesic action are extensively discussed.

Mode of action of antipyretic analgesics Inhibition of cyclooxygenase enzymes In 1971, Vane1 showed that the anti-inflammatory action of NSAIDs rests in their ability to inhibit the activity of the COX enzyme, which in turn results in a diminished synthesis of proinflammatory prostaglandins. This action is considered not the sole but a major factor of the mode of action of NSAIDs. The pathway leading to the generation of prostaglandins has been elucidated in detail. Within this process, the COX enzyme (also referred to as prostaglandin H synthase) catalyzes the first step of the synthesis of prostanoids by converting arachidonic acid into prostaglandin H2 , which is the common substrate for specific prostaglandin synthases. The enzyme is bifunctional, with fatty-acid COX activity (catalyzing the conversion of arachidonic acid to prostaglandin G2 ) and prostaglandin hydroperoxidase activity (catalyzing the conversion of prostaglandin G2 to prostaglandin H2 ).

In the early 1990s, COX was demonstrated to exist as two distinct isoforms.2,3 COX-1 is constitutively expressed as a “housekeeping” enzyme in nearly all tissues, and mediates physiological responses (e.g., cytoprotection of the stomach, platelet aggregation). COX-2, expressed by cells that are involved in inflammation (e.g., macrophages, monocytes, synoviocytes), has emerged as the isoform that is primarily responsible for the synthesis of prostanoids involved in pathological processes, such as acute and chronic inflammatory states. The expression of the COX-2 enzyme is regulated by a broad spectrum of other mediators involved in inflammation. Accordingly, glucocorticoids and anti-inflammatory cytokines (interleukin-4, -10, -13) have been reported to inhibit the expression of the COX-2 isoenzyme.2,4,5 On the other hand, products of the COX-2 pathway (e.g., prostaglandin E2 by virtue of its second messenger, cyclic adenosine monophosphate [cAMP]) may exert a positive feedback action on the expression of its biosynthesizing enzyme in the inflamed tissue6 as well as in numerous cell types.7–10 Likewise, the arachidonic acid derivative and endocannabinoid anandamide was shown to elicit COX-2 expression via de novo synthesis of ceramide.11,12 All conventional NSAIDs interfere with the enzymatic activity of both COX-1 and COX-2 at therapeutic doses.13 In fact, many of the side effects of NSAIDs (e.g., gastrointestinal ulceration and bleeding, platelet dysfunctions) are the result of a suppression of COX-1–derived prostanoids. Likewise, COX-1 inhibition confers hypersensitivity to aspirin and other chemically unrelated NSAIDs in 5%–20% of patients with chronic asthma and in an unknown fraction of patients with chronic urticaria–angioedema. Here, inhibition of COX-1 leads to activation of the lipoxygenase pathway and production of cysteinyl leukotrienes that induce bronchospasm and nasal obstruction. Asthmatic patients

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256 who are intolerant to NSAIDs produce low levels of bronchodilatatory prostaglandin E2 (probably because of a lack COX-2) and have increased levels of leukotriene C4 synthase and reduced levels of metabolites (lipoxins) released through the transcellular metabolism of arachidonic acid.14 On the other hand, inhibition of COX-2–derived prostanoids facilitates the anti-inflammatory, analgesic, and antipyretic effects of NSAIDs. Consequently, the hypothesis that selective inhibition of COX-2 might have therapeutic actions similar to those of NSAIDs, but without causing the unwanted side effects, was the rationale for the development of selective COX-2 inhibitors. However, the simple concept of COX-2 being an exclusively proinflammatory and inducible enzyme cannot be sustained in the light of more recent experimental and clinical findings. Accordingly, COX-2 has also been shown to be expressed under basal conditions in organs including the ovary, uterus, brain, spinal cord, kidney, cartilage, and bone and even in the gut, suggesting that this isozyme may play a more complex physiological role than previously recognized (for review, see Hinz and Brune15 ). Moreover, during the past few years, evidence has increased to suggest that a constitutively expressed COX-2 may play a role in renal and cardiovascular functions, which is discussed in detail later (see “Selective COX-2 Inhibitors”). Impact of biodistribution on pharmacological effects of antipyretic analgesics Following the discovery that aspirin-like drugs exert their pharmacological action by suppressing the synthesis of prostaglandins, the question was asked regarding why aspirin and its pharmacological relatives, the (acidic) NSAIDs, exert anti-inflammatory activity and analgesic effects, whereas the nonacidic drugs phenazone and acetaminophen are analgesic but less anti-inflammatory.16 It was speculated that all acidic anti-inflammatory analgesics, which are highly bound to plasma proteins and show a similar degree of acidity (pKa values between 3.5 and 5.5), should lead to a specific drug distribution within the body of humans or animals. In fact, high concentrations of these compounds are reached in the bloodstream, liver, spleen, and bone marrow (because of high protein binding and an open endothelial layer of the vasculature), but also in body compartments with acidic extracellular pH values.17 The latter type of compartment includes the inflamed tissue, the wall of the upper gastrointestinal tract, and the collecting ducts of the kidneys. By contrast, acetaminophen and phenazone, compounds with almost neutral pKa values and

b. hinz and k. brune a scarce binding to plasma proteins, are distributed homogeneously and quickly throughout the body because of their ability to penetrate barriers, such as the blood–brain barrier, easily.18 It is evident that the degree of prostaglandin synthesis inhibition depends on the potency of the drug and its local concentration. In addition to other factors, the differential distribution of acidic and nonacidic antipyretic analgesics has been proposed to explain why the acidic compounds (NSAIDs) are more anti-inflammatory and cause acute side effects in the gastrointestinal tract (ulcerations), the bloodstream (inhibition of platelet aggregation), and the kidney (fluid and sodium retention), whereas the nonacidic drugs are less anti-inflammatory and elicit no gastric and (acute) renal toxicity. Another explanation for the minor anti-inflammatory action of acetaminophen (the so-called peroxide theory) is discussed later (see “Aniline Derivatives”). Concerning gastrointestinal toxicity, there are, in fact, at least two major components contributing to NSAIDs’ ulcerogenic action in the stomach, namely a topical irritant effect on the epithelium and the ability to suppress prostaglandin synthesis.19–22 Topical irritant properties are confined to acidic NSAIDs, which accumulate in gastric epithelial cells because of the phenomenon of “ion trapping.”18 In this context, NSAIDs have been suggested to produce mucosal injury by uncoupling oxidative mitochondrial phosphorylation in epithelial cells, resulting in diminished cellular adenosine triphosphate production, cellular toxicity due to calcium and reactive oxygen species, and subsequent increased mucosal permeability.21 Noteworthy, the uncoupling property of NSAIDs resides within their carboxylic or enolic acid groups. Accordingly, modifications of the carboxyl group (e.g., flurbiprofen dimer or nitroxybutyl modification of flurbiprofen) render the molecule inactive as an uncoupler of oxidative phosphorylation.21 Further evidence against a sole role of prostaglandin inhibition in conferring the gastrointestinal toxicity of NSAIDs may be derived from observations in COX-1 knockout mice, which do not spontaneously develop gastric ulcers but still develop gastric erosions in response to oral administration of indomethacin.23

Mechanisms of hyperalgesia Inflammation causes an increased synthesis of COX-2– dependent prostaglandins, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Prostaglandins regulate the sensitivity of so-called polymodal nociceptors that are present in nearly all tissues.

antipyretic analgesics A significant portion of these nociceptors cannot be easily activated by physiological stimuli such as mild pressure or some increase of temperature.24 However, following tissue trauma and subsequent release of prostaglandins, “silent” polymodal nociceptors become excitable to pressure, temperature changes, and tissue acidosis.25 This process results in a phenomenon called hyperalgesia – in some instances, allodynia. Prostaglandin E2 and other inflammatory mediators facilitate the activation of tetrodotoxin-resistant Na+ channels in dorsal root ganglion neurons.26–28 Compelling evidence indicates that small dorsal root ganglion neurons are the somata that give rise to thinly and unmyelinated C and A␦ nerve fibers, both conducting nociceptive stimuli. Increased opening of these Na+ channels involves activation of the adenylyl cyclase enzyme and increases in cAMP, possibly leading to protein kinase A–dependent phosphorylation of the channels. Meanwhile, two sensory neuron–specific tetrodotoxin-resistant sodium channel ␣ subunits, Nav 1.8 and Nav 1.9, have been characterized in dorsal root ganglia.29 Another important target of protein kinase A–mediated phosphorylation is the capsaicin receptor (transient receptor potential vanilloid 1 [TRPV1]), a nonselective cation channel of sensory neurons involved in the sensation of temperature and inflammatory pain.30–32 TRPV1 responds to temperatures above 40◦ C and to noxious stimuli, including capsaicin, the pungent component of chili peppers, and extracellular acidification. On the basis of this mechanism, prostaglandins produced during inflammatory states may significantly increase the excitability of nociceptive nerve fibers, including reactivity to temperatures below 40◦ C (i.e., body temperature), thereby contributing to the activation of “sleeping” nociceptors and the development of burning pain. As such, it appears reasonable that at least a part of the peripheral antinociceptive action of acidic antipyretic analgesics arises from prevention of this peripheral sensitization. Apart from sensitizing peripheral nociceptors, prostaglandins act in the central nervous system to produce central hyperalgesia. Experimental data suggest that both acidic and nonacidic COX inhibitors antagonize central hyperalgesia in the dorsal horn of the spinal cord by modulating the glutamatergic signal transfer from nociceptive C-fibers to secondary neurons, which propagate the signals to the higher centers of the central nervous system. Some COX-2 is expressed constitutively in the dorsal horn of the spinal cord and becomes upregulated briefly after a trauma, such as damage to a limb, in the corresponding sensory segments of the spinal cord.33 The induction of

257 spinal cord COX-2 expression may facilitate transmission of the nociceptive input. In line with a role of COX-2 in central pain perception, Smith et al.34 reported that selective COX-2 inhibition suppressed inflammation-induced prostaglandin levels in cerebrospinal fluid, whereas selective inhibition of COX-1 was inactive in this regard. These observations were substantiated by findings showing a widespread induction of COX-2 expression in spinal cord neurons and in other regions of the central nervous system following peripheral inflammation.35 Several mechanisms have been proposed to underlie the facilitatory action of prostaglandin E2 on central pain sensation. Baba et al.36 showed that prostaglandin E2 at relatively high concentrations directly depolarizes wide dynamic range neurons in the deep dorsal horn. More convincingly, prostaglandin E2 at significantly lower concentrations reduces the inhibitory tone of the neurotransmitter glycine onto neurons in the superficial layers of the dorsal horn37 by phosphorylation of the specific glycine receptor subtype GlyR ␣3,38 thereby causing a disinhibition of spinal nociceptive transmission. In a recent study, the same group identified prostaglandin E2 receptors of the EP2 receptor subtype as key signaling elements in spinal inflammatory hyperalgesia,39 thus opening new avenues for the development of new analgesics.

Antipyretic analgesics for the treatment of cancer pain Cancer pain reflects syndromes with a complex etiology involving soft tissue injury or mechanical distortion (tumor expansion in viscera, bone/fascia), lytic processes (e.g., in tumor erosion of the bone or skin), release of neurohumors that activate small afferents, and nerve injury secondary to tumor compression, activation of immune processes, or iatrogenic events such as nerve section for tumor removal (e.g., in postmastectomy pain or radiation injury). The potent inhibitory effect of antipyretic analgesics on pain secondary to bony invasion clearly reflects the important role of prostaglandins in mediating the pain secondary to the lytic processes of tumor invasion. Antipyretic analgesics are the first line of implementation according to the sequence-staged scheme of the World Health Organization (WHO) for cancer pain. With progressive incrementation in the pain state, their use is supplemented by the addition of opioid drugs. The efficacy of NSAIDs in patients with tumor pain has been shown in numerous clinical trials.40–45

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Table 13.1. Indications for antipyretic analgesics Acidic antipyretic analgesics (anti-inflammatory antipyretic analgesics, NSAIDs)a Acute and chronic pain, produced by inflammation of different etiology High dose Middle dose Arthritis: chronic polyarthritis, Diclofenac, indomethacin, Diclofenac, indomethacin, (rheumatoid arthritis), ankylosing ibuprofen, piroxicam ibuprofen, piroxicam, spondylitis (Morbus Bechterew), (phenylbutazone)b (phenylbutazone)b acute gout (gout attack) Cancer pain (e.g., bone metastasis) (Indomethacin),c diclofenac,c (Indomethacin),c diclofenac,c ibuprofen,c piroxicamc ibuprofen,c piroxicamc Active arthrosis (acute pain – No Diclofenac, indomethacin, inflammatory episodes) ibuprofen, piroxicam Myofascial pain syndromes No Diclofenac, ibuprofen, (antipyretic analgesics are often piroxicam prescribed but of limited value) Posttraumatic pain, swelling No (Indomethacin), diclofenac, ibuprofen Postoperative pain, swelling No (Indomethacin), diclofenac, ibuprofen Nonacidic antipyretic analgesics Acute pain and fever Pyrazolinones (high dose) Pyrazolinones (low dose) Spastic pain (colics) Yes Yes Conditions associated with high Yes Yes fever Cancer pain Yes Yes Headache, migraine No Yes General disturbances associated No Yese with viral infections a b c d e f

Low dose No

Aspirin,d ibuprofenc Ibuprofen, ketoprofen Ibuprofen, ketoprofen Aspirin,d ibuprofenc Ibuprofen

Anilines (high dose is toxic) No No Yes Yesf Yes

Dosage range of NSAIDs and example of monosubstances (but note dosage prescribed for each agent). Indicated only in gout attacks. Compare the sequence-staged scheme of WHO for cancer pain. Blood coagulation and renal function must be normal. If other analgesics and antipyretics are contraindicated (e.g., gastroduodenal ulcer, blood coagulation disturbances, or asthma). In particular patients.

By virtue of their combined analgesic and antiinflammatory actions, acidic antipyretic analgesics have been shown to be especially effective in the treatment of moderate to severe pain resulting from bone metastases, mechanical distention of the periosteum, mechanical compression of muscles and tendons (e.g., associated with sarcoma), mechanical distention of the pleura or peritoneum (e.g., associated with intrathoracic or intra-abdominal tumors), and inflammation and stiffness of joints or muscles due to anticancer therapy.46 Nonacidic antipyretic analgesics possess a similar analgesic potency, although they elicit less anti-inflammatory activity. Remarkably, it is impossible to predict which antipyretic analgesic is best tolerated by a particular cancer pain patient. Moreover, neither the minimal effective analgesic dose nor the toxic dose is known for the individual patient with cancer pain, and it may be higher or lower than the recommended dose range of the respective antipyretic analgesic.47 However,

the pharmacokinetic differences of antipyretic analgesics and their profile of adverse effects have some bearing on their optimal clinical use.

Acidic antipyretic analgesics Based on the finding that aspirin at high doses (⬎3 g/day) not only inhibits fever and pain but also interferes with inflammation, Winter et al.48 developed an assay to search for drugs with a similar profile of anti-inflammatory activity. Amazingly, all substances that survived the test of experimental pharmacology and clinical trials turned out to be acids with a high degree of lipophilic–hydrophilic polarity, similar pKa values, and a high degree of plasma protein binding (for review, see Brune and Lanz49 and Hinz50 ). Suggestions for indications including treatment of cancer pain are listed in Table 13.1.

antipyretic analgesics Apart from aspirin, all these compounds differ in their potency; that is, the single dose necessary to achieve a certain degree of effect ranges from a few milligrams (e.g., lornoxicam) to about 1 g (e.g., salicylic acid). They also differ in their pharmacokinetic characteristics, that is, the speed of absorption (time to peak [tmax ], which may also depend on the galenic formulation used), the maximal plasma concentrations (cmax ), the elimination half-life (t1/2 ), and the oral bioavailability. Interestingly, all traditional NSAIDs lack a relevant degree of COX-2 selectivity.13 This is surprising because they have all been selected on the basis of high anti-inflammatory potency and low gastrotoxicity, which depend on COX-1 inhibition. The key characteristics of the most important NSAIDs are compiled in Table 13.2 (most data are from Brune and Lanz49 ). This table also contains the data of aspirin, which differ in many respects from those of other NSAIDs and are therefore discussed at the end of this section in detail (see “Compounds of Special Interest”). Otherwise, the drugs can be categorized in four different groups, which are discussed in the following subsections. NSAIDs with low potency and short elimination half-life The prototype NSAID with low potency and a short elimination half-life is ibuprofen. Depending on its galenic formulation, fast or slow absorption of ibuprofen may be achieved. A fast absorption of ibuprofen was observed following administration of the respective lysine salt.51 The bioavailability of ibuprofen is close to 100%, and the elimination is always fast, even in patients suffering from mild or severe impairment of liver or kidney function.49 Ibuprofen is used as single doses ranging from 200 mg to 800 mg. A maximum dose of 3.2 g/day (United States) or 2.4 g/day (Europe) for rheumatoid arthritis is possible. At low doses, ibuprofen appears particularly useful for the treatment of acute occasional inflammatory pain. High doses of ibuprofen also may be administered, although with less benefit, for the treatment of chronic rheumatic diseases. Remarkably, at high doses, the otherwise harmless compound has been shown to result in an increased incidence of gastrointestinal side effects.52 In some countries, ibuprofen is also administered as the pure S-enantiomer, which comprises the active entity of the racemic mixture in terms of COX inhibition. On the other hand, a substantial conversion of the less potent COX inhibitor R-ibuprofen (comprises 50% of the usual racemic mixture) into the active S-enantiomer has been observed following administration of the racemic mixture.53 Other drugs of this group are salicylates and

259 mefenamic acid. The latter does not appear to offer major advantages. By contrast, this and other fenamates are rather toxic at overdosage (central nervous system). The drugs of this group are particularly useful for blocking occasional mild inflammatory pain. NSAIDs with high potency and short elimination half-life NSAIDs with high potency and a short elimination half-life are prescribed predominantly for the treatment of rheumatic (arthritic) pain. The most widely used compound of this group is diclofenac, which appears to be less active on COX-1 compared with COX-2.13,54 This is taken as a reason for the relatively low incidence of gastrointestinal side effects of diclofenac.55 The limitations of diclofenac result from its usual formulation (monolithic acid-resistant coated drag´ee or tablet). In fact, retention of such formulations in the stomach for hours or even days may cause retarded absorption of the active ingredient.49 Moreover, diclofenac has a considerable first-pass metabolism that causes its limited (about 50%) oral bioavailability. Consequently, a lack of therapeutic effect may require adaptation of the dosage or change of the drug. New formulations (microencapsulations, salts, etc.) remedy some of these deficits.56 The slightly higher incidence of liver toxicity associated with diclofenac may result from the high degree of first-pass metabolism, but other interpretations appear feasible. Recently, it was demonstrated that pharmacologically relevant concentrations of diclofenac are generated through limited but sustained bioactivation following oral administration of aceclofenac.54 As aceclofenac per se does not interfere with the COX enzymes, diclofenac seems to confer a major part of the pharmacological action of aceclofenac. Interestingly, metabolic generation of diclofenac after administration of a 100-mg dose of aceclofenac was associated with an apparently improved COX-2 selectivity compared with a 75-mg dose of a sustained-release diclofenac formulation.54 This group contains other important drugs, such as lornoxicam, flurbiprofen, and indomethacin (very potent), but also ketoprofen and fenoprofen (less active). All of them show a high oral bioavailability and good effectiveness, but also a relatively high risk of unwanted drug effects.55 NSAIDs with intermediate potency and intermediate elimination half-life The third group is intermediate in potency and speed of elimination and comprises drugs such as diflunisal and

b. hinz and k. brune

260 Table 13.2. Physicochemical and pharmacological data of acidic antipyretic analgesics Pharmacokinetic/chemical subclasses

Binding to plasma proteins

Low potency/short elimination half-life Salicylates Aspirin 3.5 50%–70% Salicylic acid

3.0

80%–95%, dose dependent

2-Arylpropionic acids Ibuprofen

4.4

99%

Anthranilic acids Mefenamic acid 4.2 90% High potency/short elimination half-life 2-Arylpropionic acids Flurbiprofen 4.2 ⬎99%

Oral bioavailability

tmax a

t1/2 b

Single dose (maximal daily dose) for adults

∼50%, dose dependent 80%–100%

∼15 minutes 0.5–2 hours

∼15 minutes

0.05–1 gc (∼6 g)

2.5–4.5 hours, dose dependent

0.5–1 g(∼6 g)

100%

0.5–2 hours

2 hours

200–800 mg (2.4 g)

70%

2–4 hours

1–2 hours

250–500 mg (1.5 g)

No data

1.5–3 hours 1–2 hours

2.5–4(–8) hours 2–4 hours

50–100 mg (200 mg) 25–100 mg (200 mg)

1–12 hours,e very variable 0.5–2 hours

1–2 hours

25–75 mg (150 mg)

2–3(–11) hours,d very variable

25–75 mg (200 mg)

0.5–2 hours

4–10 hours

4–12 mg (16 mg)

2–3 hours

8–12 hours, dose dependent

250–500 mg (1 g)

90%–100%

2–4 hours

12–15 hoursd

250–500 mg (1.25 g)

20%–50%

3–6 hours

20–24 hours

0.5–1 g (1.5 g)

∼100%

3–5 hours

89% ∼100%

7–8 hours 0.5–2 hours

14–160 hoursd 20 hourse 25–175 hoursd

20–40 mg; initial: 40 mg 7.5–15 mg 20–40 mg; initial: 40 mg

Ketoprofen 5.3 Aryl-/heteroarylacetic acids Diclofenac 3.9

99%

∼90%

99.7%

∼50%, dose dependent

Indomethacin

4.5

99%

∼100%

Oxicams Lornoxicam

4.7

99%

∼100%

Intermediate potency/intermediate elimination half-life Salicylates Diflunisal 3.3 98%–99% 80%–100% 2-Arylpropionic acids Naproxen 4.2 99% Arylacetic acids 6-Methoxy-2-naphthyl4.2 99% acetic acid (active metabolite of nabumetone) High potency/long elimination half-life Oxicams Piroxicam 5.9 99% Meloxicam Tenoxicam a b c d e

4.08 5.3

99.5% 99%

Time to reach maximum plasma concentration after oral administration. Terminal half-life of elimination. Single dose for inhibition of thrombocyte aggregation: 50–100 mg; single analgesic dose: 0.5–1 g. Enterohepatic circulation. Monolithic acid-resistant tablet or similar galenic form.

antipyretic analgesics naproxen. Because of its slow absorption, diflunisal is rarely used anymore. NSAIDs with high potency and long elimination half-life The fourth group consists of the oxicams (meloxicam, piroxicam, and tenoxicam). These compounds are characterized by a high degree of enterohepatic circulation, slow metabolism, and slow elimination.49 Because of their long half-life (days), oxicams do not represent drugs of first choice for the treatment of acute pain of short duration. The main indication of the oxicams is inflammatory pain that persists for days, that is, pain resulting from cancer (bone metastases) or chronic polyarthritis. The high potency and long persistence in the body may be the reason for the somewhat higher incidence of serious adverse drug effects in the gastrointestinal tract and in the kidney observed in the presence of these drugs.55 Compounds of special interest Aspirin, the prototypic NSAID, deserves special discussion. This drug irreversibly inactivates both COX-1 (highly effective) and COX-2 (less effective) by acetylating an active-site serine. Consequently, this covalent modification interferes with the binding of arachidonic acid at the COX active site. Most cells compensate for the enzyme loss due to acetylation by aspirin via de novo synthesis of this enzyme. However, as platelets are unable to generate fresh enzyme, a single dose of aspirin may suppress platelet COX-1–dependent thromboxane synthesis for the whole lifetime of thrombocytes (8–11 days) until new platelets are formed. Following oral administration, aspirin is substantially cleaved before, during, and shortly after absorption to yield salicylic acid. Consequently, the oral bioavailability is low and the plasma half-life of aspirin is only about 15 minutes. Aspirin may be used as a solution (effervescent) or as a (lysine) salt, allowing very fast absorption, distribution, and pain relief. Aspirin may cause bleeding from existing ulcers because of its long-lasting antiplatelet effect and topical irritation of the gastrointestinal mucosa.57 The inevitable irritation of the gastric mucosa may be acceptable in otherwise healthy patients. Aspirin should not be used in pregnant women (premature bleeding, closure of ductus arteriosus) or children before puberty (Reye’s syndrome), in addition to the contraindications pertinent to all NSAIDs. When low doses of aspirin (≤100 mg) are administered, aspirin acetylates the COX-1 isozyme of platelets presystemically in the portal circulation before aspirin is

261 deacetylated to salicylate in the liver. By contrast, COX2–dependent synthesis of vasodilatory and antithrombotic prostacyclin by vascular endothelial cells outside the gut is not altered by low-dose aspirin. The reason for this phenomenon lies in the rapid cleavage of aspirin, leaving little if any unmetabolized aspirin after primary liver passage. Thus, low-dose aspirin has its only indication in the prevention of thrombotic and embolic events. An unresolved question concerns the use of low-dose aspirin together with other COX-2–selective or –nonselective NSAIDs. In this context, it has been shown that the combination of low-dose aspirin with COX-2–selective inhibitors may abrogate the gastrointestinal-sparing effects of the latter compounds.52,58 Moreover, ibuprofen and naproxen (the latter at higher than nonprescription doses) can interfere with the antiplatelet activity of low-dose aspirin when they are coadministered.59,60 The underlying mechanism might be a competitive inhibition at the acetylation site of platelet COX-1. The clinical implication of this interaction is unclear. It is, however, potentially important because the cardioprotective effect of aspirin, when used for secondary prevention of myocardial infarction, could be decreased or negated if NSAIDs also are used. In this context, a small epidemiological study of survivors of myocardial infarction suggested that concurrent ibuprofen but not diclofenac undermined the efficacy of aspirin in preventing a second myocardial infarction.61 Therefore, current recommendations by the U.S. Food and Drug Administration62 advise patients who use immediate-release aspirin and take a single 400 mg-dose of ibuprofen should dose the ibuprofen at least 30 minutes or longer after aspirin ingestion, or more than 8 hours before aspirin ingestion.

Nonacidic antipyretic analgesics Aniline derivatives The main representative of the aniline derivatives as a group is acetaminophen (Table 13.3). This drug possesses weak anti-inflammatory but efficient analgesic and antipyretic activity. The major advantage of acetaminophen lies in its relative lack of serious side effects provided that the dose limits are obeyed, although serious events can be observed with low doses, although rarely so.63 A small proportion of acetaminophen is metabolized to the highly toxic nucleophilic N-acetyl-benzoquinoneimine that is usually inactivated by reaction with sulfhydryl groups in glutathione. However, following ingestion of large doses of acetaminophen, hepatic glutathione is depleted, resulting in covalent binding of N-acetyl-benzoquinoneimine to

b. hinz and k. brune

262

Table 13.3. Physicochemical and pharmacological data of paracetamol and pyrazolinone derivatives Chemical/pharmacological class Aniline derivatives Acetaminophen (INN, paracetamol) Pyrazolinone derivatives Phenazone

Binding to plasma proteins

Oral bioavailability

5%–50%, dose dependent ⬍10%

Propyphenazone

∼10%

Dipyrone (INN, metamizolc ) 4-Methylaminophenazoned 4-Aminophenazoned

⬍20% 58% 48%

a b c d

tmax a

t1/2 b

Single dose (maximal daily dose) for adults

70%–100%, dose dependent

0.5–1.5 hours

1.5–2.5 hours

0.5–1 g (4 g)

∼100%, dose dependent ∼100%, dose dependent – ∼100% –

0.5–2 hours

11–12 hours

0.5–1 g (4 g)

0.5–1.5 hours

1–2.5 hours

0.5–1 g (4 g)

– 1–2 hours –

– 2–4 hours 4–5.5 hours

0.5–1 g (4 g) – –

Time to reach maximum plasma concentration after oral administration. Terminal half-life of elimination. Noraminopyrinemethansulfonate-Na. Metabolites of metamizol.

DNA and structural proteins in parenchymal cells (e.g., in liver and kidney; for review, see Seeff 64 ). Under these circumstances, dose-dependent, potentially fatal hepatic necrosis may occur. When detected early, overdosage can be antagonized within the first 12 hours after intake of acetaminophen by administration of N-acetylcysteine, which regenerates detoxifying mechanisms by replenishing hepatic glutathione stores. Accordingly, acetaminophen should not be given to patients with seriously impaired liver function. Typical indications of acetaminophen are fever and pain occurring in the context of viral infections. In addition, many patients with recurrent headache benefit from acetaminophen and its low toxicity. Acetaminophen is also used in children, but despite its somewhat lower toxicity in juvenile patients, fatalities due to involuntary overdosage have been reported. According to a recent update of American College of Rheumatology guidelines for osteoarthrosis, acetaminophen remains first-line therapy because of its cost, efficacy, and safety profiles.65 In fact, acetaminophen provides effective relief of pain for many patients with osteoarthrosis, and has been demonstrated to be safe in a wide range of populations, providing less severe or no gastrotoxic side effects compared with NSAIDs.66 Like NSAIDs, acetaminophen is routinely used in the treatment of cancer pain. The pharmacological mode of action of acetaminophen is still a matter of debate. In this context, it is commonly stated that acetaminophen acts centrally and is at best a weak inhibitor of prostaglandin synthesis by COX1 and COX-2.67 This concept is based on early work by

Flower and Vane,68 who showed that prostaglandin production in brain is 10 times more sensitive to inhibition by acetaminophen than that in spleen. However, this finding was not supported by later studies.69–71 Moreover, it turned out that acetaminophen elicits no measurable inhibition of prostaglandin formation in broken cell preparations, but a profound suppression in intact cells.72 Attempts to explain the pharmacological action of acetaminophen as inhibition of a central COX isoform, derived from the same gene as COX-1 and referred to as COX-3,73 meanwhile have been rejected for several reasons.74 Currently, the most plausible mode of action of the drug is the “peroxide theory” that has been suggested on the basis of observations showing that acetaminophen inhibits the COX enzymes by reducing the higher oxidation state of these proteins.75 In line with this finding, high levels of peroxides were shown to overcome the inhibitory effect of acetaminophen on the COX enzymes in platelets and immune cells. Therefore, high extracellular levels of peroxide in the inflamed tissue also may explain why acetaminophen does not suppress inflammation associated with rheumatoid arthritis76,77 – and why early investigations led to the claim that acetaminophen possesses no anti-inflammatory activity at all. On the other side, it is noteworthy that acetaminophen decreases tissue swelling following oral surgery in humans, with activity very similar to that of ibuprofen.78,79 A peripheral anti-inflammatory action is further supported by findings showing acetaminophen as an inhibitor of nociception and edema in the rat carrageenan footpad model,80,81 an inflammatory condition critically dependent on COX-2–derived prostaglandins.34

antipyretic analgesics The pharmacological profile of acetaminophen is very similar to that of selective COX-2 inhibitors (for review, see Graham and Scott72 ). Like coxibs, acetaminophen given orally at recommended single doses elicits no toxic effect on the gastrointestinal tract,82 does not inhibit platelet function,58,83 and hardly provokes bronchoconstriction in aspirin-sensitive asthmatics.84 In accordance with these observations, a recent clinical study has shown that oral administration of 1000 mg of acetaminophen to human volunteers inhibited blood monocyte COX-2 by more than 80%, that is, to a degree comparable with that of NSAIDs and selective COX-2 inhibitors.85 In this study, acetaminophen displayed about a fourfold selectivity for inhibition of COX-2 both in vitro and in vivo.85 By contrast, a COX-1 blockade relevant for inhibition of platelet function (⬎95%) was not achieved,85 reflecting the weak antiplatelet activity and good gastrointestinal safety of acetaminophen. Concerning the impact of acetaminophen on cardiovascular function, a prospective cohort study found that regular consumption of acetaminophen was associated with a significantly higher risk for development of hypertension compared with no use.86 Noteworthy, the relative risk of acetaminophen was similar to that of NSAIDs. Moreover, a recently published large prospective study showed that use of acetaminophen at more than 15 tablets per week confers nearly the same risk for cardiovascular events as traditional NSAIDs.87 The reason for this unexpected behavior is unclear and deserves further investigation. However, in view of its substantial COX-2 inhibition and recent concepts linking long-term suppression of COX-2 to cardiovascular side effects (see “Selective COX-2 Inhibitors), an evaluation of acetaminophen’s cardiovascular risks appears to be warranted in future studies. Pyrazolinone derivatives Following the discovery of phenazone 120 years ago, the pharmaceutical industry has tried to improve this compound in three ways: Phenazone was chemically modified to 1) create a more potent compound, 2) yield a water-soluble derivative to be given parenterally, and 3) produce a compound that is eliminated faster and more reliably than phenazone. The results of these attempts are the phenazone derivatives aminophenazone, dipyrone (international nonproprietary name [INN], metamizol), and propyphenazone (Table 13.3). Aminophenazone is not in use anymore because it has been associated with formation of nitrosamines that may increase the risk of stomach cancer. The other two compounds differ from

263 phenazone in their potency and elimination half-life, their water solubility (dipyrone is a water-soluble prodrug of 4methylaminophenazone), and their general toxicity (propyphenazone and dipyrone do not lead to the formation of nitrosamines in the acidic environment of the stomach). Phenazone, propyphenazone, and dipyrone are the predominantly used antipyretic analgesics in many countries (Latin America, many countries in Asia, Eastern and Central Europe). All nonacidic phenazone derivatives are devoid of gastrointestinal and (acute) renal toxicity. In contrast to acetaminophen, dipyrone is safe even when given at overdosages. Pharmacological aspects of dipyrone deserve special discussion. The drug is available in oral, rectal, and injectable forms. Dipyrone is indicated for severe pain conditions, particularly for those associated with smooth muscle spasm or colics affecting the gastrointestinal, biliary, or urinary tracts. Moreover, dipyrone is useful for treatment of cancer pain and migraine as well as fever refractory to other treatments. In a double-blind, randomized, parallel clinical trial, the analgesic effect of dipyrone (2 g every 8 hours) in patients with chronic cancer pain was similar to that of oral morphine (10 mg every 4 hours).88 Dipyrone has been accused of causing agranulocytosis. Although there appears to be a statistically significant link, the incidence is extremely rare (one case per million treatment periods).89–91 Another evaluation of epidemiological studies showed that the estimated excess mortality per million users due to community-acquired agranulocytosis, aplastic anemia, anaphylaxis, and serious upper gastrointestinal complications is 0.25 for dipyrone, which is comparable with that of acetaminophen (0.2), but significantly lower than that for aspirin (1.85) or diclofenac (5.92).92 These differences are a result of gastrointestinal complications that represent the main cause of NSAIDinduced mortality. However, a persisting debate concerning dipyrone’s risk of agranulocytosis hampered further clinical investigations with the drug. Accordingly, there are no clinical studies addressing dipyrone’s impact on chronic noncancer pain.93 Likewise, animal studies suggesting a minor anti-inflammatory action of dipyrone as compared with NSAIDs94,95 have not been readdressed in humans. In a recently published clinical study, dipyrone was shown to cause a fast and pronounced inhibition of COX-2 in human blood monocytes of probands treated with the drug at pharmacological doses,96 supporting the view that a significant portion of dipyrone’s analgesic action may be a result of peripheral mechanisms. Moreover, diyprone caused a pronounced COX-1 inhibition, which was similar to that observed with various traditional NSAIDs.96 Given

264 the gastrointestinal safety of dipyrone shown in epidemiological studies97,98 and its apparently contradictory impact on COX-1, it was suggested that physicochemical factors (lack of acidity) rather than differences in COX-1 inhibition may be responsible for dipyrone’s favorable gastric tolerability as compared with acidic NSAIDs.

Selective COX-2 inhibitors Selective inhibitors of the COX-2 enzyme, also referred to as coxibs, have been developed as substances with therapeutic actions similar to those of NSAIDs, but without causing gastrointestinal side effects. By definition, a substance may be regarded as a selective COX-2 inhibitor if it causes no clinically meaningful COX-1 inhibition at maximal therapeutic doses. Selective COX-2 inhibitors currently used are the sulfonamide celecoxib, the methylsulfone etoricoxib and (still marketed in Mexico, Ecudor, The Bahamas) the phenylacetic acid derivative lumiracoxib. Of these, celecoxib is the only COX-2 inhibitor available in the United States. Another COX-2 inhibitor, marketed in the European Union for treatment of postoperative pain, is parecoxib, an injectable prodrug of valdecoxib. Pharmacological data on COX-2 inhibitors used for oral treatment of pain are compiled in Table 13.4. Presently, however, for all these compounds, the labeling does not include tumor pain. Differences in physicochemical characteristics are reflected in different pharmacokinetic behavior (for review, see Brune and Hinz99 ). Accordingly, the nonacidic compounds celecoxib and etoricoxib distribute homogenously in the body (Vd ≈ 1 kg/L), whereas the acidic lumiracoxib, like other acetic acid derivatives (e.g., diclofenac), distributes unequally to concentrate in blood, inflamed tissue, kidney, and liver (Vd ≈ 0.15 kg/L).49 Because of its very high lipophilicity, the absorption of celecoxib is relatively slow and incomplete; this compound undergoes considerable first-pass metabolism (20%–60% oral bioavailability), and its rate of elimination (t1/2 ∼6–12 hours) appears to be highly variable.100–102 Etoricoxib is eliminated from the body slowly (t1/2 ∼20–26 hours) and is absorbed at a fast rate, which appears to cause its fast onset of action.103 Of the COX-2 inhibitors, lumiracoxib has the highest selectivity toward COX-22 in vitro and the shortest pharmacological half-life (t1/2 ∼2–6 hours). Lumiracoxib, as it is an amphiphilic molecule, persists for a long time in the synovial fluid, which might explain the long-lasting efficacy of this drug; patients with rheumatoid arthritis treated with lumiracoxib at 400 mg once daily for 7 days had approximately threefold higher steady-state concentrations of lumiracoxib in synovial fluid as compared

b. hinz and k. brune with plasma.104 As this kinetics of distribution is likely to extend the therapeutic action of lumiracoxib beyond that expected from plasma pharmacokinetics, the data support the use of lumiracoxib in a once-daily regimen for the treatment of rheumatoid arthritis. Administering lumiracoxib at 400 mg, however, considerably exceeds the dose necessary to inhibit COX-2 at the time of maximal plasma concentration, implying that the long-lasting analgesic effect of lumiracoxib at therapeutic doses, administered once a day, might be also be a result of the fact that administration of the drug at high doses translates into an extended pharmacodynamic half-life. Since the end of 2006, lumiracoxib had been approved at the indicated 100-mg dose in some European Union countries, including Germany. In other countries, including the United Kingdom, lumiracoxib is approved for the symptomatic relief of osteoarthritis at 100–200 mg daily and at 400 mg daily for the short-term relief of moderate to severe acute pain associated with primary dysmenorrhea, dental surgery, and orthopedic surgery. A shortcoming of the compound lies in its dose-dependent liver toxicity. Accordingly, the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) revealed a transaminase rise of more than three times the upper limit of normal in 2.6% of patients receiving 400 mg of lumiracoxib, which was more than that of NSAIDs (0.6%), but was reversible on drug discontinuation.58 In August 2007, Australia’s drugs regulator – the Therapeutic Goods Administration – canceled the registration of lumiracoxib because of concerns over hepatic toxicity (eight cases of serious liver side effects, including two deaths, with another two patients needing liver transplants) in patients receiving the drug at daily doses ≥200 mg.105 Referring to estimations, approximately 60,000 patients have used lumiracoxib in Australia, and the majority of these have been prescribed 200-mg tablets for the management of osteoarthrosis. According to the manufacturer’s notion, the 100-mg dose of lumiracoxib, which is the recommended dose worldwide for treatment of osteoarthritis, has not been associated with an unexpected incidence of liver-related side effects in an osteoarthrosis population. However, the European Medicines Agency likewise recommended (in December 2007) the withdrawal of lumiracoxib at the approved 100-mg level due to a few cases of nonlethal liver damage. Recent data have shown that lumiracoxib elicits a similar COX-2 inhibitory profile at 50, 100, and 200 mg raising the question whether doses lower than 100 mg are sufficient for pain therapy.106 All COX-2 inhibitors undergo oxidative drug metabolism by cytochrome P450 (CYP) enzymes. Celecoxib has been

61

344

272

700

Valdecoxib (parecoxib)h

Methylsulfons Etoricoxib

Rofecoxib

Arylacetic acid Lumiracoxibk ∼13 L

∼90 L

∼87% ∼99%

∼120 L

∼90 L

∼98%

∼92%

∼400 L

Vd c

∼97%

Binding to plasma proteins

∼74%

∼93%i

∼100%

∼83%

20%–60%

Oral bioavailability

1–3 hours

2–4 hours

∼1 hour

2–4 hours

2–4 hours

tmax d

2–6 hours

15–18 hours

20–26 hours

6–10 hours

6–12 hours

t1/2 e

Oxidation to hydroxylumiracoxibl (CYP2C9)

Cytosolic reductase j

Oxidation to 6 -hydroxymethyletoricoxib (major role: CYP3A4; ancillary role: CYP2C9, 2D6, 1A2)

Oxidation to hydroxyvaldecoxib (CYP2C9, 3A4)g

Oxidation (CYP2C9, 3A4)g

Primary metabolismf (CYP enzymes)

b

Despite withdrawal from the market, rofecoxib, valdecoxib, and lumiracoxib are included for comparative reasons. Ratio of half maximal inhibitory concentration (IC50 ) values (IC50 COX-1/IC50 COX-2) in the human whole-blood assay. c Volume of distribution. d Time to reach maximum plasma concentration after oral administration. e Terminal half-life of elimination. f All metabolites are less active than the parent compound (except parecoxib). g Compounds may inhibit CYP2D6. h Parecoxib is the water-soluble prodrug of valdecoxib, releasing valdecoxib within about 15 minutes, tmax : ∼30 minutes. i Less at not recommended dosage. j Compound may inhibit CYP1A2. k Lumiracoxib is still marketed in Mexico, The Bahamas, and Ecuador for osteoarthritis (100 mg) and acute pain (400 mg). l Analogous to diclofenac, the metabolism of lumiracoxib probably involves other CYP enzymes, such as CYP2C8 or CYP2C19. Abbreviations: IM, intramuscular; IV, intravenous.

a

30

Sulfonamides Celecoxib

COX-1/ COX-2 ratiob

Table 13.4. Physicochemical and pharmacological data of selective COX-2 inhibitorsa

Lumiracoxib was withdrawn in 2007–2008 in several countriesk

90 mg (90 mg) for rheumatoid arthritis 120 mg (120 mg) for acute gouty arthritis Rofecoxib was withdrawn in September 2004

60 mg (60 mg) for osteoarthrosis

100–200 mg (400 mg) for osteoarthrosis and rheumatoid arthritis Valdecoxib was withdrawn in March 2005 Parecoxib (still marketed): 20–40 mg IV/IM (80 mg) for short-term pain relief after surgery

Single dose (maximal daily dose) for adults

266 shown to inhibit the metabolism of the CYP2D6 substrate metoprolol, a widely used ␤-blocker.101 This interaction also may interfere with the elimination of other CYP2D6 substrates, including sedatives, serotonin reuptake inhibitors, tricyclic antidepressants, and some neuroleptics. On the basis of their diverse pharmacokinetics, use of different COX-2 inhibitors in different clinical settings is recommended. Accordingly, the slow absorption and variable first-pass metabolism of celecoxib limit its utility for treatment of acute pain. By contrast, etoricoxib appears promising for this indication, particularly when prolonged action is required, as in gouty arthritis and rheumatoid arthritis. The hypothesis that selective COX-2 inhibitors may provide an improved risk–benefit ratio in terms of gastrointestinal safety as compared with conventional NSAIDs was tested in three large phase III clinical trials in a total of 35,000 patients. In the Gastrointestinal Outcomes Research (VIGOR) study108 and in TARGET,59 rofecoxib and lumiracoxib were found to decrease the risk of confirmed gastrointestinal events (including ulcerations, bleedings, and perforations) associated with traditional NSAIDs by more than 50%. In the Celecoxib Long-term Arthritis Safety Study (CLASS), however, a significant beneficial effect of celecoxib was evident only when the definition of upper gastrointestinal end points was expanded to include symptomatic ulcers.52 Moreover, outcomes of the first 6 months were published instead of the complete 1-year data of this study. In accordance with a decisive role of COX-1 in aspirininduced asthma, COX-2 inhibitors were well tolerated by aspirin-sensitive asthmatic patients in several reexposure studies.109–112 However, these findings are not yet seen as proof, and the product information of all COX-2 inhibitors still regards aspirin-induced asthma as a contraindication. COX-2 inhibitors have been associated with an increased incidence of cardiovascular side effects. In fact, in placebocontrolled randomized clinical studies, rofecoxib and celecoxib were shown to increase the incidence of cardiac infarctions and other cardiovascular reactions after a prolonged period of treatment.113,114 With respect to the original purpose of these studies (i.e., Adenomatous Polyposis Prevention Study with Rofecoxib [APPROVE] and Adenoma Prevention with Celecoxib [APC]), both trials demonstrated a significant reduction in new adenoma formation associated with the use of COX-2 inhibitors in patients with a previous history of colorectal carcinomas. Moreover, in high-risk patients, short-term treatment with valdecoxib or parecoxib was associated with an increased number of severe thromboembolic events.115 These observations had various pharmaco-political conse-

b. hinz and k. brune quences: Rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market, and regulatory bodies were prompted to request changes in the labeling of both selective and nonselective COX inhibitors, including those available for over-the-counter use.116 To minimize this risk, the respective substances should be taken at the lowest effective dose for the shortest possible duration of treat ment.117,118 In contrast to COX-2 inhibitors, no placebo-controlled randomized trial was designed to define the cardiovascular risk of NSAIDs. However, a recently published metaanalysis of 138 randomized trials119 concluded that the incidence of serious vascular events is similar between a COX-2 inhibitor and any non-naproxen NSAID, and that the risk of naproxen is in the placebo range. The summary rate ratio for vascular events, compared with placebo, was 0.92 for naproxen, 1.51 for ibuprofen, and 1.63 for diclofenac. Furthermore, population-based nested case-control studies have shown an increased risk of myocardial infarction associated with the current use of both COX-2 inhibitors and traditional NSAIDs.120,121 Finally, comparable rates of thrombotic cardiovascular events have been reported for the highly selective COX-2 inhibitor etoricoxib and the traditional NSAID diclofenac in the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-Term) study program,122 which involved ∼35,000 patients with osteoarthritis or rheumatoid arthritis, suggesting that there is presently no rationale for a further differentiation of COX-2 inhibitors and NSAIDs in terms of cardiovascular safety. The currently most plausible explanation for the cardiovascular hazard conferred by long-term use of selective and nonselective COX-2 inhibitors is a permanent blockade of COX-2–dependent prostaglandins, including prostacyclin. In fact, prostacyclin, which is suppressed by over 60% by NSAIDs and COX-2 inhibitors,123 is not only a potent inhibitor of platelet aggregation, but also interferes with processes leading to hypertension, atherogenesis, and cardiac dysfunction. In the cardiorenal hypothesis, changes in arterial blood pressure have been proposed to underlie the long-term cardiovascular side effects of both NSAIDs and COX-2 inhibitors. The involvement of COX-2 in human renal function is supported by numerous clinical studies that showed that COX-2 inhibitors, similar to NSAIDs, can cause peripheral edema, hypertension, and exacerbation of preexisting hypertension by inhibiting water and salt excretion by the kidneys.124–126 These observations are of major importance given that relatively small changes in blood pressure could have a significant impact on cardiovascular events. In patients with osteoarthritis, increases in systolic blood pressure of 1–5 mm Hg have been associated with

antipyretic analgesics 7100–35,700 additional ischemic heart disease and stroke events over 1 year.127 Recently, it has been suggested that both degree and time course of intravascular COX-2 inhibition might determine the differential profile of cardiovascular side effects associated with NSAIDs and COX-2 inhibitors.102 Claims that NSAIDs inhibit COX-1, thereby conferring cardioprotection, proved wrong because platelet COX-1 activity has to be suppressed ⬎95% to translate into inhibition of platelet aggregation.128 Such a complete COX-1 inhibition over the whole dosing interval is achieved only with low-dose aspirin and, in some individuals, with high-dose naproxen (500 mg twice daily).128,129 Other NSAIDs, such as ibuprofen and diclofenac, suppress COX-1 (⬎95%) only at peak plasma concentrations. This is consistent with an increased cardiovascular risk with high-dose diclofenac and ibuprofen, but not with naproxen.119

Future developments The available traditional antipyretic analgesics and selective COX-2 inhibitors still leave space for additional compounds. In past years, inhibition of the microsomal prostaglandin E synthase I that is coexpressed with COX-2 under diverse inflammatory conditions has been suggested to represent a potential target for treatment of inflammatory pain.130 From the pharmacological point of view, an inhibition of this enzyme would open the opportunity to inhibit the production of COX-2–dependent proinflammatory prostaglandin without a concomitant blockade of COX-2–dependent prostacyclin, which confers various protective actions in the cardiovascular and renal system. Finally, targeting of individual prostaglandin receptor subtypes may permit a separation of desired and unwanted effects of NSAIDs. Recently, blockade of the EP2 receptor has attracted attention as a possible target for centrally acting, antihyperalgesic agents.39 Alternative strategies might interfere with targets beyond prostanoid synthases or prostanoid receptors, such as transient receptor potential channels, tetrodotoxin-resistant sodium channels, and inhibitory glycine receptors (for review, see Zeilhofer and Brune K131 ). Currently, however, palliative therapy of cancer pain has to rely on COX inhibitors, whose diverse pharmacokinetics and adverse reaction profiles should be considered in daily practice. References 1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs. Nat New Biol 231:232–5, 1971.

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hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 289:735–41, 1999. Schwartz JI, Vandormael K, Malice MP, et al. Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet. Clin Pharmacol Ther 72:50–61, 2002. Whelton A, Maurath CJ, Verburg KM, Geis GS. Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am J Ther 7:159–75, 2000. Singh G, Miller JD, Huse DM, et al. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol 30:714–19, 2003. Reilly IA, FitzGerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 69:180–6, 1987. Capone ML, Tacconelli S, Sciulli MG, et al. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation 109:1468–71, 2004. Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potent novel drug target. Proc Natl Acad Sci U S A 96:7220–5, 1999. Zeilhofer HU, Brune K. Analgesic strategies beyond the inhibition of cyclooxygenases. Trends Pharmacol Sci 27(Suppl 9):467–74, 2006.

14

Adjuvant analgesic drugs a,b russell k. portenoy and mervyn koh c a b

Beth Israel Medical Center, Albert Einstein College of Medicine, and c Tan Tock Seng Hospital

Introduction The term adjuvant analgesic was originally coined to refer to a small number of drugs that were commercialized for reasons other than pain but could be used as analgesics in selected circumstances. When these nontraditional analgesics were prescribed to cancer patients to supplement the analgesia provided by opioids, they were considered to be adjuvant to the mainstay therapy – hence the term. In recent years, the number, diversity, and conventional use of these nontraditional analgesics have increased dramatically. Several are now indicated and promoted for specific types of noncancer pain and many are used as first-line therapies in varied populations. Accordingly, the term adjuvant analgesic is now a commonly applied misnomer and refers to a large and diverse group of drugs that have an expanding role in pain medicine.1 In the management of cancer pain, the term adjuvant analgesic also must be distinguished from other labels, specifically adjuvant drug and co-analgesic. According to the three-step analgesic ladder model of cancer pain pharmacotherapy developed under the auspices of the World Health Organization in the mid-1980s,2 adjuvant drugs comprise both analgesics used to supplement opioid therapy (adjuvant analgesics) and drugs used to manage the side effects of the opioids. Given this dual labeling, the drugs intended to provide analgesia are best denoted by the more specific term adjuvant analgesics. The label co-analgesic has been used synonymously with adjuvant analgesic in the cancer treatment setting and also could be used whenever referring to a drug added for analgesic purposes to an existing opioid regimen. Adjuvant analgesics (or co-analgesics) usually are added to an opioid regimen for one of two purposes: 1) to improve pain relief when optimal titration of the opioid does not yield an adequate response, or 2) to allow opioid dose 272

reduction when opioid titration has yielded adequate analgesia but side effects are problematic and the goal is opioidsparing without compromising pain relief. Given the potential for additive toxicity when opioid dose changes are combined with changes in other drug therapies, it usually is best to optimize the opioid regimen before initiating a trial of an adjuvant analgesic. Although some clinicians attempt to improve patient response by initiating an opioid and an adjuvant analgesic concurrently, this approach requires careful monitoring and carries additional risk. If significant toxicity occurs, both drugs must be discontinued, and there would be no certainty about which was the offending agent. Usually, only a few days are required to identify an opioid dose that appears to provide the best balance between efficacy and side effects. In broader terms, the adjuvant analgesics represent a strategy for addressing the patient who has demonstrated poor responsiveness to an opioid during dose titration. A working knowledge of these drugs is necessary in positioning a trial of one or more among the variety of options that may be employed to improve symptom control in this context.

Classification of the adjuvant analgesics In an effort to simplify the clinical approach to the use of the large and growing number of adjuvant analgesics for cancer pain, a classification may be proposed for the most commonly used drugs:1 1. Analgesics potentially used for all chronic pains (multipurpose analgesics) 2. Analgesics used for neuropathic pains 3. Analgesics used for bone pain 4. Analgesics used for pain and other symptoms in bowel obstruction

adjuvant analgesic drugs This classification is based on the information from existing clinical trials and common practice. Although the number and sophistication of clinical trials continue to increase, most drugs have been subjected to limited study, and there are very few controlled trials conducted in the cancer population. Given the lack of data and the necessity of extrapolation of data from noncancer populations to the cancer population, the categories should be viewed as tentative, consistent with conventional practice but subject to change as more information is forthcoming. It is a starting point for clinical decision making and not an evidence-based model. Future studies in the cancer population will undoubtedly provide a better empirical basis for the selection of the varied drugs in the different categories. Multipurpose analgesics A large number of clinical trials in diverse patient populations offer evidence that some drugs or drug classes produce nonspecific analgesic effects that potentially could be effective in pain syndromes of any type. This description applies to the corticosteroids, antidepressants, and the ␣2 -adrenergic agonists. Topical agents, such as a local anesthetic cream or patch, also are commonly used for a broad range of syndromes. In the cancer population, the corticosteroids are the only systemic drugs that are commonly used as multipurpose analgesics. Opioids are widely accepted as the first-line therapies for chronic pain that is moderate to severe, and the effectiveness of these drugs has meant that the other classes, such as the antidepressants, are used generally for syndromes that are relatively less responsive to opioid therapy. The neuropathic pain syndromes are the usual targets of these therapies. Corticosteroids The corticosteroids have been shown to improve pain, appetite, nausea, malaise, and overall quality of life.3–7 Based on extensive clinical experience, the accepted painrelated indications include refractory neuropathic pain, bone pain, pain associated with capsular expansion or duct obstruction, pain from bowel obstruction, pain caused by lymphedema, and headache caused by increased intracranial pressure. Despite many years of experience, there have been few clinical trials of the individual corticosteroids, and the current data remain inadequate to evaluate drug-selective differences, dose–response relationships, predictors of efficacy, or the durability of favorable effects. The mechanism

273 of analgesic action also is unknown and may be multifactorial. Corticosteroids reduce peritumoral edema and may relieve pain by reducing mass effect, leading to diminished stretch on pain-sensitive structures. Anti-inflammatory effects could inhibit the release of compounds that sensitize or activate primary afferent nerves, and direct inhibitory effects on abnormal discharges produced by injured nerves also may have analgesic consequences. Finally, benefits for pain could be secondary to the potential for positive mood effects produced by these drugs. The risk of adverse effects associated with corticosteroid therapy increases with both the dose and duration of use. Although the long-term administration of corticosteroids is common practice when the intended use is for treatment of an inflammatory disease, their prolonged use for pain alone usually is not preferred unless the clinical context is advanced illness. In this setting, the risks of therapy are outweighed by the imperative to provide comfort and the potential of corticosteroids to improve multiple symptoms concurrently. One large survey of relatively low-dose, long-term therapy in a population with advanced illness observed that the most common side effect was oral candidiasis.6 Potential other adverse effects include increased risk of infection, myopathy, diabetes, hypertension, cushingoid habitus, and increased risk of skin breakdown. Serious side effects include gastrointestinal bleeding and neuropsychiatric syndromes (ranging from mild dysphoria to severe anxiety or depression, or psychosis). Patients who receive corticosteroids must be carefully monitored for these potential toxicities. There is large variation in the clinical use of corticosteroids as analgesics. Most surveys indicate a preference for dexamethasone, presumably because its relatively low mineralocorticoid effects suggest a better safety profile. To date, however, there is no empirical evidence that this drug is either safer or more effective than any other in the cancer population. In the setting of chronic pain associated advanced illness, it is common practice to employ a low-dose regimen of dexamethasone or another corticosteroid typically when the opioid regimen does not yield satisfactory effects or when pain is accompanied by other symptoms that may be targeted by the corticosteroid.1 For example, dexamethasone may be administered with an initial loading dose of 10–20 mg orally, followed by a fixed-schedule dose of 1– 2 mg twice daily. A poor response in the absence of side effects may be followed by upward titration of the dose. Treatment of this type usually is open ended, often continuing until the patient’s death.

274 A high-dose corticosteroid regimen has been advocated in some settings. Originally developed for the treatment of emerging spinal cord or cauda equina syndrome related to epidural cancer, the positive analgesic effects in this condition led to empirical extrapolation to other types of pain. The regimen originally developed for spinal cord compression typically consists of a dexamethasone loading dose of as much as 100 mg intravenously, followed by 96 mg orally in divided doses; the dose is then tapered over approximately 2 weeks, usually as radiotherapy is administered to shrink the tumor mass. Although better pain relief has been suggested as a rationale for this approach, there have been no high-quality comparative studies of pain outcomes, and the evidence of benefit over a lower-dose regimen has not been established.8 There is also concern about the side effects associated with higher-dose therapy. In one study of patients with epidural spinal cord compression, for example, a high-dose regimen was more effective than no treatment in preserving ambulation after 6 months, but also was accompanied by a substantial (11%) risk of side effects, including psychosis and gastric bleeding.9 Given the lack of data, it is not surprising that clinical practice varies in the use of a relatively high-dose regimen for analgesia and other purposes. Patients with emerging spinal cord or cauda equina signs present a concern about permanent neurological impairment that probably justifies the use of a high-dose regimen, either the original one or one that uses lower doses, but doses still much higher than is typical for the setting of chronic pain in advanced illness. Patients with other painful neoplastic complications presenting at critical points (e.g., superior vena cava syndrome with cardiovascular compromise) may be considered similarly. When pain is the primary issue, a highdose regimen often is considered in the context of so-called “crescendo” pain, or rapidly worsening pain that has not responded to an opioid. Some clinicians will begin treatment using the regimen recommended originally for spinal cord compression, and others will choose an alternative – for example, a dexamethasone loading dose of 10–20 mg followed by a dose of 16 mg/day in divided doses. In the absence of data, this choice is based solely on clinical judgment. Analgesics used for cancer-related neuropathic pain In addition to the corticosteroids, two broad categories of systemic adjuvant analgesics are used most often for opioid-refractory, cancer-related neuropathic pain. The first group – the antidepressants – are multipurpose analgesics, whose use generally is limited to neuropathic pain in the

r.k. portenoy and m. koh cancer population. The second group – the anticonvulsants – is conventionally administered for neuropathic pain, whether or not the setting is cancer. A recent evidencebased guideline for the treatment of nonmalignant neuropathic pain10 recommended that an anticonvulsant (specifically gabapentin or pregabalin) be considered the first-line adjuvant analgesic, unless there is a comorbid depressive disorder that warrants a first-line trial of an analgesic antidepressant. Analgesic antidepressants The analgesic effects of antidepressants have been recognized as early as 1960.11 The analgesia produced by the tricyclic antidepressants has been extensively investigated, with numerous trials in very diverse syndromes providing support for their potential use as multipurpose analgesics.1 Their efficacy in neuropathic pain is well established,10 and despite minimal evidence in the cancer population,12 the potential benefit of these drugs in cancer-related neuropathic pain is widely accepted. In recent years, the development of selective monoamine reuptake inhibitors, particularly those active at both norepinephrine and serotonin sites, has yielded an alternative for antidepressant analgesia (Table 14.1), which may be preferred in the medically ill because of a better side effect liability;13 see later). Tricyclic antidepressants Despite their widespread acceptance, the tricyclic antidepressants are seldom used in the cancer population.14,15 Presumably, this relates to a lack of clinician appreciation for the value of these drugs, or perhaps concern about side effects. Use of the newer selective monoamine reuptake blockers is associated with fewer side effects and may eventually lead to a greater readiness to employ an analgesic antidepressant for patients who may benefit. Tricyclic antidepressants act primarily by inhibiting presynaptic serotonin and noradrenergic uptake. This action can relieve depression or increase activity in monoaminedependent pain-modulating systems, or both. In addition, these compounds also have been shown to have other analgesic mechanisms, such as inhibition of sodium and calcium channels in neuronal tissues.16,17 They also block postsynaptic ␣-adrenergic, H1 -histaminergic, and muscarinic receptors, which may in part account for troubling side effects. The tricyclic antidepressants encompass a group of tertiary amine compounds, including amitriptyline, imipramine, and doxepin, and secondary amine compounds such as nortriptyline and desipramine. The latter drugs are more

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275

Table 14.1. Analgesic antidepressants Starting dose

Effective dose

Comments

Tricyclic antidepressants Amitriptyline 10–25 mg HS

50–150 mg HS

Sedation, confusion, arrhythmias, urinary retention, blurred vision. Contraindicated in narrow-angle glaucoma. Nortriptyline and desipramine usually preferred in the medically ill.

Imipramine Nortriptyline Desipramine

50–150 mg HS 50–150 mg HS 50–150 mg HS

10–25 mg HS 10–25 mg HS 10–25 mg HS

Selective serotonin reuptake inhibitors Paroxetine 10–20 mg/day

20–40 mg/day

Citalopram

20–40 mg/day

10–20 mg/day

Limited evidence of analgesic efficacy. Usually not preferred when pain relief is the goal.

Serotonin noradrenaline reuptake inhibitors Venlafaxine 37.5 mg/day

37.5–112.5 mg twice daily

Duloxetine Milnacipran

20–30 mg/day 25 mg/day

30–60 mg twice daily 100 mg/day

Others Bupropion

50–75 mg twice daily

75–150 mg twice daily

Mirtazapine

7.5–15 mg at night

15–45 mg at night

Good evidence of efficacy, particularly for duloxetine, which along with nortriptyline and desipramine, often is considered first line for pain

Limited evidence. Usually considered when sedation or fatigue is prominent. Seizures, limited evidence. Used as a hypnotic.

Abbreviation: HS, at bedtime.

selective at noradrenergic reuptake sites than the tertiary amine drugs, and the side effects associated with the tricyclic class, including orthostasis and cardiac arrhythmia, anticholinergic effects such as dry mouth and urinary retention, and somnolence or mental clouding, are less likely to occur during administration of the secondary amine drugs.1 All the tricyclic compounds are relatively contraindicated in patients with heart conduction defects, poor cardiac function, severe prostatic hypertrophy, and narrow-angle glaucoma. Patients with cancer-related neuropathic pain usually are considered for a trial of one of the secondary amine tricyclic drugs because of concern about side effects in the medically frail. There have been no comparative trials, and either nortriptyline or desipramine may be selected. The starting dose is low, 10–25 mg at night. The dose is increased every few days in the absence of satisfactory relief or side effects. The analgesic dose range usually is lower than the antidepressant dose range, and analgesia typically, but not always, appears sooner than mood elevation. Most patients who experience pain relief respond at a dose of 50–150 mg/day, but the available data suggest a drug concentration–response relationship for at least one of the tricyclics,18 and if neither analgesia nor intolerable

side effects occur as doses are increased, continued dose escalation should be considered. If dose escalation reaches approximately 100 mg/day, it is reasonable to measure the plasma concentration. Although the concentrations associated with analgesia are not known, this measurement can nevertheless inform decision making. If the level is at the upper end of the range associated with antidepressant effects, or higher, further dose escalation usually should not be undertaken because of concern about the potential for serious adverse effects in the medically ill. It is also reasonable to obtain an electrocardiogram before therapy if there is a history of heart disease or advanced age, and when doses are increased above 100 mg/day. Selective monoamine reuptake inhibitors The selective serotonin reuptake inhibitors (SSRIs) and the selective serotonin and norepinephrine reuptake inhibitors (SNRIs) increase the amount of serotonin or serotonin and norepinephrine, respectively, available for neurotransmission. Presumably, their analgesic mechanism of action overlaps that of the tricyclic antidepressants. Their actions are far more selective, however, and this probably accounts for their more favorable side effect profile.

276 The SSRIs include fluoxetine, paroxetine, citalopram, and others. The SNRIs include venlafaxine, duloxetine and milnacipran. There are very few data supporting the analgesic efficacy of the SSRIs. A study of fluoxetine showed that it had no significant effect on neuropathic pain,19 and the efficacy of paroxetine and citalopram was suggested in very limited and small randomized trials.20,21 Given the extant information, it is unclear that the SSRI drugs can serve as useful adjuvant analgesics, and they are not preferred when a primary goal of therapy is better relief. The data pertaining to analgesic efficacy are more compelling for the SNRIs. Venlafaxine, for example, was efficacious in painful diabetic neuropathy and painful polyneuropathy of other origins,22,23 and the data from multiple clinical trials of duloxetine were sufficiently positive to support approval in the United States as an analgesic for pain in diabetic neuropathy24 and fibromyalgia.25 There are also data supporting the analgesic efficacy of milnacipran in the latter condition.26 In the opioid-refractory cancer patient, particularly one with depressed mood, the most reasonable approach to a trial of an analgesic antidepressant is to begin with an SNRI, preferably duloxetine, or a secondary amine tricyclic drug (nortriptyline or desipramine). There have been no comparative trials of these agents, and although a trial comparing imipramine and venlafaxine found that the likelihood of analgesia was greater with the former drug,27 the data are too limited, and patients are too varied in their responses, to conclude that tricyclic antidepressants are more effective as a class. The side effects associated with the SNRIs, such as nausea, sexual dysfunction, and somnolence or mental clouding, usually are tolerable if a low initial dose is used. Duloxetine, for example, usually is administered at a starting dose of 20–30 mg/day,28 which is then increased to the usual effective dose of 60 mg/day after a week; a trial of a higher dose, up to 120 mg/day, may be considered thereafter. Clinical observation suggests that there is substantial individual variation in the response to the analgesic effects of the antidepressants, as there is to their antidepressant effects. Accordingly, the failure to respond to one drug does not presage a poor analgesic response to them all. In the cancer population, sequential trials of one or more corticosteroids, one or more of the specific antidepressants, and one or more of the preferred analgesic anticonvulsant (see below) is the conventional initial strategy for opioidrefractory neuropathic pain. The priority in selecting the various drugs from these categories usually is based on other symptom targets or comorbid disorders, availability, patient preference, cost, and other considerations. If the

r.k. portenoy and m. koh patient has a comorbid depressive disorder, a switch from one analgesic antidepressant to another – for example, from duloxetine to desipramine – is justified. Other antidepressants Although other antidepressants, such as bupropion and mirtazapine, have been used as adjuvant analgesics, there is very limited experience with these drugs. Bupropion is noradrenergic and dopaminergic, and was demonstrated to be analgesic in a small controlled trial conducted in a population with mixed types of neuropathic pain.29 This drug is unlikely to produce somnolence and is experienced by some patients as activating, an effect that may be favorable in those with cancer-related fatigue. For this reason, a trial is sometimes considered, notwithstanding the limited evidence of analgesic outcomes. Side effects of bupropion include dry mouth, nausea, and tremulousness, and the most worrisome adverse effect is seizures, particularly at higher doses. The drug is relatively contraindicated in those who are predisposed to seizures by a history of epilepsy or new neurological pathology. Mirtazapine acts on presynaptic ␣2 -adrenergic receptors and causes an increase in norepinephrine release. Experience with this drug in the treatment of neuropathic pain is very limited, but it has been reported to be useful in an open-label trial conducted in a sample with cancer pain and other symptoms.30 Its main side effects are sedation and weight gain, and the drug is sometimes considered for a trial as an analgesic if the target symptom is accompanied by insomnia or anorexia. Anticonvulsant analgesics The anticonvulsants represent a heterogeneous group of drugs that vary in mechanisms and clinical effects (Table 14.2). Two drugs – gabapentin and pregabalin – are now established analgesics for neuropathic pain and indeed are commonly considered to be first line in those patients without comorbid depression.10 Given the variable evidence that other anticonvulsants are analgesic, alternative anticonvulsants usually are considered only if opioidrefractory pain has not responded to the first-line strategies described previously. All anticonvulsants are dosed in the manner in which they are used for their primary indication of epilepsy. Gabapentin and pregabalin Gabapentin and pregabalin both act by binding to the socalled ␣2 ␦ protein, which is a subunit of a system that modulates flux through the N-type, voltage-gated calcium

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Table 14.2. Analgesic anticonvulsants

Gabapentin

Pregabalin

Starting dose

Effective dose

Comments

100–300 mg HS

300–1200 mg three times daily

First line for pain

50–200 mg/day

300–600 mg twice daily

Valproic acid

250 mg once to three times daily

500–1000 mg three times daily

Carbamazepine

100–200 mg once or twice daily

300–800 mg twice daily

Lamotrigine

25 mg/day

100–200 mg twice daily

Topiramate

25 mg/day

Tiagabine

4 mg HS

Levetiracetam

250–500 mg twice daily

100–200 mg twice daily 4–12 mg twice daily 500–1500 mg twice daily

No drug–drug interactions No hepatic metabolism Sedation and mental clouding are the most common side effects First line for pain Linear kinetics increase The simplicity of dosing No drug–drug interactions No hepatic metabolism Sedation and mental clouding are the most common side effects Limited evidence Many drug–drug interactions Limited evidence Bone marrow suppression is a concern Limited evidence Concern about cutaneous hypersensitivity Limited evidence. Sedation and weight loss may be a concern. Very limited evidence Sedation is a concern Very limited evidence Sedation is a concern

Abbreviation: HS, at bedtime.

channel. Binding to this protein reduces calcium influx and lessens the likelihood of neuronal depolarization. This mechanism is responsible for the analgesic effects produced by these drugs. Unlike other anticonvulsants, gabapentin and pregabalin are not metabolized in the liver and have no known drug– drug interactions. They are excreted by the kidneys, which necessitates dose reduction in the setting of renal impairment. Their main side effects are mental clouding, dizziness, and somnolence; edema and weight gain are less common. The major difference between gabapentin and pregabalin is pharmacokinetic. Absorption of gabapentin is facilitated by a saturable transporter in the small bowel and central nervous system. At relatively higher doses, such as 1800 mg/ day, kinetics become nonlinear as less absorption occurs with each dose increase. This drug therefore has a pharmacokinetic ceiling, which exists in tandem with the usual

pharmacodynamic ceiling observed with the adjuvant analgesics (i.e., responders reach a maximal level of response, and dose escalation above this does not increase benefit further). In contrast, pregabalin’s absorption is not dependent on a saturable transport mechanism. It, too, has an unpredictable pharmacodynamic ceiling, but no pharmacokinetic ceiling, a characteristic that tends to simplify dosing. Gabapentin and pregabalin have been extensively studied in diverse types of neuropathic pain, particularly postherpetic neuralgia and painful diabetic neuropathy.31–39 They are approved for the latter conditions in the United States. Gabapentin was subjected to a controlled trial in a population of opioid-treated patients with cancer-related neuropathic pain and was proven to be beneficial for both spontaneous pain and dysesthesia within 10 days;34 there was no improvement in shooting, burning, and lancinating pain.

278 In the medically frail cancer patient, gabapentin usually is initiated at a dose of approximately 100–300 mg/day. The dose is gradually escalated while monitoring analgesia and side effects. If pain relief does not occur, dose escalation in the absence of an analgesic ceiling or adverse effects typically extends to 3600 mg/day administered in two to three divided doses, and sometimes higher. Positive effects are more likely to be achieved if the dose can be increased to at least 1800 mg/day. Given this broad potential effective dose range, and the need to explore the pharmacokinetic ceiling by increasing the dose once or twice after an apparent ceiling has been reached, it is not uncommon for a trial of gabapentin to require multiple dose escalations over several weeks. The starting dose of pregabalin usually is 50–75 mg/day (a lower dose can be used in the medically frail), and escalation to the usual effective dose of 150–300 mg twice daily typically is accomplished in two or three steps over a week. The narrower effective dose range and the linear pharmacokinetics combine to render pregabalin a simpler drug to use in the clinical setting. There have been no head-to-head prospective studies comparing the relative efficacy of gabapentin and pregabalin. Controlled trials of pregabalin that have included “gabapentin failures” demonstrate that patients may respond to the former drug even if the latter has not been tolerated. One retrospective observational study suggested that pregabalin may be more effective than gabapentin, but the studies necessary to evaluate this have not been done.40 At the present time, it is most reasonable to assume that there is individual variation in the response to gabapentin and pregabalin, notwithstanding their identical modes of action, and patients who do not respond well to one might be considered for a trial of the other. Other anticonvulsants Many other anticonvulsant drugs have been studied as analgesics.41 Older anticonvulsants – carbamazepine, valproate, phenytoin, and clonazepam – are perceived as having potential analgesic effects based on trials performed several decades ago. Carbamazepine was shown to be useful in trigeminal neuralgia,42 and it remains one of the preferred drugs for this condition today; trials in other conditions, such as central pain,43 suggests utility in other neuropathic pain conditions. In the cancer population, however, its risk of serious bone marrow suppression has limited its use. Controlled trials of valproate in postherpetic neuralgia and painful diabetic neuropathy have yielded conflicting results.44,45 It, too, is seldom tried for cancer-related neuropathic pain. Similar uncertainly surrounds the efficacy of

r.k. portenoy and m. koh phenytoin;46,47 given the side effect liability of this drug, it is rarely considered for a trial if other drugs for opioidrefractory neuropathic pain are available. Clonazepam, a benzodiazepine that has been used for seizures, was shown to be useful in controlling neuropathic cancer pain in a case series of five patients;48 despite the lack of further evidence, this drug is sometimes tried when pain is accompanied by severe anxiety. This is also the case with alprazolam, which was suggested to be analgesic in a small survey of cancer patients with neuropathic pains.49 In addition to gabapentin and pregabalin, numerous other drugs have been developed as anticonvulsants. Most have been studied as potential analgesics for neuropathic pain, but results have been mixed. Although some of these drugs are tried for neuropathic pain that has been refractory to preferred agents, none has become an established analgesic comparable with gabapentin and pregabalin. Lamotrigine was efficacious in studies of central pain, trigeminal neuralgia, and painful HIV polyneuropathy but has not been analgesic in other trials.50 This drug is associated with a small risk of serious cutaneous hypersensitivity, which is relatively increased in younger patients. The drug should not be used in patients younger than 15 years, and slow titration of the dose from a low initial dose is necessary to reduce the risk of hypersensitivity. Lamotrigine usually is considered for adults only after trials of several preferred drugs for neuropathic pain have been ineffective.10 Topiramate has been shown to be useful in some, but not all, studies of painful diabetic polyneuropathy.51,52 A study in a sample with nonmalignant radiculopathy was positive,53 and a trial in patients with trigeminal neuralgia was negative.54 Its side effect liability, which includes dizziness, somnolence, nausea, and weight loss, may be poorly tolerated by medically ill patients. Like lamotrigine, topiramate occasionally is considered for a trial in a patient with a challenging neuropathic pain that has not responded to other drugs. Oxcarbazepine is a metabolite of carbamazepine, which is similarly anticonvulsant and has a safer pharmacological profile. It has been shown to be analgesic in trigeminal neuralgia and several other types of neuropathic pain; studies evaluating its efficacy in painful diabetic polyneuropathy have yielded mixed results.55 Although its relatively favorable side effect liability suggests that it might be considered early when other drugs have failed, enthusiasm is tempered by its uncertain efficacy. Other anticonvulsants have even less evidence of value in neuropathic pain41 and are rarely considered for a therapeutic trials. Tiagabine is a GABA(␥ -aminobutyric acid)ergic

adjuvant analgesic drugs drug that was found in an open-label trial to significantly reduce pain and improve sleep in a small study of patients with chronic pain.56 A small pilot study of levetiracetam was promising,57 but a recent controlled trial of this drug in postmastectomy pain syndrome was negative.58 Zonisamide did not significantly reduce pain in one controlled trial conducted in patients with diabetic neuropathy.59 Other drugs used for neuropathic pain

279 either drug is initiated at a very low dose to reduce the risk of somnolence and dizziness. Based on clinical observations, the effective dose range for clonidine is 0.2–0.6 mg/day and the range for tizanidine is 4–40 mg/day. Dexmedetomidine, another ␣2 -adrenergic agonist that is available in parenteral formulation, has been used anecdotally in the cancer population as an analgesic or sedative with analgesic effects. Its use in the management of pain and distress during the dying phase remains to be explored.

Several other drugs or drug classes may be useful for cancerrelated neuropathic pain. The evidence for the analgesic effects of these agents is evolving. They are typically considered after an opioid has been adequately titrated and trials of a corticosteroid, one or more analgesic antidepressants, and trials of gabapentin and/or pregabalin have proved ineffective. The decision to select one or more of these drugs for trials, like the decision to select a secondline or third-line anticonvulsant or antidepressant, usually is influenced by the presence of comorbidities that may be secondary targets for the treatment, clinical assessment about the risk of side effects, cost and availability, and the experience of the clinician. In the absence of comparative trials, this selection is essentially a trial-and-error process guided by careful patient assessment and sound clinical judgment.

GABAergic drugs As noted previously, tiagabine is GABAergic anticonvulsant that is rarely considered for a trial when neuropathic pain has been refractory to other treatments. Baclofen is a GABA-B agonist that has been available for the indication of spasticity for many years and is efficacious in trigeminal neuralgia.63 Despite the paucity of additional evidence, a long clinical experience with this drug suggests that it may be useful in other types of neuropathic pain. A low starting dose, such as 10 mg/day, is used to reduce the likelihood of sedation, and dose escalation can proceed until positive effects occur or side effects supervene. The therapeutic dose varies widely, ranging from 30 mg/day to more than 200 mg/day. Because abrupt discontinuation of this drug has been associated with seizures, tapering of the dose is necessary in the event of a poor response.

α2 -Adrenergic agonists The ␣2 -adrenergic agonists have established analgesic efficacy in a variety of pain syndromes,60–62 and for this reason, they may be considered multipurpose analgesics. They bind to postsynaptic ␣2 -adrenergic receptors, which may be found on peripheral afferent nerves and in the spinal cord and brainstem. Presumably, modulation of descending pain inhibitory pathways produced by interaction with these receptors underlies the analgesic effects of these drugs. The available ␣2 -adrenergic agonists in the United States comprise clonidine, tizanidine, and dexmedetomidine. Clonidine is approved as an analgesic for epidural use and has been shown to have efficacy for cancer pain, particularly cancer-related neuropathic pain.62 Patients with cancer pain who undergo a trial of neuraxial analgesia commonly receive this drug as part of a combination therapy that typically also includes an opioid and a local anesthetic. Oral or transdermal clonidine may be considered for trial when pain is refractory to other adjuvant analgesics, but tizanidine often is preferred because of its relatively lesser propensity to cause hypotensive effects. Treatment with

Sodium channel blockers Drugs whose primary action is blockade of sodium channels have long been used as local anesthetics and systemically administered antiarrhythmics. Multiple studies have confirmed that the systemic administration of local anesthetic drug also has analgesic effects64,65 and that this approach may play an important role in managing severe neuropathic pain. In contrast, studies that have evaluated the analgesic efficacy of oral sodium channel blockers present a less clear conclusion. Oral sodium channel blockers, such as mexiletine and tocainide, have been demonstrated to have efficacy in trigeminal neuralgia and painful diabetic neuropathy.66–68 A relatively high side effect liability, however, and the potential for cardiotoxicity have combined to relegate these drugs to rarely considered agents when neuropathic pain has been refractory to other trials. If a trial is undertaken, low initial doses are needed to reduce the risk of dizziness and nausea. Although studies of intravenous or subcutaneous lidocaine infusion have yielded mixed results in cancer-related neuropathic pain,69–72 the established efficacy of this treatment in other clinical settings64,65 and its ability to produce

280 a rapid response that long outlasts the kinetics of the drug suggest that it should be among the therapies considered to provide rapid analgesia in the setting of severe neuropathic pain. This approach may be particularly useful in the setting of “crescendo” neuropathic pain that is not responding well to an opioid. The usual protocol involves a brief intravenous infusion of lidocaine at a dose ranging from 1 mg/kg to 5 mg/kg delivered over 20–30 minutes. The risk of side effects, which typically include dizziness and tremor, can be minimized by use of a protocol that starts with a relatively low dose (e.g., 1 mg/kg over 20 minutes) and follows with subsequent higher-dose infusions during the same if response is inadequate. Although cardiac toxicity is unusual at the low doses administered, it is reasonable to limit this therapy to patients without severe heart disease, and to administer it with electrocardiogram monitoring. There have been efforts to use a brief lidocaine infusion as a diagnostic tool to evaluate the likelihood of clinical response to an oral agent in the same class, such as mexiletine.73 The utility of this approach in the cancer population is not known, and although it is reasonable to provide a trial of mexiletine in a patient who has favorable but short-lived effects from lidocaine infusion, the use of an infusion for the specific purpose of predicting response to the oral agent is not justified at this time. N-methyl-D-aspartate receptor antagonists The N-methyl-d-aspartate (NMDA) receptor complex is involved in the development of both neuropathic pain and opioid tolerance.74 Commercially available NMDA antagonists now indicated for other conditions may have utility in the treatment of cancer-related neuropathic pain. Ketamine is a noncompetitive antagonist of the NMDA receptor. It is a dissociative anesthetic that is available in a parenteral formulation and used at higher doses to induce anesthesia.75 It does not depress respirations or cardiac function at clinical doses and, indeed, is associated with increased sympathetic outflow, which may cause tachycardia and hypertension. A significant concern during its use as an anesthetic is the occurrence of psychotomimetic effects on emergence from unconsciousness. These effects may be severe and relatively prolonged. The analgesic effects of ketamine at subanesthetic doses are well established, and the drug increasingly has been viewed as a potentially valuable therapy for refractory cancer pain, including neuropathic pain that has been unresponsive to other drugs or has a crescendo pattern of rising intensity.75–80 A variety of treatment strategies have been

r.k. portenoy and m. koh developed and there is no consensus yet concerning the approach that minimizes risk or increases effectiveness. The drug may be used as a brief infusion, as a planned longer intravenous or subcutaneous infusion, or with the intention of a switch to oral therapy using the injectable form.81,82 Some clinicians initiate therapy with oral administration, but given the limited experience with this route, an unsatisfactory response should not be considered predictive of the effects that might be obtained through parenteral administration. When ketamine is administered as a brief infusion, the usual intention is to gain rapid control of pain and determine whether analgesia will persist following the end of the infusion.80 When longer infusions are used, often for periods that extend for many days, other analgesic treatments may be undertaken concurrently, after which the ketamine is tapered. Some patients are administered a prolonged infusion with the intention to relieve distress at the end of life; this treatment is continued until death. Regardless of the overall strategy for ketamine administration, it is routine practice to coadminister either a benzodiazepine or a neuroleptic at the time ketamine dosing begins. This is done in the hope of reducing the likelihood of dissociative, dysphoric, or psychotomimetic side effects. One approach uses lorazepam at a dose of 1 mg before the start of the ketamine treatment, followed by 1 mg every 6– 8 hours thereafter. A loading dose, which may be 0.1–0.5 mg/kg delivered as a slow intravenous push, may or may not be used to initiate therapy, again irrespective of the overall strategy. The initial infusion typically is started at a very low dose of approximately 0.05–0.1 mg/kg/hour. Ketamine has a relatively short half-life of several hours, and titration of the dose can be performed two or three times per day. The dose usually is increased until favorable effects are achieved or the patient experiences side effects. Responders usually achieve favorable effects at a dose of 0.1–1.5 mg/kg/hour. Maximal daily doses have been in the reported range of 450–700 mg/day.76,78 In contrast to ketamine, evidence is meager that other commercially available NMDA receptor antagonists have clinically useful analgesic effects. A recent trial suggests that the antitussive dextromethorphan will not be useful in the population with cancer pain;83 at doses of 60–120 mg four times a day, it did not produce significant opioid reduction and was associated with increased dizziness. Although a single-dose controlled trial of amantadine demonstrated that this drug may have analgesic effects in cancer-related neuropathic pain,84 clinical experience in the treatment of chronic pain has been limited and the anecdotal experience

adjuvant analgesic drugs has not been favorable. Controlled trials of memantine, a drug used for dementia, have been disappointing despite the suggestion of analgesic benefits in anecdotal reports.85 All of these oral NMDA receptor antagonists are considered only rarely for therapeutic trials, and only in situations of neuropathic pain that has been intractable to other viable therapies. Cannabinoids There has been renewed interest in the potential therapeutic use of cannabinoids, drugs that are alkaloids or synthetic derivatives of compounds originating from the Cannabis sativa plant. Although their clinical use has been complicated by concern about abuse, the emerging scientific understanding of the nature of cannabinoid physiology and the success of clinical trials for a variety of indications have yielded commercialization of several drugs for oncology practice. Cannabinoid receptors were discovered in the 1980s and include at least two subtypes: CB-1 receptors, which are found in the central and peripheral nervous systems, and CB-2 receptors, which are present on immune cells.86 Several endocannabinoids, endogenous ligands that bind the cannabinoid receptors, also have been discovered. The locations of these receptors and their ligands have piqued interest in cannabinoids as potential therapies for neurological diseases, including pain, and dysimmune disorders. Cannabinoids have been known to have antiemetic and appetite-stimulant effects for many years. Commercially available drugs, such as dronabinol and nabilone, have these indications.87 Studies of these drugs have indicated relatively weak analgesic efficacy and a relatively high side effect liability.88 Newer cannabinoids are more promising.89 An oral extract of Cannabis containing a 1:1 ratio of two alkaloids, tetrahydrocannabinol and cannabidiol, is efficacious in neuropathic pain and opioid-refractory cancer pain.90 This drug has been approved in the United Kingdom and Canada for opioid-refractory cancer pain. These approvals portend expanded use of this drug, or other cannabinoids, for pain. More experience will be needed to clarify the positioning of newer cannabinoids relative to the adjuvant analgesics now established in practice. At present, in most countries, the potential to use a cannabinoid is limited to oral agents on the market for other reasons, such as nabilone or dronabinol, and the evidence of efficacy is too limited to recommend this approach unless pain has been refractory to other therapies.

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Adjuvant analgesics used for bone pain The assessment of a patient with bone pain may suggest the need for radiation therapy or an intervention such as kyphoplasty or surgery. Patients with multifocal pain usually are managed with opioids and adjuvant analgesics used specifically for bone pain. In addition to a corticosteroid, such as dexamethasone, drugs to consider in this setting include bisphosphonates, calcitonin, and bone-seeking radionuclides (Table 14.3). Bisphosphonates Bisphosphonates have been shown to be useful in preventing skeletal-related events, including fracture and pain, and may improve the quality of life in cancer patients with bone pain.91 They act by directly inhibiting osteoclast activity, stimulating osteoblasts to produce osteoclast-inhibiting factor, and causing osteoclast apoptosis.92,93 There is substantial evidence that the commercially available bisphosphonates can reduce bone pain. Although positive findings have not been uniform,94 studies of clodronate demonstrate efficacy in breast cancer and multiple myeloma patients.95,96 Intravenous pamidronate has been shown in large studies to reduce bone pain in breast cancer97,98 and was superior to oral clodronate in a 3-month trial.99 These studies demonstrated that analgesia following pamidronate infusion did not maximize until several doses at monthly intervals had been administered. Zoledronic acid, which may be infused over minutes rather than the hours recommended for pamidronate, has been shown to reduce bone pain in some100 but not all101,102 studies of populations with metastatic bone pain. A direct comparison between zoledronic acid and pamidronate in breast cancer and multiple myeloma patients did not show any significant differences in control of bone pain.103 Both the intravenous and oral formulations of ibandronate have been shown to reduce bone pain in breast cancer patients.104,105 Pain declined within a few weeks and remained significantly lower than placebo after 96 weeks. This drug also has been shown to be efficacious in reducing bone pain in multiple myeloma patients.106 Although these data suggest an important potential role for the bisphosphonates in the management of pain and other complications caused by bone metastases, the potential benefits are balanced by the risks.107 Hypocalcemia is possible when these drugs are administered to normocalcemic patients, and renal toxicity has been reported with both pamidronate and zoledronic acid.91 The oral agents can cause esophagitis, which may be severe, and intravenous formulations often produce a transitory flu-like syndrome.

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282 Table 14.3. Adjuvant analgesics used for bone pain

Bisphosphonates Clodronate

Pamidronate Zoledronic acid Ibandronate Calcitonin

Dose

Comments

900 mg IV every 3–4 weeks or 1040–2400 mg/day orally

Good evidence of efficacy. Used for multifocal bone pain. Osteonecrosis of the jaw is a concern, and poor oral health is a relative contraindication.

60–90 mg IV every month 4 mg IV every 3–4 weeks 6 mg IV every 3–4 weeks or 50 mg/day orally 1 IU/kg/day SC or 200 IU/day intranasally

Bone-seeking radionuclides

Strontium-89 Samarium-153

Dose must be lowered in renal insufficiency Very limited evidence. Not preferred when pain is the indication. Evidence of efficacy. If available, should be considered if bone marrow has reserve and further chemotherapy with bone marrow suppression is not planned.

– –

Abbreviations: IV, intravenously; SC, subcutaneously.

Recently, concern has been raised about osteonecrosis of the jaw, which is a potentially serious complication characterized by painful erosions, ulcers, and sinus tracts.108–110 This complication usually occurs after many months of treatment and is relatively more common during therapy with pamidronate and zoledronic acid than other bisphosphonates; it is rare during oral therapy. There is evidence that a history of oral trauma, dental infections, or surgery is a risk factor, but this has not been found uniformly.110 Given these risks, bisphosphonate therapy should be considered for treatment of metastatic bone pain only if the patient’s prognosis is longer than a few months. One of the intravenous formulations should be used. Although the impact of poor oral health on the occurrence of osteonecrosis of the jaw remains uncertain, many clinicians view active oral infection or tooth loss to be a relative contraindication to therapy. Electrolytes and renal function should be checked before treatment and monitored soon thereafter. Renal insufficiency is a relative contraindication, and if treatment is offered to patients with poor renal function, the dose should be lowered. As noted, a decline in renal function should lead to discontinuation of treatment. If the primary goal is pain relief, treatment should be stopped if symptoms are not improved after several months. Calcitonin Small controlled trials have yielded conflicting information about the potential for subcutaneous calcitonin to reduce metastatic bone pain.111,112 Given the lack of evidence, this

treatment generally is not recommended,113 and an empirical trial should be considered only when other treatments are not available or effective. Bone-seeking radionuclides Radionuclides with a high affinity for bone and low radiation emission, such as strontium-89 and samarium-153, may potentially have analgesic effects in metastatic bone pain. A recent systematic review114 concluded that there is evidence of efficacy over a time frame of 1–6 months. This potential benefit must be balanced against the risk of leukopenia and thrombocytopenia. Although bone marrow toxicity typically occurs within weeks of treatment and usually recovers by 3 months, some patients experience severe or prolonged bone marrow depression. If available, treatment with a bone-seeking radionuclide may be considered in the setting of multifocal bone pain if bone marrow suppression is not severe and further loss of bone marrow reserve would not preclude additional cancer therapy. Adjuvant analgesics used for pain in bowel obstruction Patients with malignant bowel obstruction experience pain, distention, and vomiting. If surgical decompression is not possible, symptom control is paramount. Drugs that have been used effectively for this condition include corticosteroids, anticholinergic compounds, and octreotide. Although some data suggest that corticosteroids may help relieve obstruction, this has been difficult to confirm, and although supporting data are limited,115 it is

adjuvant analgesic drugs widely accepted that these drugs can reduce symptom distress.116,117 Anticholinergic drugs, such as hyoscine (scopolamine) hydrobromide, hyoscine (scopolamine) butylbromide, and glycopyrrolate, also may reduce pain and other symptoms by inhibiting gastrointestinal secretions or peristalsis.117,118 Hyoscine hydrobromide can be given by injection or transdermal patch. Theoretically, the risk of confusion or other central nervous system side effects may be less with glycopyrrolate and hyoscine butylbromide because of their relatively lesser penetration of the blood–brain barrier; however, this advantage has not been shown convincingly in clinical studies. The somatostatin analogue octreotide reduces gastric, pancreatic, and intestinal secretions and also reduces intestinal motility. In several studies directly comparing octreotide with anticholinergic drugs, octreotide was superior in reducing symptoms, secretions, and nausea and vomiting.117,119–121 The usual starting dose is 100–250 ␮g/ day, either by continuous infusion or twice daily subcutaneous injection; the usual maximum dose in patients with bowel obstruction is 750 ␮g/day. A trial of octreotide is usually combined with a corticosteroid and an anticholinergic drug, and this combination may increase the likelihood that the obstruction will remit.122

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93. Vitte C, Flisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete inhibitor osteoclast-mediated resorption. Endocrinology 137:2324–33, 1996. 94. Fulfaro F, Casuccio A, Ticozzi C. The role of bisphosphonates: a review of phase III trials. Pain 78:157–69, 1998. 95. Tubiana-Hulin M, Beuzeboc P, Mauriac L, et al. Doubleblinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastasis [in French]. Bull Cancer 88:701–7, 2001. 96. McCoskey EV, Maclennan IC, Drayson MT. A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. Br J Hematol 100:317–25, 1998. 97. Hortobagyi GN, Thriault RL, Lipton A. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 16:2038–44, 1998. 98. Lipton A, Theriault RL, Hortobagyi GN. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma with osteolytic bone metastases: long-term follow-up of 2 randomized, placebocontrolled trials. Cancer 88:1082–90, 2000. 99. Jagdec SP, Purohito P, Heatley S. Comparison of the effect of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 12:1433–8, 2001. 100. Kohno N, Aogi K, Minami H. Zoledronic acid significantly reduces skeletal complications compared to placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 23:3314– 21, 2005. 101. Saad F. Treatment of bone complications in advanced prostate cancer: rationale for bisphosphonate use and results of a phase III trial with zoledronic acid. Semin Oncol 29(Suppl 21):19– 27, 2002. 102. Rosen LS, Gordon D, Tchekmdyian S. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomised trial. J Clin Oncol 21:3150–7, 2002. 103. Rosen LS, Gordon D, Kaminski M. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blinded, comparative trial. Cancer J 7:377– 87, 2001. 104. Body JJ, Diel IJ, Lichinister MR, et al.; MF 4265 Study Group. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 14:1399–405, 2003. 105. Body JJ, Diel IJ, Bell R, et al. Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 111:306–12, 2004. 106. Menssen HD, Sakalova A, Fontana A. Effects of long-term intravenous ibandronate on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 20:2253–9, 2002. 107. Gralow J, Tripathy D. Managing metastatic bone pain: the role of bisphosphonates. J Pain Sympt Manage 33:462–72, 2007.

r.k. portenoy and m. koh 108. Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 144:753–61, 2006. 109. Barnias A, Kastritis E, Bamia C. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–7, 2005. 110. Estilo CL, Van Poznak CH, Wiliams T, et al. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. Oncologist 13:911–20, 2008. 111. Roth A, Kolaric K. Analgesic activity of calcitonin in patients with painful osteolytic metastases of breast cancer: results of a controlled randomized study. Oncology 43:283–7, 1986. 112. Blomqvist C, Elomaa I, Porkka L. Evaluation of salmon calcitonin treatment in bone metastases from breast cancer – a controlled trial. Bone 9:45–51, 1988. 113. Martinez-Zapata MJ, Roque M, Alonso-Coello P. Calcitonin for metastatic bone pain. Cochrane Database Syst Rev CD003223, 2006. 114. Roque M, Martinez-Zapata MJ, Alonso-Coello P. Radioisotopes for metastatic bone cancer. Cochrane Database Syst Rev CD003347, 2003. 115. Mercadante S, Casuccio A, Mangione S. Medical treatment for inoperable malignant bowel obstruction: a qualitative systematic review. J Pain Symptom Manage 33:217–23, 2007. 116. Ripamonti C, Twycross R, Baines M. Clinical practice recommendations for the management of bowel obstruction in patients with end-stage cancer. Support Care Cancer 9:223– 33, 2001. 117. Laval G, Girarder J, Lassauniere J. The use of steroids in the management of inoperable intestinal obstruction in terminal cancer patients: do they remove the obstruction? Palliat Med 14:3–10, 2000. 118. De Conno F, Caraceni A, Zecca E. Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Symptom Manage 6:484–6, 1991. 119. Ripamonti C, Mercadante S, Groff L. Role of octreotide, scopolamine butylbromide and hydration in symptom control of patients with inoperable bowel obstruction and nasogastric tubes: a prospective randomized trial. J Pain Symptom Manage 19:23–34, 2000. 120. Mercadante S, Ripamonti C, Casuccio A. Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer 8:188–91, 2000. 121. Mystakidou K, Tsilika E, Kalaidopoulou O. Comparison of octreotide administration vs. conservative treatment in the management of inoperable bowel obstruction in patients with far advanced cancer: a randomized, double-blinded, controlled clinical trial. Anticancer Res 22:1187–92, 2002. 122. Mercadante S, Ferrera P, Villari P. Aggressive pharmacological treatment for reversing bowel obstruction. J Pain Symptom Manage 28:412–16, 2004.

15

Neuraxial analgesia lewis c. holford and michael cousins University of Sydney at Royal North Shore Hospital

Introduction Improvements in the understanding of the pathophysiology of pain, increased availability of pharmacological agents, adoption of different modes of drug administration, and development of comprehensive multidisciplinary care all have contributed to increasing the number of patients with effective control of cancer pain. The Guidelines for Cancer Pain Relief established by the World Health Organization (WHO)1 have been useful in emphasizing the effectiveness of oral morphine as a mainstay of cancer pain treatment. Although the analgesic “ladder” drew attention to the importance of using opioids of increasing potency and adding adjuvant therapies as necessary,2 the strategy today is to tailor the ingredients of a multimodal oral regimen to each patient’s requirements at a particular stage of the disease. Several algorithms exist for the treatment of cancer pain, including the WHO Cancer Pain Ladder and the Agency for Healthcare Policy and Research (AHCPR) and National Cancer Care Network (NCCN) cancer pain treatment guidelines.3 However, 10%–20% of patients will require more intensive measures to control pain, particularly in the terminal phases of their illness. Treatment options include primary therapies such as radiotherapy, chemotherapy, and surgery to reduce pain in specific cases; parenteral or spinal administration of analgesic agents; neurolytic blocks; and surgical neuroablative procedures. In a prospective study of 2118 patients with cancer pain managed according to WHO guidelines, neuraxial analgesic administration (epidural and intrathecal) was used in 3% of the patients.2 The true incidence of patients requiring this technique remains unknown because the size of the group from which patients in reported series are selected is unknown, and inclusion criteria vary in different centers according to local experience, expertise, and referral patterns. Neuraxial drug delivery should be considered in

appropriately selected patients when severe cancer pain cannot be controlled with systemic drugs because of inadequate effect or dose-limiting side effects.4,5 Both the AHCPR and NCCN guidelines recommend consideration of epidural or intrathecal infusion for pain that is refractory to medical management, and there is a growing consensus that neuraxial therapy, which has the advantages of reversibility and a more favorable risk–benefit ratio, may be warranted before irreversible neuroablative approaches.6–8 In addition, there is evidence that early application of intraspinal therapy may result in more effective analgesia, with reduced adverse events and an improved survival rate, as compared with traditional analgesic treatment.3,9,10 Spinal or intraspinal (i.e., neuraxial) administration may be used as a general term that encompasses delivery of drug to a potential space outside the dura (epidural administration) or delivery directly into the cerebrospinal fluid (intrathecal or subarachnoid administration). Further details of the techniques of epidural and intrathecal injection are available in texts.11 Spinal infusions of opioids and other medications have been increasingly used since the 1980s for the treatment of uncontrolled chronic pain following the elucidation of physiology of spinal nociception and the development of technologies for long-term intraspinal drug administration.12 Although morphine has been the mainstay for longterm spinal therapy, other medications are used for spinal administration, including other opioids and nonopioid analgesics. Ongoing outpatient management of refractory cancer pain is possible with implanted catheters and pumps for spinal drug delivery.12,13 The site of drug delivery (epidural, intrathecal, or intracerebroventricular [ICV]) and choice of system (tunneled catheter, fully implanted system, internal or external infusion device) depend on the site and nature of the pain, expected duration of therapy, local expertise in invasive techniques, availability of ongoing outpatient care, cost, and perceived risk–benefit ratio for each patient. 287

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Spinal opioids Demonstration of spinally mediated opioid analgesia in animal studies by Yaksh and Rudy14 in 1976 was followed relatively rapidly by case reports of administration of spinal opioids to patients with refractory cancer pain.15,16 Cousins and Mather17 reviewed the pharmacology and initial clinical use of spinal opioids in 1984. Spinal opioids are increasingly used for cancer pain management, as the lower doses required often result in a decrease in systemic side effects, and long-term delivery systems (epidural and intrathecal) have been developed. A recent systematic review of the efficacy of neuraxial opioids in cancer pain reported excellent pain relief in 62% of patients who received intrathecal opioids, 72% of patients who received epidural opioids, and 73% of patients who received ICV opioids.18

Pharmacokinetics of spinal opioids Pharmacokinetic models for epidural and intrathecal opioids have been described17 but are predominantly based on acute bolus administration rather than chronic infusion. A close relationship exists between lipid solubility and both onset and duration of analgesia.17,19 The duration of analgesia is inversely related to the lipid solubility of the agent, but is also influenced by the rate of dissociation from receptors.12 Morphine is relatively hydrophilic, and high cerebrospinal fluid (CSF) concentrations are achieved after intrathecal administration. Morphine diffuses slowly from CSF to opioid receptors, nonspecific binding sites, and clearance sites (arachnoid granulations), resulting in a long duration of analgesia and greater migration to the brain, with the potential for delayed respiratory depression in opioid-na¨ıve patients. Uptake into the systemic circulation occurs to a minor degree.17 Spinal administration of morphine offers more benefit than other opioids in terms of dose sparing between spinal and systemic routes.5 Phenylpiperidine derivatives (meperidine, fentanyl, alfentanil, sufentanil) are highly lipid soluble. Most of the intrathecally administered drug is cleared from the CSF by rapid diffusion into the spinal cord and via the epidural space into epidural fat and the systemic circulation, resulting in limited rostral spread. The kinetics of epidural injection are further complicated by factors of dural penetration, fat deposition, and systemic absorption.20,21 After epidural injection of morphine, only a low concentration of the more lipid soluble, nonionized moiety will be present in solution, and therefore peak CSF concentration and central distribution of morphine are obtained slowly (cervical CSF concentrations peak between

l.c. holford and m. cousins 1 and 3 hours).21,22 The larger doses of opioid required for epidural administration result in high plasma levels of morphine initially,17,21 but the duration of analgesia follows CSF rather than plasma opioid concentrations. Hydromorphone is a semisynthetic hydrogenated ketone of morphine and, following epidural administration, has CSF and blood kinetics similar to morphine’s but a faster onset of analgesia that may relate to an initial supraspinal effect.22 The phenylpiperidine derivatives have a rapid onset of analgesia after epidural dosing that coincides with an early peak drug concentration in CSF,23,24 and rapid clearance to the circulation results in clinically relevant plasma levels. Even after bolus or short-term administration, it is likely that systemic redistribution contributes to analgesia.25 As lipid solubility increases, a greater proportion of epidurally administered drug reaches the systemic circulation. Plasma concentrations of alfentanil, which has high lipid solubility, are similar after epidural and intravenous administration; therefore, epidural administration offers little clinical advantage.26 Pharmacodynamics and efficacy of spinal opioids Opioid receptors are found throughout the spinal gray matter but are most prominent in the substantia gelatinosa, and are predominantly of the mu subtype (70% mu, 20% delta, and 10% kappa).27 Opioids act at presynaptic sites to reduce primary afferent transmitter release and, at postsynaptic sites, produce hyperpolarization via activation of potassium channels to inhibit dorsal horn neurons. When systemic opioids fail to provide adequate analgesia or are associated with excessive side effects (clouding of consciousness, nausea, vomiting), optimization of opioid delivery to receptors by spinal administration may result in enhanced analgesia,6 and the associated reduction in systemic opioid concentrations may minimize side effects. Determining the relative efficacy of different routes of administration is difficult in the absence of dose equivalence data. In an animal model, spinal morphine was more effective than systemic morphine in inhibiting evoked dorsal horn neuronal responses after spinal nerve ligation in rats.28 This may suggest that the spinal route is more efficacious than the systemic route. Alternatively, an improved effect may be the result of a relatively higher dose being administered spinally, as fewer dose-limiting side effects are seen when compared with systemic administration.28 Many clinical trials report improvement in pain with conversion from oral to spinally administered opioids, but often the preceding opioid doses and attempts at optimization of opioid type and dose are not reported. In a double-blind, crossover study of nine patients with cancer pain, both epidural and

neuraxial analgesia subcutaneous administrations of morphine were comparable in terms of efficacy and acceptability for the patient, and both treatments provided better pain relief with fewer adverse effects compared with prestudy oral morphine.29 In a series of 92 patients with cancer pain, 19 patients required subcutaneous opioid because of efficacy or uncontrolled side effects. However, 13 of these patients subsequently progressed to intrathecal morphine, supplemented in some cases by clonidine, calcitonin, or bupivacaine, and achieved improvements in pain relief.30 Conversion from systemic to spinal routes of opioid administration requires selection of an approximately equianalgesic dosage, which is then titrated according to effect. The epidural starting dose is generally 10%, and the intrathecal dose is 1% of the 24-hour intravenous morphine requirement; however, conversion rates need to be individually determined.29 A conversion tool has been suggested that further adjusts the initial dose according to the severity of pain (visual analogue scale score), previous systemic opioid requirements, presence of neuropathic pain, and the age of the patient.31 As the spinal dose is titrated against the analgesic response, preexisting systemic opioid is gradually tapered to prevent withdrawal effects. One suggested regimen is an initial reduction by 50% of the calculated 24-hour systemic opioid dose, followed by further 20% reductions daily,8 with concomitant uptitration of the spinal dose. If an inadequate response is achieved with one opioid, an improvement may be achieved by rotation to a different opioid. Fifteen percent to 25% of patients receiving long-term intrathecal morphine therapy experience pharmacological complications or inadequate analgesia.32 Rotation to hydromorphone in patients has been shown to be effective in patients whose pain is uncontrolled with intrathecal morphine.32,33 Changing from epidural morphine to buprenorphine improved analgesia in 32% of patients and reduced side effects, and changing from buprenorphine to morphine improved analgesia in another 46% of patients.34 Improvement in drug-related complications was found when epidural morphine therapy was changed to buprenorphine or methadone.35 Intrathecal DADL (D-Ala2-D-Leu5) enkephalin, a moderately selective delta receptor agonist, has been used to provide analgesia in patients tolerant to morphine.36 Sufentanil has a high intrinsic efficacy, necessitating lower fractional receptor occupancy37 and may be more effective in the presence of tolerance to other opioids.38 Morphine Traditionally, morphine has been the primary agent for spinal administration for pain management39 and is the

289 only opioid approved by the U.S. Food and Drug Administration (FDA) for the intrathecal management of pain.40 There is now evidence for the safety and analgesic efficacy of spinal morphine in the treatment of cancer pain from an increasing number of clinical trials.3,9,10,18,40–42 A prospective multicenter randomized controlled trial showed intrathecal opioid therapy with an implanted drug delivery system plus comprehensive medical management may result in more effective analgesia, with reduced adverse events and an improved survival rate, as compared with comprehensive medical management alone.9,10 A prospective international multicenter study of longterm intrathecal morphine therapy with a patient-activated implanted delivery system for the treatment of refractory cancer pain revealed better analgesia and reduced side effects in comparison with prior systemic opioid therapy.41 A retrospective review of 4107 patients presenting with cancer pain revealed that 79 received neuraxial analgesia for refractory pain. Neuraxial analgesia resulted in a significant reduction in the proportion of patients with severe pain, from 86% to 17%. There was no difference between intrathecal and epidural groups.3 Hydromorphone Hydromorphone is the second most commonly used analgesic for spinal administration.39 Unlike morphine, which is a pure mu agonist, it activates predominantly mu opioid receptors and also, to a lesser extent, delta opioid receptors.43 Its greater lipophilic properties convey a number of advantages over morphine, including increased potency, faster onset of action, and potential for a lower incidence of undesirable side effects due to the absence of known active metabolites and reduced rostral spread of the drug.22,32 Intrathecal hydromorphone produces an equianalgesic response at 20% of the intrathecal morphine dose. In an implanted delivery system, this results in longer refill intervals or lower concentrations of drug. A retrospective study of intrathecal hydromorphone in 37 patients with chronic nonmalignant pain in whom continuous intrathecal morphine therapy had failed because of pharmacological complications or inadequate analgesia demonstrated an improvement in analgesia and a reduction in incidence of side effects.32 A retrospective review of 24 patients with nonmalignant chronic pain receiving intrathecal hydromorphone monotherapy following unsuccessful treatment with systemic opioids or intrathecal morphine showed a significant reduction in pain scores with an unchanged incidence of adverse effects.33

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Fentanyl and sufentanil Fentanyl and sufentanil are highly lipophilic, potent mu opioid receptor agonists. Both have higher intrinsic efficacy than morphine, necessitating lower fractional receptor occupancy to induce an equianalgesic response.37,44 Receptor activation is a prerequisite for receptor downregulation, and there is evidence for reduced drug tolerance with chronic intrathecal infusion of sufentanil compared with intrathecal morphine.38,44 Both fentanyl and sufentanil have FDA approval for short-term epidural administration during or after labor or surgery and, although not approved for long-term intraspinal administration, there is increasing acceptance of intrathecal use of these agents for the management of chronic pain.39,45 Evidence for use of these opioids for chronic pain is limited to a few relatively small studies showing them to be effective and relatively well tolerated, but there are limited data on long-term safety and efficacy.40,44 Meperidine Intraspinal meperidine has potential advantages because of its combined opioid and local anesthetic action.46 A small prospective study demonstrated the efficacy of intrathecal administration in intractable neuropathic cancer pain, although it was associated with increased plasma levels of the metabolite normeperidine, which may lead to central nervous system (CNS) excitatory effects.47,48 Methadone Methadone is a racemic mixture of d and l isomers, with the d isomer being a moderately potent N-methyl-d-aspartate (NMDA) antagonist and the l isomer a mu opioid receptor agonist. There are no randomized controlled trials of longterm intrathecal or epidural infusion. Epidural methadone has been administered for cancer pain management,49 but dose requirements and adverse effects tend to be greater than with morphine.50 A small prospective study of intrathecal methadone for chronic nonmalignant pain reported pain reduction in 51% of patients.51 Side effects of spinally administered opioids Side effects of spinally administered opioids include the following. Respiratory depression Respiratory depression, resulting from cephalad migration of hydrophilic morphine, has been reported after bolus

l.c. holford and m. cousins spinal administration in opioid-na¨ıve patients. In many series of patients with cancer pain who previously received opioids by other routes, respiratory depression after spinal opioids has not been seen.34,52–57 A systematic review found the overall incidence of respiratory depression to be 1.7% in cancer patients receiving epidural opioids and 1.6% in patients receiving intrathecal opioids.18 Respiratory depression may occur rarely in these patients if doses are escalated rapidly, complications such as liver failure supervene,58,59 or intrathecal pump refills are inadvertently injected subcutaneously or directly into the catheter via a side port.59 Slowly increasing chronic respiratory depression may occur with long-term intrathecal administration of morphine.60 An infusion of naloxone reverses respiratory depression, without reversal of analgesia. Nausea and vomiting Nausea and vomiting after epidural morphine has been observed 6 hours after administration, which coincides with other evidence of rostral spread of morphine in CSF to intracerebral structures.61 Short-term epidural use of lipidsoluble opioids such as meperidine, fentanyl, and sufentanil62–64 may be associated with the lowest incidence of nausea and vomiting, but comparison among different agents is still inadequate. The incidence of nausea and vomiting seems to be less with repeated epidural dosing and is low in patients who require long-term spinal opioid therapy.12 Pruritus Pruritus occurs in up to 24% of patients after acute administration of spinal morphine but diminishes with chronic administration.34,54,56 Urinary retention Urinary retention is usually self-limiting with chronic administration.34,54–57,59 Hyperalgesia Hyperalgesia may develop with chronic high doses of spinal morphine.65,66 Allodynia also has been described after acute intrathecal morphine administration in a patient with neuropathic pain after spinal cord injury.67 High concentrations of intrathecal morphine and associated hyperalgesia have been investigated in rats. This effect is non– opiate receptor mediated,68 as it is exaggerated rather than reversed by naltrexone, and may relate to high levels of the metabolite morphine-3-glucuronide43 or to enhanced NMDA receptor activation.12 Opioid-induced hyperalgesia should be considered in patients on extremely high doses

neuraxial analgesia of intraspinal opioids (e.g., in excess of 20 mg of morphine per day) who develop generalized hyperalgesia and occasionally myoclonus.69 Management involves symptomatic treatment and rotation to an alternative opioid, with consideration of the addition of a nonopioid medication. Endocrine abnormalities Endocrine abnormalities have been noted after prolonged intrathecal administration of opioids.70,71 The majority of patients have been found to develop hypogonadotropic hypogonadism, with reduced levels of testosterone in men, reduced estradiol and progesterone in women, and reduced luteinizing hormone in both men and women. The associated reduced libido improved in most patients after administration of gonadal steroids. A smaller proportion of patients (15%) developed growth hormone deficiency or central hypocorticism.70 Catheter tip masses The development of an intrathecal catheter tip mass was first reported in 1991.72 Studies in dog models showed intrathecal morphine sulfate produced a concentrationdependant catheter tip inflammatory reaction.73 There have been reports of significant numbers of cases, with an estimated cumulative risk of developing an intrathecal mass in the chronic pain population reported as 0.04% over 1 year, increasing to 1.15% over 6 years.74,75 A subsequent prospective analysis of 208 patients presenting for routine pump refills found the incidence of intrathecal masses to be 3%.76 They appear to be a result of an inflammatory reaction following intrathecal administration of certain drugs, most commonly opioids, that ceases once the drug is discontinued.76,77 Most cases follow intrathecal morphine, but hydromorphone and fentanyl also have been implicated. There also have been reports of granulomas in patients receiving intrathecal baclofen.78,79 The presenting symptoms leading to the diagnosis of an intraspinal mass range in severity from loss of drug efficacy to complete paraplegia.75 The investigation of choice for diagnosing intrathecal granulomas is a T1-weighted MRI, the granuloma appearing as an enhancing mass with the tip of the catheter embedded within it. MRI may be used safely in patients with an implanted intrathecal system when the magnet strength is ⬍2.0 Tesla; alternatively, CT-myelography may be used.76,77 Management is determined by the patient’s clinical condition. Surgical consultation is warranted in the presence of significant spinal cord compression or progressive neurological deficit and may lead to surgical removal of the mass. Asymptomatic or mildly symptomatic patients may

291 be treated conservatively, and a consensus panel suggested that presence of a catheter tip inflammatory mass should not necessarily mandate removal of the pump or catheter and permanent cessation of intrathecal therapy. Drug delivery into the mass should be ceased and the catheter revised, with appropriate oral–systemic replacement to prevent withdrawal.77 Prevention should include positioning of the catheter tip in the lumbar thecal sac, if feasible, and using the lowest possible opioid dosage and concentration to achieve adequate analgesia. Noncardiac peripheral edema The reported incidence of peripheral edema due to intrathecal opioids ranges from 6.1% to 21.7%.80 Predisposing factors appear to be preexisting leg edema and venous insufficiency.80

Intracerebroventricular opioids Opioids may be delivered supraspinally via ICV catheters and have an analgesic effect that is thought to be mediated by activation of descending inhibitory pathways that project to the spinal cord. Recently, the antinociceptive effect of ICV morphine was shown to be mediated in part through release of serotonin (5-hydroxytryptamine [5-HT]) in the spinal cord, activation of 5-HT3 receptors, and subsequent release of the inhibitory neurotransmitter ␥ -aminobutyric acid (GABA).81 ICV morphine has been shown to improve analgesia in cancer patients whose pain was uncontrolled by other measures.82–88 After ICV injection, high concentrations of morphine are achieved in ventricular CSF.88 Analgesia occurs within 10 minutes, reaches a maximum between 6 and 10 hours, and persists for 12–48 hours.86,89 Symptoms and side effects after injection may include nausea and vomiting, diaphoresis, sedation, and confusion.90 A suggested initial intraventricular dose is one tenth of the intrathecal dose.7 Daily doses range from 0.15 to 2 mg initially (depending on previous requirements for oral opioid), tend to increase slowly,88 and may reach as high as 15 mg/day.82 A recent systematic review of patients with intractable cancer pain receiving epidural, intrathecal, or ICV opioids reported excellent pain relief in 73% of patients administered ICV opioids, compared with 72% and 62% in the epidural and intrathecal groups, respectively. Nausea, pruritus, urinary retention, and constipation occurred more frequently in the epidural and intrathecal groups, whereas respiratory depression was more common in the ICV group.18 Patients with pain uncontrolled by less invasive measures; obstruction to circulation of CSF, making lumbar

292 intrathecal therapy ineffective; or local factors precluding foreign body implantation in the thoracic and lumbar region may be suited to ICV catheters.6,7,90 Pain in any site can be controlled by ICV opioids, but intractable pain in the head and neck region has been suggested as a specific indication for this route of therapy.58,86

Local anesthetic agents Local anesthetic agents have a long history of use for anesthesia and analgesia because of their ability to reversibly inhibit increases in sodium channel permeability and impair axonal conduction. Local anesthetics may be administered at multiple sites along the neuraxis, and the effects and potential complications will vary according to the route used. Local anesthetics have significant systemic toxic effects if an excessive dose is given or the dose is inadvertently injected intravascularly (e.g., during epidural injection). The relative toxicity of different agents varies and is also influenced by the rate of injection and rapidity with which a particular plasma concentration is achieved. CNS symptoms range from lightheadedness and perioral numbness at low plasma concentrations to visual and auditory disturbances, muscular twitching, loss of consciousness, convulsions, coma, and respiratory arrest at high concentrations.91,92 Cardiovascular toxicity relates to effects of local anesthetics on the electrophysiology of cardiac muscle, with resultant arrhythmias, depression of cardiac muscle contractility, and a biphasic action on peripheral vasculature (vasodilatation at high concentrations). Preparations containing S-bupivacaine rather than the racemic mixture are associated with reduced cardiac toxicity, as is ropivacaine (marketed as a solution containing only the S-isomer).91 Systemic absorption of lower nontoxic doses of local anesthetics may contribute to an analgesic effect, as additional effects of lignocaine on the NMDA and neurokinin-1 receptors have been identified.93 These factors must be considered in the interpretation of therapeutic response. Systemically administered local anesthetic, such as subcutaneous infusion of lignocaine, has been shown to improve management of refractory neuropathic pain in patients with cancer.94 In patients with cancer pain inadequately controlled by opioid alone, safe and effective management has been demonstrated with addition of local anesthetic to the epidural or intrathecal infusion.31,65,95–101 Bupivacaine Bupivacaine is the agent most frequently used, as it has a long duration of action and exhibits little tachyphylaxis.92,98

l.c. holford and m. cousins Local anesthetics can provide intense segmental analgesia and anesthesia, but high doses are associated with side effects. Reductions in blood pressure resulting from sympathetic fiber blockade often are seen in the first 24 hours of treatment,98,102 but after this initial stabilization, postural hypotension is rarely a significant problem. Bowel and bladder dysfunction may occur with epidural bupivacaine concentrations greater than 0.15% or intrathecal doses greater than 30 mg/day.98 Motor weakness has been shown to occur with epidural bupivacaine concentrations greater than 0.35%98 and with intrathecal doses greater than 45 mg/ day.100 After acute bolus administration, bupivacaine toxicity is seen at serum concentrations of 1–2 mg/mL; however, in a group receiving chronic epidural bupivacaine, serum concentrations were frequently 4–5 mg/mL, without symptoms of CNS toxicity.98 The majority of patients can remain active and be managed at home with appropriate family and nursing support.103 The side effects associated with high doses of local anesthetic may be acceptable to some patients with otherwise intractable pain or to those who are bedridden in the terminal phases of their illness.103 A number of studies have reported an improvement in pain relief with the addition of bupivacaine to intrathecal drug mixtures.97 Prolonged use of intrathecal combinations of morphine and bupivacaine has been reported in case series of patients with cancer pain,99 with two series reporting adequate pain control until death in 105 patients.100,104 In 51 patients with cancer pain, 17 proceeded from morphine only to a morphine/bupivacaine spinal infusion mixture. Pain control subsequently improved in 10 patients, with only moderate improvement in four patients; 11 patients required continuation of oral morphine supplementation.101 In these case series, bupivacaine was added when pain control was inadequate with opioid alone. Interpretation of these data is hampered by lack of randomization, variable inclusion criteria (particularly type of pain), and variable definitions of satisfactory pain relief. Two prospective studies have shown improvement in analgesia with bupivacaine and morphine combinations compared with opioid alone, although there was neither blinding nor randomization in one study105 and incomplete blinding in the other.106 In both studies, pain intensity at the time of entry varied among patients, and infusions were titrated to effect in individual patients. A retrospective study of 109 patients receiving intrathecal opioid infusions revealed that patients with a poor response to opioid alone reported significantly lower pain scores and a mean reduction in opioid dosage of 23% with the addition of bupivacaine.96 However, a randomized double-blind multicenter crossover study of 24 patients with chronic nonmalignant pain found

neuraxial analgesia that addition of bupivacaine to intrathecal morphine or hydromorphone failed to produce significant improvement in pain control.107 A retrospective review of 1146 patients with refractory nonmalignant chronic pain receiving opioid or opioid in combination with local anesthetic via an epidural or intrathecal route reported higher rates of satisfactory pain relief in patients receiving opioid and local anesthetic than in patients receiving opioids alone.108 Ropivacaine Ropivacaine is a pure S-enantiomer that offers several potential advantages over bupivacaine. It appears to have significantly reduced CNS and cardiovascular toxicity and has been shown to produce less motor blockade, with effective sensory blockade when compared with bupivacaine. It has lower lipid solubility, resulting in increased spinal segmental spread. However, it is less potent than bupivacaine and has a shorter duration of action.109,110 Most reports regarding ropivacaine concern short-term epidural use. There are no studies on long-term spinal administration in chronic pain. In a crossover trial of intrathecal bupivacaine and ropivacaine in one patient with cancer pain, no differences were seen in pain intensity, level of sensory disturbances, motor weakness, or required number of rescue boluses.111 A prospective randomized double-blind crossover trial of 12 patients comparing intrathecal ropivacaine with bupivacaine found no significant differences in efficacy or side effects between the two agents. Required daily dosage of ropivacaine was 23% higher and cost three times more to achieve the same degree of pain relief.112

Nonopioid spinal analgesic agents Both presynaptic and postsynaptic effects at the primary afferent synapse in the dorsal horn can modulate pain transmission, and analgesic agents either enhance endogenous inhibitory mechanisms or reduce excitatory transmission. Several classes of receptors are found on the terminals of the primary afferents, where they are coupled to voltage-gated calcium channels and reduce transmitter release. Receptors located on the soma of second-order neurons are coupled to potassium channels, and activation leads to hyperpolarization of the projection neuron. If a receptor subtype is present both presynaptically and postsynaptically, the joint inhibition of transmitter release and hyperpolarization of the second-order neuron yield potent and selective blockade.113 Nociception also may be modulated by agents that block or reduce excitation. Antagonists of the postsynaptic NMDA receptor or agents that alter the intracellular

293 consequences of NMDA receptor activation have analgesic actions by reducing excitatory nociceptive transmission. Because pain presents as an event with several pharmacologically and functionally distinct components, analgesia may be improved by use of a combination of analgesic agents acting at different receptor sites.113 Analgesic efficacy, side effects, and systemic and local toxicity of potential spinal analgesics must be evaluated carefully before clinical use. Much of the current data relating to nonopioid spinal analgesics are based on case reports or short-term administration, and it is difficult to determine the most appropriate long-term regimen. The 2003 Polyanalgesic Consensus Conference Panel developed guidelines regarding the minimal evidence of safety and efficacy required for a drug to be deemed acceptable for use as an intraspinal analgesic.114 Essential preclinical data from physicochemical studies included solubility, pH, drug stability, compatibility of the drug with the delivery device, and data from validated animal pain models on toxicity, mechanism of action site, pharmacokinetics, and efficacy. Essential clinical “minimal evidence” was defined as data regarding side effects and safety, typically derived from noncontrolled studies or case studies with desirable “minimal evidence” consisting of pharmacokinetic and efficacy data. In relation to combination therapy, the panel recommended that drug combinations and admixtures be evaluated by the same criteria used for single agents because mixing of drugs could alter pharmacokinetics, safety, efficacy, drug stability, and drug–device compatibility. Clonidine The analgesic activity of ␣2 -adrenergic agonists, such as clonidine, is mediated through presynaptic and postsynaptic ␣2 receptors localized in the superficial layers of the spinal dorsal horn.113,115 Reduction of pain intensity after epidural clonidine correlates with its concentrations in the CSF, but not in serum,116 and much lower bolus doses of clonidine are needed to produce potent and long-lasting analgesia through the intrathecal route than via the epidural or systemic route.117 Clonidine has potential advantages as a spinal analgesic agent. 1. Analgesia is produced by a different mechanism;118 therefore, clonidine may be effective in individuals tolerant to morphine.119 ␣2 -Agonists significantly shift the opioid dose–response curve to the left when they are coadministered intrathecally118 and have a synergistic analgesic action.120 Addition of clonidine to intrathecal infusions of morphine121 and hydromorphone122 has

294 successfully controlled previously intractable cancer pain. Continuous epidural infusions of morphine and clonidine have been managed effectively in patients at home.123 2. Clonidine may be more effective for neuropathic pain.124,125 In a double-blind crossover study, 85 patients with intractable cancer pain received epidural clonidine or placebo in addition to ongoing epidural morphine. Epidural clonidine (30 mg/hour) resulted in successful analgesia in 45% of patients (placebo, 21%), particularly in patients with neuropathic pain (56% vs. 5%).124 A prospective cohort study reported the use of intrathecal clonidine monotherapy in 31 patients with chronic intractable pain uncontrolled with aggressive medical and interventional therapy, 29 of whom had exclusively or predominantly neuropathic pain etiology.126 Thirteen patients reported ≥50% long-term pain relief over the follow-up period of 16.7 months, with minimal dose escalation. A randomized double-blinded placebocontrolled trial evaluating the efficacy of intrathecal clonidine and morphine in the treatment of neuropathic pain following spinal cord injury found a mixture of clonidine and morphine to be more effective than either drug administered alone, with a significant reduction in pain compared with placebo.127 3. The side effect profile of clonidine differs from that of opioids. Clonidine has a hypotensive action that is counteracted at larger doses by a direct peripheral vasoconstrictive effect.126,128,129 Rebound hypertension may occur with sudden cessation of spinally administered clonidine.124 Marked bradycardia has been reported,130 but only minor reductions in heart rate not requiring treatment have been seen in many series.64,124,126,128,129,131 Sedation is usually transient,64,123,128 but may persist for up to 6 hours with larger bolus doses.123,129 Clonidine does not produce respiratory depression,128,131 and nausea was less marked with the combination of epidural clonidine and morphine compared with morphine alone.124 A recent case report documents a spinal cord lesion developing in a patient receiving long-term intrathecal clonidine and bupivacaine for chronic pain.132

l.c. holford and m. cousins antinociceptive effects134–136 and displays additive or synergistic interactions with opioids.135,137 Synergistic analgesia also has been shown between spinally administered midazolam and glutamate receptor antagonists acting at the NMDA receptor or the AMPA receptor. Analgesia was achieved at lower doses when the agents were combined, and this was associated with a reduction in untoward behavioral changes and motor disturbances seen at doses required for single-agent analgesia.138 Improvements in control of severe cancer pain by the addition of intrathecal midazolam to intrathecal opioid and/or local anesthetic have been reported in isolated cases.139,140 Studies of the neurotoxicity of spinally administered midazolam have yielded conflicting results. Four studies found histological signs of neurotoxicity in rat141 and rabbit142–144 models after bolus administration. However, numerous other histological studies have failed to show any increase in neurotoxic effects over control animals after acute or chronic administration.145–149 A study of 547 patients who received intrathecal midazolam in the perioperative setting reported no increase in symptoms suggestive of neurological complications compared with controls.150 No side effects or signs of neurotoxicity were reported following case studies on the use of intrathecal midazolam for chronic nonmalignant pain.151–153 The use of intraspinal midazolam remains controversial. Although some consider it an appropriate medication in the control of intractable chronic pain,151 others have recommended a more cautious approach, especially when used in combination with other medications.40,145,154,155 The role of midazolam, the preservative-containing solution, and the pH of the solution in the long-term safety of intrathecal administration require further evaluation. Baclofen is an agonist at GABA-B receptors. In animal models, baclofen has been shown to elicit dose-dependent analgesia.65,118 Clinically, spinal subarachnoid administration of baclofen has been used to manage spasticity.12,156 Recent evidence suggests it also may have a potential role in the management of chronic pain not associated with spasticity,114,157,158 but analgesic effects have not been studied extensively. NMDA antagonists

␥-Aminobutyric acid agonists Activation of GABA-A receptors results in an increase in inhibitory chloride conductance. Midazolam binds to the benzodiazepine site of the GABA-A receptor complex and increases the amplitude and duration of GABAinduced synaptic current.133 Intrathecal midazolam has

Systemic noncompetitive NMDA receptor antagonists (dextromethorphan, dextrorphan, ketamine, and MK-801) reduce excitatory nociceptive transmission in the spinal cord. When delivered as a sole agent spinally, ketamine has no acute effect on tail flick latency159 but has been shown to reduce allodynia in rat models of neuropathic pain.160,161 In

neuraxial analgesia clinical practice, spinally administered ketamine has limitations for use as a sole agent, in terms of both efficacy and dose-limiting side effects,162–164 and therefore may be better suited to combination therapy. Both animal159,165 and clinical studies166 have shown potentiation of opioid analgesia by an NMDA receptor antagonist. In addition, intrathecally coinfused NMDA antagonists attenuate morphine tolerance in animal models.167–169 These data suggest that a combination of an NMDA antagonist and opioid may have advantages for long-term infusions in clinical practice. In patients with terminal cancer pain, addition of once-daily epidural ketamine, 0.2 mg/kg, to the regimen of twice-daily epidural morphine administration resulted in improved analgesia when compared with a control group (who received a third daily bolus of epidural morphine, 2 mg). Two other parts in this study found a benefit with addition of neostigmine, 100 mg, but no benefit with epidural midazolam, 500 mg.170 A blinded crossover trial of twicedaily bolus doses of intrathecal morphine with or without addition of ketamine, 1 mg, also was conducted in patients with terminal cancer pain. Addition of ketamine reduced the dose requirements for both intrathecal morphine and breakthrough analgesia, but there was no statistical difference in the incidence of side effects, possibly because of the small number of patients studied.171 Histopathological changes of subpial spinal cord vacuolation were reported in a terminally ill cancer patient who received intrathecal racemic ketamine with preservatives for 3 weeks.172 In another case of a patient who received intrathecal racemic ketamine for intractable cancer pain, postmortem histological examination revealed lymphocytic vasculitis in the spinal cord near the catheter tip.173 Preservative-free ketamine did not cause neurotoxic effects after repeated administration in animals,174,175 and subsequent studies suggested preservatives used in the commercial solution of the racemic mixture of ketamine were responsible for the observed histopathological findings.176 The active enantiomer S(+)-ketamine has been considered less neurotoxic than the racemic mixture. Clinical reports have shown intrathecal preservative-free S(+)-ketamine to be safe and effective in the management of refractory cancer-related neuropathic pain.177,178 However, following a report of severe neuropathological changes in a patient who received 28 days of intrathecal preservative-free S-ketamine,179 a randomized blinded study in rabbits revealed that intrathecal preservative free S(+)-ketamine caused significant toxic damage to the spinal cord.180 In the light of the evidence regarding neurotoxicity of ketamine and S(+)-ketamine, it has been suggested that further toxicology studies to establish longterm safety are required before neuraxial use of ketamine

295 and S(+)-ketamine can be recommended outside the setting of severe refractory pain in terminal disease.40,178,180 Ziconotide Ziconotide is the first clinically available agent in the class of neuronal (N-type) calcium channel blockers. It is a synthetic ␻-conopeptide derived from the venom of the marine snail Conus magnus and approved for intrathecal use by the FDA in 2004 and the European Medicines Agency in 2005.181 It is a very potent and highly selective N-type voltage-sensitive calcium channel blocker that inhibits presynaptic release of neurotransmitters including substance P, calcitonin gene-related peptide, and glutamate from primary nociceptive afferents terminating in the superficial laminae of the dorsal horn.182–185 Ziconotide does not bind to opioid receptors, and tolerance does not develop with continued administration.182,186 Intrathecal administration produces antinociception in animal models of acute182,183,187 and persistent pain.188 In clinical studies, intrathecal ziconotide has been shown to reduce postoperative daily patient-controlled analgesia (morphine) consumption189 and has improved control of chronic neuropathic pain.190 The safety and analgesic efficacy of intrathecal ziconotide have been demonstrated in three randomized, double-blind, placebo-controlled studies.191–193 A study of intrathecal ziconotide in 112 patients with chronic refractory pain due to cancer or AIDS demonstrated a clinically and statistically significant analgesic effect compared with placebo.191 In a study of 257 patients with severe chronic nonmalignant pain unresponsive to conventional therapy, intrathecal ziconotide resulted in a 31.2% reduction in visual analogue scale of pain intensity (VASPI) score compared with a 6% reduction in the control group (P ⬍ 0.001).192 However, a significantly higher incidence of adverse events was noted in the ziconotide group. A third study193 evaluated the drug in 220 patients with severe chronic pain using a slower titration schedule and lower maximum dose than were used in the previous two trials. A starting dose of 0.1 ␮g/hour (compared with 0.4 ␮g/ hour191,192 ) titrating to a mean of 0.29 ␮g/hour over 3 weeks (compared with 0.91 ␮g/hour191 and 1.02 ␮g/hour192 ) resulted in a statistically significant improvement in VASPI score and a reduced incidence of serious adverse events. A subsequent study194 investigated the safety and efficacy with long-term use in 155 patients who had been responsive to short-term treatment in either of two previous trials.191,192 Patients continued to experience improved pain control and functionality for up to 12 months of treatment, with no evidence of tolerance. One hundred forty-seven

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296 patients reported adverse events, with 39.4% of patients discontinuing treatment as a result; however, these events usually were mild or moderate and reversible with dose reduction or cessation. Ziconotide has a narrow therapeutic window, and adverse side effects reported include elevated creatine kinase levels, meningitis (due to microinfusion device contamination), dizziness, nausea, somnolence, headache, ataxia, and abnormal gait.181,189,195 Neuropsychiatric symptoms are prominent, and routine psychological support for patients has been recommended.40 A low starting dose and slower titration schedule should be used to reduce the likelihood of serious adverse effects, and an expert consensus panel recommended a starting dose of not more than 0.5 ␮g/24 hours, increasing by not more than 0.5 ␮g/24 hours and no more often than once weekly.196 Neostigmine A high density of muscarinic cholinergic receptors is found in the spinal dorsal horn, and intrathecal administration of muscarinic agonists results in behavioral analgesia.197,198 Neostigmine inhibits acetylcholinesterase and reduces the breakdown of acetylcholine. In clinical trials, intrathecal neostigmine produced dose-related analgesia, with the therapeutic dose lying between 50 and 500 ␮g.199 Two patients with metastatic abdominal cancer achieved relief of pain for approximately 20 hours after single intrathecal injections of neostigmine (100 and 200 ␮g, respectively).200 However, side effects of nausea, vomiting, urinary retention, motor weakness, and decreased deep tendon reflexes are common at high doses.118–120 Therefore, interest is now focused on potential benefits of low doses of neostigmine coadministered with other intrathecal analgesics. Synergistic analgesic interactions have been shown between neostigmine and morphine,201–203 and also neostigmine and clonidine.197,201,202 In a controlled trial conducted in patients with terminal cancer pain, addition of a bolus of epidural neostigmine (100 ␮g) to epidural morphine increased the duration of analgesia.170 An additive analgesic effect has been reported between intrathecal neostigmine and epidural clonidine in a volunteer study,204 but this combination has not been investigated for the management of cancer pain. Future studies are required to establish the safety and efficacy of neostigmine. Somatostatin Somatostatinergic pain-inhibiting mechanisms have been identified. Epidural or intrathecal somatostatin resulted in

“excellent” or “good” pain relief in six of eight patients with terminal cancer and intractable pain unrelieved by large doses of opioids.205 However, all patients required escalating doses of somatostatin during treatment (mean duration, 11.3 days; dose range, 250–3000 mg daily infusion). The clinical role of spinal somatostatin is limited, as it decreases spinal cord blood flow; may augment postsynaptic effects of glutamate, leading to local neuronal injury; and has been found to have deleterious morphological effects on the spinal cord in mice, rats, and cats.206 In addition, somatostatin is unsuitable for prolonged infusion as it is a relatively unstable peptide, and the stable analogue octreotide (somatostatin-14) may be more clinically useful.207 Intrathecal treatment with octreotide (5–20 mg/hour for 13–90 days) has been used in patients with cancer pain unrelieved by oral opioids. Pain scores were reduced, and supplemental oral opioid use also decreased.208 A recent prospective double-blind study in 20 patients found that intrathecal octreotide at a maximum rate of delivery of 20 ␮g/hour showed no significant improvement in pain relief when compared with saline. There were no side effects or neurotoxicity, and the authors suggested that further studies with increased doses are warranted.209 Adenosine Adenosine agonists acting at the A1 receptor in the superficial layers of the spinal dorsal horn produce analgesia. Multiple potential analgesic mechanisms include presynaptic reduction in transmitter release, postsynaptic effects, inhibitory actions that suppress spinal NMDA-mediated responses in sensitized pain states, release of neurotransmitters such as norepinephrine, and interactions with opioids.210–212 Adenosine receptor agonists produce antinociception in animal models of acute pain213 and reduce hyperalgesia and allodynia in inflammatory211 and nerve injury214 models. In clinical case reports, intravenous infusion of adenosine215 and intrathecal injection of adenosine216 and its agonist R-PIA217 have been shown to reduce allodynia and hyperalgesia in patients with neuropathic pain. No behavioral or histological evidence of neurotoxicity has been found in animal studies,218 and preliminary efficacy and safety studies have been conducted in adult volunteers.219,220 Spinal adenosine potentiates morphine in an additive manner, and a combination of spinal morphine with inhibitors of endogenous adenosine metabolism or reuptake produced a complete reversal of allodynia in a nerve injury model.210 The role of adenosine in combination spinal therapy for the management of cancer pain requires further evaluation.

neuraxial analgesia Combinations of spinal analgesic agents In some patients with advanced cancer, pain may not be adequately controlled by spinal opioids, and management of pain in this situation requires thorough reevaluation. Disease progression, development of new pain types (e.g., bone pain resulting from pathological fracture, neuropathic pain resulting from compression of peripheral nerves or the spinal cord), and malfunction of the spinal delivery system all must be considered. In a prospective randomized trial of spinal analgesia versus comprehensive medical management, 75% of patients with refractory cancer pain had a neuropathic component to their pain.9 Opioids alone are most effective for the management of continuous somatic pain, whereas neuropathic pain, visceral pain, and intermittent or incident pain tend to be less responsive,35,65,221,222 and control may be improved by using a combination of analgesic drugs.223 For example, delivering a spinal opioid with a local anesthetic improves the control of incident (i.e., movement-related) pain,124,224 whereas the addition of clonidine to an opioid enhances the control of neuropathic pain.127 Evidence from controlled trials for the efficacy of spinal analgesic combination therapy has been reviewed.223 Currently, there is insufficient evidence to determine the indications or comparative benefits for the large number of possible combinations of spinal analgesic agents. Interest in the development of combination spinal analgesic therapy has focused on the following aims: 1. Improvement in analgesic efficacy. When two drugs are administered together their effects may be a) antagonistic if the combination’s effect is less than the sum of the effects produced by each agent alone, b) additive if their combined effect equals the sum of the effects produced by each agent alone, or c) synergistic if the effect of the combination exceeds the sum of the effects produced by each agent alone. Preclinical studies have identified a number of synergistic interactions with intrathecal coadministration of different compounds,113 but few clinical studies have been performed to rigorously characterize whether various combinations have additive or synergistic interactions.225 Clinically, the distinction between the latter two types of interaction is less important than confirming that analgesia is improved when the combination is compared with a single agent, with no increase in side effects. 2. Reduction in side effects. The limited efficacy of single agents may result in dose escalation and dose-limiting side effects (e.g., neostigmine). The combination of two

297 agents with the common desired end point of analgesia but with different side effect profiles may enhance the therapeutic ratio of the therapy. 3. Reduction in the development of opioid tolerance. Tolerance to opioid analgesia refers to a decline in analgesic effect during ongoing drug administration and the need to escalate opioid dose to maintain the same effect. Combination of a nonopioid analgesic with an opioid may reduce the development of tolerance indirectly by reducing the opioid requirement. Van Dongen et al.106 reported a diminished progression of intrathecal morphine dose during intrathecal coadministration of morphine and bupivacaine when compared with intrathecal morphine alone. Alternatively, some analgesic agents may directly affect the development of tolerance. With respect to the latter mechanism, opioid tolerance in part involves excitatory amino acids that provoke central sensitization and hyperalgesia.226 Manipulations that inhibit NMDA receptor activation, calcium influx, or the intracellular consequences of NMDA receptor activation227,228 may forestall tolerance and dependence. Therefore, in addition to a combined analgesic effect, infusion of an NMDA antagonist with an opioid may reduce opioid tolerance and dose escalation during chronic administration. The lack of a firm evidence base and a survey revealing wide variation in practice patterns prompted an expert interdisciplinary panel to gather in 1999 to address the use of intrathecal analgesia in the management of chronic pain.39 The panel reviewed the results of the survey, preclinical and clinical data, and their own clinical experience and recommended an algorithmic approach to selection of drugs and guidelines for administration based on best evidence and expert opinion.229 These recommendations were reviewed and updated at subsequent meetings in 2003 and 2007.40,114 A similar multidisciplinary panel was convened in 2003 to specifically address the use of intrathecal drug delivery in the management of intractable cancer pain.230 There is evidence that the use of an algorithmic approach can optimize pain management. A 2002 randomized multicenter clinical trial comparing an implantable intrathecal drug delivery system (IDDS) plus comprehensive medical management (CMM) versus CMM alone in patients with refractory cancer pain not only showed that the IDDS group achieved better outcomes than the controls, but also demonstrated that algorithm use by pain specialists in the group receiving CMM alone also reduced pain by 39% and medication toxicity by 17%.9 A randomized trial also demonstrated an improvement in pain reduction with

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2007 POLYANALGESIC ALGORITHM FOR INTRATHECAL THERAPIES

Second Line

(a) Morphine (d) Fentanyl

Third Line

(g) Clonidine

First Line

Fourth Line

Fifth Line

Sixth Line

(b) Hydromorphone (e) Morphine/hydromorphone + ziconotide (h) Morphine/hydromorphone/fentanyl Bupivacaine + /clonidine + ziconotide

(c) ziconotide (f) Morphine/hydromorphone + Bupivacaine/clonidine

(i) Sufentanil

(j) Sufentanil + Bupivacaine +/clonidine + ziconotide (k) Ropivacaine, buprenophine, midazolam meperidine, ketorolac Experimental Drugs (e.g. gabapentin)

Fig. 15.1. Summary of recommendations for intrathecal polyanalgesic therapies, 2007. First Line: Morphine (a) and ziconotide (c) are approved by the Food and Drug Administration of the United States for intrathecal analgesic use and are recommended for first line therapy for nociceptive, mixed, and neuropathic pain. Hydromorphone (b) is recommended based on widespread clinical usage and apparent safety. Second Line: Because of its apparent granuloma sparing effect and because of its wide apparent use and identified safety, fentanyl (d) has been upgraded to a second line agent by the consensus conference when the use of the more hydrophilic agents of first line (a,b) results in intractable supraspinal side-effects. Combinations of opioid + ziconotide (e) or opioid + Bupivacaine or clonidine (f) are recommended for mixed and neuropathic pain and may be used interchangeably. When admixing opioids with ziconotide, attention must be paid to the guidelines for mixing ziconotide with other agents. Third line: Clonidine (g) alone or opioids such as morphine/hydromorphone/fentanyl with Bupivacaine and/or clonidine mixed with ziconotide (h) may be used when agents in the second line fail to provide analgesia or side-effects occur when these agents are used. Fourth line: Because of its proven safety in animals and humans and because of its apparent granuloma-sparing effects, sufentanil alone (i) or mixed with Bupivacaine and/or clonidine plus ziconotide (j) is recommended in this line. The addition of clonidine, Bupivacaine, and or ziconotide can be used in patients with mixed or neuropathic pain. ∗ In patients with end of life, the panelists felt that midazolam and octreotide should be tried when all other agents in first line to fourth line have failed. Fifth line: These agents (k) although not experimental, have little information about them in the literature and use in recommended with caution and obvious informed consent information about them in the literature and use in recommended with caution and obvious informed consent regarding the paucity of information regarding the safety and efficacy of their use. Sixth line: Experimental agents (1) must only be used experimentally and with appropriate Independent Review Board (IRB) approved protocols. Reproduced with permission from Neuromodulation, International Neuromodulation Society.

the use of algorithms as compared with routine oncology care.231 The 2007 Polyanalgesic Consensus Conference published an updated algorithm for the use of intrathecal analgesic medications and combinations in a rational and prioritized order (Fig. 15.1). The algorithm was designed for use in screening trials in the assessment of patient suitability for intrathecal pump implantation and in altering treatment in patients already receiving long-term intrathecal infusions. Line one medications should be selected for initial therapy, with progression to lower-line medications if these become ineffective at a safe dosage and concentration (Table 15.1) or if intolerable side effects develop. In 2003, a multidisciplinary consensus panel addressing the use of intrathecal medication delivery in cancer pain recommended one of two treatment algorithms based

on whether the patient was stratified as a “short-term survivor” with a high stage of disease, incapacitation due to pain, and/or life expectancy of less than 12 months, or a “long-term survivor.”230 It was felt that long-term survivors should be treated according to the current Polyanalgesic Consensus Conference algorithm for patients with chronic pain. A separate algorithm was developed for short-term survivors because of the potential for escalating pain requiring rapid dose escalation and complex polyanalgesia (Fig. 15.2). This allowed for more aggressive therapy and higher acceptable maximum doses and concentrations (Tables 15.2 and 15.3). The 2007 Polyanalgesic Consensus Conference panel agreed that an accelerated algorithm be used for patients at end of life, including consideration of intrathecal agents not recommended for patients with nonmalignant pain.40

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Table 15.1. Summary of concentrations and doses of intrathecal agents commonly used Drug

Maximum concentration

Maximum dose/day

Morphine Hydromorphone Fentanyl Sufentanil

20 mg/mL 10 mg/mL 2 mg/mL 50 ␮g/mL (not available for compounding) 40 mg/mL 2 mg/mL 100 ␮g/mL

15 mg 4 mg No known upper limit

Bupivacaine Clonidine Ziconotide

No known upper limit 30 mg 1.0 mg 19.2 ␮g (Elan recommendations)

Reproduced with permission from Neuromodulation, International Neuromodulation Society.

Spinal delivery systems The choice of epidural or intrathecal administration, and the type of spinal delivery system, requires consideration of many factors: 1. The patient’s life expectancy and required duration of therapy 2. The site, type, and expected progression of the tumor 3. Patient and social factors if systems requiring daily injections or home treatment are used 4. Varying availability of ongoing care and expertise with invasive techniques among geographic regions

For opiate-intolerant nausea, add droperidol.

FIRST LINE

Morphine or hydromorphone Nociceptive

Morphine or hydromorphone with bupivacaine Mixed

Bupivacaine Neuropathic

SECOND LINE

Morphine, hydromorphone, or fentanyl/sufentanil with bupivacaine and clonidine

Morphine, hydromorphone, or fentanyl/sufentanil with bupivacaine and clonidine

Morphine, hydromorphone, or fentanyl/sufentanil with bupivacaine.

Nociceptive

Mixed

Neuropathic

THIRD LINE

Morphine, hydromorphone, or fentanyl/sufentanil with more than TWO adjuvants Use opiate + local anesthetic + clonidine and: Baclofen for spasticity, myoclonus, or neuropathic pain Bupivacaine for neuropathic pain Second opioid (hydrophilic/lipophilic) as an adjuvant

FOURTH LINE

Morphine, hydromorphone, or fentanyl/sufentanil with more than THREE adjuvants In addition to second-line adjuvants add: Ketamine for neuropathic pain for cord compression Midazolam for neuropathic pain Droperidol for neuropathic pain Some patients may require six adjuvants to control pain at end of life with minimum side effects. Tetracaine for chemical paralysis for inoperable cord compression, tachyphylaxis, or acute hyperalgesia rescue

Fig. 15.2. Cancer pain best-practices algorithm. Recommendations for intraspinal polyanalgesia in cancer patients with pain. From Stearns et al.230

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Table 15.2. Recommended dosages and concentrations for medications utilized in the intrathecal cancer pain algorithm for short-term survivors Drug

Dosage (mg/day)

Maximum concentration (mg/mL)

First-line medications (1–3 medications in mixture) Morphine 0.1–50 50 Hydromorphone 0.1–100 100 Bupivacaine 3–50 38 Droperidol (nausea indication) 0.025–0.15 0.5 Second-line medications (2–4 medications in mixture); above medications and/or: Fentanyl 0.01–5 20 Sufentanil 0.001–0.5 2 Clonidine 0.025–0.8 2 Third-line medications (4–6 medications in mixture); above medications and/or: Baclofen 10–1000 2 Second opioid: Morphine 0.1–15 30 Hydromorphone 0.1–10 30 Fentanyl 0.01–0.15 1 Fourth-line medications (⬎3 medications); possibly neurotoxic, use for rescue only; above medications and/or: Tetracaine 30–85 100 Ketamine 0.025–1.0 2 Midazolam (HCL form only) 0.025–1.0 2 Droperidol (pain indication) 0.025–0.25 1 Abbreviation: HCL, hydrochloride. From Stearns et al.230

5. Drug and dose requirements with regard to the choice between epidural and intrathecal therapy 6. Cost–benefit and risk–benefit ratios Epidural catheters have potential advantages, as segmental delivery of local anesthetic can be achieved in patients with severe neuropathic pain (e.g., tumor invading the brachial plexus). The dura also offers a potential barrier to infection. However, catheter dislodgement and the development of epidural fibrosis that limits drug delivery to the epidural space are potential disadvantages. Because intrathecal catheters deliver drug directly into the CSF, lower doses are required, and this route may be preferable for long-term therapy. Nitescu et al.232 compared sequential epidural and intrathecal administration of Table 15.3. Recommended dosages and concentrations for medications used in the intrathecal cancer pain algorithm for long-term survivors

Drug

Dosage (mg/day)

Maximum concentration (mg/mL)

Morphine Hydromorphone Bupivacaine Clonidine

15 5–10 2–30 0.01–1.0

30 30 38 2

morphine–bupivacaine in 25 patients with advanced cancer pain. Lower volumes and doses were required for the intrathecal route, with a mean dose ratio of one seventh of the epidural dose being effective intrathecally. Pain relief was reported as poor at the end of the epidural treatment and improved on commencement of intrathecal therapy. This is likely to reflect mechanical factors, such as catheter tip fibrosis affecting drug delivery with prolonged epidural catheterization. The method of drug delivery via catheters also is variable. In the short term, percutaneous catheters may be used. Temporary percutaneous catheters often are used for epidural or intrathecal drug trials to ensure that the patient’s pain responds to spinal therapy without excessive side effects before proceeding to implantation of more invasive systems. Low cost and ease of insertion of percutaneous catheters may make this simple delivery system sufficient if the patient is expected to live only 1–2 weeks.7,233,234 Tunneled catheters with external filters or cuffs have a lower incidence of infection and dislodgement than percutaneous catheters.54,55,102,104,235–237 Fully implanted epidural or intrathecal catheters may be connected to subcutaneous patient-activated reservoirs238 that deliver a fixed volume of drug, or subcutaneous portals that can be accessed by percutaneous injection236,239,240 to deliver intermittent boluses or external infusions. No difference in pain scores or

neuraxial analgesia neuropsychological function was found when intermittent bolus administration of morphine was compared with continuous infusion,239 but greater dose escalation was seen in the continuous infusion group. Advantages of infusion techniques are more evident when using combination therapies. Bolus doses of local anesthetic may result in motor weakness and hemodynamic instability,5 and many nonopioid analgesics have a shorter duration of action than spinally administered morphine. Implanted infusion pumps are being used increasingly and have several advantages: 1) continuous infusion of analgesics is possible, 2) the reservoir requires only intermittent accessing and refilling, and 3) patients are not hampered by external pumps or the requirement for frequent injections. Implanted pump systems are most suited to lowvolume intrathecal rather than epidural infusions to avoid too-frequent refilling of the reservoir (volume, 18–50 mL). The choice between programmable pumps and constantdelivery pumps241 is influenced by the nature and stability of the patient’s pain pattern, access to specialized centers, life expectancy, and cost. Disadvantages of implanted pumps include the greater complexity of insertion and the current limited life span of 3–5 years for pump batteries in programmable models. In patients with a life expectancy of longer than 3 months, implanted pumps become costeffective7,8 and are likely to have fewer catheter-related problems and lower infection rates. Spinal delivery systems also may be used during acute exacerbations of pain or subsequent surgery. Intrathecal pumps have been accessed to deliver subarachnoid local anesthetic and provide surgical anesthesia in patients requiring urological procedures or operative procedures on lower limbs, or to deliver local anesthetic for brief periods of severe exacerbation of pain.59,242 Care must be taken to aspirate concentrated drug solutions from intrathecal catheters before injection, and physicians familiar with the use of these systems should access the pump in an aseptic manner. Complications of spinal delivery systems Infection Complications related to infection vary in severity and incidence, and may be more likely in diabetic, immunosuppressed, or debilitated terminal patients. Possible routes of contamination include hematogenous spread from a distant infectious process,3 contamination of the injectate, and colonization of percutaneous catheters.243 Colonization of percutaneous catheters by skin flora can be reduced by minimizing the frequency of changes of the drug

301 syringe/cassette,243 using antimicrobial filters,244 carefully exiting the site with secure fixation of the catheter,245 and monitoring for any sign of infection.5 The highest incidence of superficial infections (i.e., involving the catheter site, but not resulting in epidural abscess or meningitis) is seen with percutaneous catheters. Tunneling catheters for a short distance does not appear to improve infection rates,237 but use of a long subcutaneous tunnel and a fibrous cuff or external filter is associated with fewer superficial infections.54,55,221 Implanted systems with a subcutaneous portal have a lower incidence of catheter-related problems, with reported infection rates of 8%–12%.236,237 If treated early, superficial infections may be limited to the subcutaneous tissues and are not associated with epidural abscess formation or meningitis. Catheter removal may not be mandatory, and the relative benefits and risks for individual patients need to be assessed. The rate of infection following fully implanted intrathecal systems has been reported as varying from 2.5% to 9%,246 with the pump pocket as the most common site of infection. CNS infection is a serious potential complication of spinal therapy. Symptoms of epidural abscess include increasing pain, new onset of back pain, and development of motor and sensory deficits.243 The incidence of epidural abscess and/or meningitis in patients with spinal delivery systems varies in different series from 0% to 16%.243,247 The true incidence of infectious complications is difficult to determine, as cases often are reported in isolation,248 the number of patients undergoing invasive treatments is unknown and continues to change, and the type of delivery system varies. In one series, implanted pumps with intrathecal catheters had a lower incidence of infection (0.64 infections per 1000 catheter-days) compared with externalized DuPen catheters (1.6 infections per 1000 catheter-days). By multivariate Cox regression analysis, only duration of surgery of at least 100 minutes was significantly associated with infection.247 The incidence of infection also varies in different units depending on the selection of patients, experience with the technique, and level of follow-up care.249 Centers with large numbers of patients tend to have lower incidences of infection.247 Patients with suspected spinal epidural abscess require prompt neurological evaluation, investigation with CT or MRI, and aggressive management, which usually includes removal of the system.246 In some cases, intrathecal reservoirs and catheters have been retained247 and used to sample CSF and administer intrathecal antibiotics.250 Guidelines for the prevention and management of infections related to intrathecal drug delivery systems have been published recently.246

302 Epidural fibrosis Formation of a sheath of fibrous tissue around chronically implanted epidural catheters has been shown in postmortem studies.251 Pain on injection occurs in up to 12% of patients with long-term epidural catheters,34,52,55,65,236,237 resulting from fibrosis around the catheter tip, and can be managed by replacing the epidural catheter or converting to an intrathecal catheter. Delivery of opioid to its site of action can be reduced by epidural fibrosis,52 leading to a recurrence of pain. Factors limiting fibrosis formation include morphine solutions without additives, a pH of approximately 5, and the use of silicone or polyurethane epidural catheters.5 Spinal cord compression by precipitation of the sodium hydroxide solute within bupivacaine around an epidural catheter tip was reported252 after 11 months of therapy in a patient with cancer pain. Neurotoxicity and neurological complications In experimental animals with chronically implanted catheters, mild deformation and local demyelination have been reported to occur where catheters contact the spinal cord. The same changes were seen in animals given saline or opioids.253 These findings indicate the need for caution in the site of placement of spinal catheters. However, the potential roles of insertion trauma, catheter material, analgesic solution, drug preservatives, and treatment duration are difficult to delineate in the evaluation of therapyinduced damage.254 No significant postmortem neurotoxic effects were seen in 10 cancer patients treated with morphine or morphine and bupivacaine intrathecal infusions via polyamide lumbar catheters for a mean of 98 days (range, 8– 452 days).255 Neurological deficits may relate to the underlying disease process with infiltration or compression by malignant tissue, effects of previous radiotherapy and antineoplastic drugs, or infection.256 Even in the absence of spinal catheterization, compression of the spinal cord or cauda equina results in clinical symptoms of back pain, sensory disturbances, incontinence, and motor weakness, which may progress to paralysis in about 5% of cancer patients with progressive disease.257 The known presence of epidural or spinal metastases presents a dilemma. Neurological complications may occur in these patients as a result of tumor progression, vertebral collapse, or obstruction of vascular supply, but may also be precipitated by trauma from spinal catheterization with bleeding or CSF leakage. Epidural and spinal metastases often are associated with severe pain, and in such cases, spinal administration may be a necessary last resort,245 providing patients are adequately informed of potential risks. In one series of 57 cancer patients with refractory pain,

l.c. holford and m. cousins epidural metastases were found in 40 patients and spinal stenosis in 33 patients.258 During the period of intrathecal treatment, patients with confirmed epidural metastases and total spinal canal stenosis needed significantly higher daily doses of opioid and bupivacaine, and had higher rates of radicular pain at injection and poor distribution of analgesia. The presence of epidural metastasis affected catheter insertion complications (multiple attempts to achieve dural puncture, aspiration of bloody CSF, difficulty advancing the catheter) and complications of intrathecal pain treatment only when it was associated with spinal stenosis. Unexpected paraparesis within 48 hours after dural puncture and intrathecal catheterization occurred in five of 201 patients (2.5%).258 Loss of CSF below the level of a subarachnoid block may trigger collapse of the tumor against the spinal cord (“spinal coning”) or exacerbate epidural venous engorgement. Some authors suggest that spinal catheters should be carefully placed cephalad to known metastases to minimize direct trauma and to improve efficacy, as tumor progression may result in obstruction of CSF circulation55,83,233,259 and hinder diffusion of drugs. Ongoing chemotherapy or radiotherapy is not necessarily a contraindication to the placement of a spinal catheter.6 Epidural hematoma Epidural hematoma formation is a rare but potentially serious complication of spinal therapies,65,245,260 as it may result in spinal cord compression and paraplegia if not recognized. The presence of a coagulopathy (e.g., as a result of liver function abnormalities or administration of anticoagulants) significantly increases the risk of epidural hematoma formation after epidural or intrathecal injection. Anticoagulant therapy should be modified or withheld before epidural or intrathecal procedures, and agentspecific guidelines have been published.261 Thrombocytopenia is also a risk factor for the development of epidural hematoma and needs to be considered in the cancer patient population. A minimum platelet count of 20 × 103 /␮L has been recommended, although platelet transfusion may be considered.230 Mechanical problems Mechanical problems such as catheter obstruction and dislodgement must be excluded if pain rapidly increases in patients during spinal therapy. The incidence of catheter dislodgement is highest for percutaneous epidural catheters (up to 40%)57,65,233,237 and reduced by use of a subcutaneous portal236,237 or an implanted intrathecal system. Newer programmable implanted models require battery replacement but have an expected life span of 3–5 years.

neuraxial analgesia Mechanical failure of implanted infusion devices may occur and result in loss of analgesia and withdrawal effects that will vary depending on the medication involved. Withdrawal from intrathecal clonidine may lead to rebound hypertension, and sudden cessation of intrathecal baclofen may be life threatening. Management in such cases will involve the use of systemic medications to provide adequate pain control and prevent withdrawal.

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7. 8.

9.

Conclusion Neuraxial analgesia should be considered if patients with cancer pain are not achieving adequate pain relief or are experiencing dose-limiting side effects, despite a range of systemic therapies for pain and symptom management. Although necessary in a minority of patients with cancer, it has the potential to significantly improve the patient’s quality of life. The development of improved catheters and pump systems for spinal delivery has increased the potential for this route of administration of analgesic agents. This may be necessary in the short term for patients with debilitating terminal disease, as well as in the longer term for patients with slowly progressive disease or neuropathic pain states relating to the cancer or its treatment. Improved pain control has been achieved in many cancer patients with spinal administration of opioids, local anesthetics, and nonopioids. Based on an increased understanding of pain pathophysiology, a range of spinal analgesics are now being investigated, and it is hoped that continuing evidence from randomized controlled studies in conjunction with appropriate application of rational evidence-based guidelines for clinical use will lead to increased acceptance of neuraxial analgesia in the control of pain and symptoms in patients with cancer-related pain.

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11.

12.

13.

14. 15.

16. 17. 18.

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l.c. holford and m. cousins 234. Mercadante S. Intrathecal morphine and bupivacaine in advanced cancer pain patients implanted at home. J Pain Symptom Manage 9:201–7, 1994. 235. Tryba M, Zenz M, Strumpf M. Long term epidural catheters in terminally ill patients – a prospective study of complications in 129 patients. Anesthesiology 73:A784, 1990. 236. Plummer JL, Cherry DA, Cousins MJ, et al. Long-term spinal administration of morphine in cancer and non-cancer pain: a retrospective study. Pain 44:215–20, 1991. 237. De Jong PC, Kansen PJ. A comparison of epidural catheters with or without subcutaneous injection ports for treatment of cancer pain. Anesth Analg 78:94–100, 1994. 238. Poletti CE, Cohen AM, Todd DP, et al. Cancer pain relieved by long-term epidural morphine with permanent indwelling systems for self-administration. J Neurosurg 55:581–4, 1981. 239. Gourlay GK, Plummer JL, Cherry DA, et al. Comparison of intermittent bolus with continuous infusion of epidural morphine in the treatment of severe cancer pain. Pain 47:135–40, 1991. 240. Shaves M, Barnhill D, Bosscher J, et al. Indwelling epidural catheters for pain control in gynaecologic cancer patients. Obstet Gynecol 77:642–4, 1991. 241. Harbaugh RE, Coombs DW, Saunders RL, et al. Implanted continuous epidural morphine infusion system. J Neurosurg 56:803–6, 1982. 242. Coombs DW, Fine N. Spinal anesthesia using subcutaneously implanted pumps for intrathecal drug infusion. Anesth Analg 73:226–31, 1991. 243. Smitt PS, Tsafka A, Teng-van de Zande F, et al. Outcome and complications of epidural analgesia in patients with chronic cancer pain. Cancer 83:2015–22, 1998. 244. De Cicco M, Matovic M, Castellani GT, et al. Time-dependent efficacy of bacterial filters and infection risk in long-term epidural catheterization. Anesthesiology 82:765–71, 1995. 245. Nitescu P, Sjoberg M, Appelgren L, Curelaru I. Complications of intrathecal opioids and bupivacaine in the treatment of ‘refractory’ cancer pain. Clin J Pain 11:45–62, 1995. 246. Follett KA, Boortz-Marx RL, Drake JM, et al. Prevention and management of intrathecal drug delivery and spinal cord stimulation system infections. Anesthesiology 100:1582–94, 2004. 247. Byers K, Axelrod P, Michael S, Rosen S. Infections complicating tunnelled intraspinal catheter systems used to treat chronic pain. Clin Infect Dis 21:403–8, 1995. 248. Van Diejen D, Driessen JJ, Kaanders JH. Spinal cord compression during chronic epidural morphine administration in a cancer patient. Anaesthesia 42:1201–3, 1987. 249. Cherry DA, Plummer JL, Gourlay GK. Letter to the editor about epidural opiates and local anesthetics for the management of cancer pain. Pain 48:469, 1992. 250. Schoeffler P, Pichard E, Ramboatiana R, et al. Bacterial meningitis due to infection of a lumbar drug release system in patients with cancer pain. Pain 25:75–7, 1986. 251. Coombs DW, Fratkin JD, Frederick AM, et al. Neuropathologic lesions and CSF morphine concentrations during chronic

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311

256. Smitt PS, Tsafka A, Van Den Bent MJ, et al. Spinal epidural abscess complicating epidural analgesia in 11 cancer patients: clinical findings and magnetic resonance imaging. J Neurol 246:815–20, 1999. 257. Schiff D, Shaw EG, Cascino TL. Outcome after spinal reirradiation for malignant epidural spinal cord compression. Ann Neurol 37:583–9, 1995. 258. Appelgren L, Nordberg C, Sjoberg M, et al. Spinal epidural metastasis: implications for spinal analgesia to treat ‘refractory’ cancer pain. J Pain Symptom Manage 13:25–42, 1997. 259. Cherry DA, Gourlay GK, Cousins MJ. Epidural mass associated with lack of efficacy of epidural morphine and undetectable CSF morphine concentrations. Pain 25:69–73, 1986. 260. Erdine S, Aldemir T. Long-term results of peridural morphine in 225 patients. Pain 45:155–9, 1991. 261. Horlocker TT, Wedel DJ, Benzon H et al. Regional anesthesia in the anticoagulated patient: defining the risks. Reg Anesth Pain Med 29:1–11, 2004.

SECTION V

OTHER INTERVENTIONAL STRATEGIES

16

Neural blockade for cancer pain b rebecca chan a and oscar de leon-casasola a b

University of Illinois College of Medicine and Roswell Park Cancer Institute

Background Cancer pain is the result of cancer growth in human tissues, or the pain produced by any of the therapies implemented to treat it. The ideal management starts with a thorough assessment via history and physical examination, as well as the judicious use of diagnostic testing to try to define the pathophysiological components involved in the expression of pain to implement optimal analgesic therapy. Adequate pain control can be achieved in a majority of patients with the implementation of an aggressive pharmacological treatment with the use of opioids and adjuvants.1,2 With the implementation of these strategies, 90%–95% of patients may achieve adequate pain control.3 Consequently, 5%– 10% of patients will need some form of invasive therapy. Thus, when following specific guidelines, a majority of patients with cancer-related pain may expect adequate pain control in the 21st century. Control of pain and its related symptoms is a cornerstone of cancer treatment, as it promotes an enhanced quality of life, improved functioning, better compliance, and a way for patients to focus on the things that give meaning to life.4 In addition to their salutary effects on quality of life, mounting evidence suggests that good pain control influences survival5,6 (see Table 16.1).

Classification of cancer pain In the evaluation of a patient with cancer pain, it is important to obtain a history with the framework of four broad categories in mind: time course, intensity, pathophysiology, and the temporal aspect. There are three categories of classifying cancer pain in terms of its time course: acute pain, subacute pain, and chronic pain. Acute pain is frequently associated with sympathetic hyperactivity and heightened distress.7 It is often temporally associated with the onset or reoccurrence of

primary or metastatic disease, and its presence should motivate the clinician to aggressively seek its cause and to aggressively adjust the pharmacological therapeutic plan. Subacute pain is the pain that some patients experience for 4–6 weeks after a major surgical procedure. This type of pain is largely undertreated and deserves special attention as it may affect patients’ ability to perform activities of daily living after being discharged from the hospital. Chronic pain is pain occurring beyond 6 weeks and mandates a combination of palliation, adjustment, and acceptance. With time, biological and behavioral adjustment to symptoms occurs and associated symptoms are blunted. Chronic pain with superimposed episodes of acute pain (breakthrough pain) is probably the most common pattern observed in patients with ongoing cancer pain. Intensity is an important variable in the diagnosis and management of cancer pain. The consistent use of measurements of pain intensity aids in following a patient’s progress, and the evaluation of psychosocial parameters may serve as a basis for interpatient comparisons. High pain scores may alert the clinician to the need for more aggressive treatment and/or hospitalization for rapid symptom control via intravenous techniques with patient-controlled analgesia (PCA) and/or adjuvants with a rapid titration protocol. The pathophysiology is important to understanding a patient’s pain. A mechanistic approach is useful when formulating the initial treatment plan. The cause of a patient’s pain can be classified roughly into three categories: somatic pain, visceral pain, and neuropathic pain. Sometimes a patient may present with pain due to multiple etiologies. Somatic pain is described as a constant, well-localized pain, often characterized as aching, throbbing, sharp, or gnawing. It tends to be opioid and nonsteroidal antiinflammatory drug (NSAID)/cyclooxygenase 2 responsive, and is amenable to relief by interruption of proximal pathways by neural blockade when indicated. Visceral pain 315

r. chan and o. de leon-casasola

316 Table 16.1. Methods of assessing performance status ECOG

Karnofsky

0

100 Normal; no complaints, no evidence of disease

1 2 3 4 5

Fully active, able to carry on all predisease activities without restriction Restricted in physically strenuous activity but ambulatory and able to carry out light or sedentary work (e.g., light housework, office work) Ambulatory and capable of all self-care but unable to work; up and about more than 50% of waking hours Capable of only limited self-care, confined to bed or chair more than 50% of waking hours Completely disabled, cannot carry on any self-care, totally confined to bed or chair Dead

90 Able to carry on normal activity; minor signs or symptoms of disease 80 Normal activity with effort; some signs or symptoms of disease 70 Cares for self; unable to carry on normal activity or to do active work 60 Requires occasional assistance but is able to care for most needs 50 40 30 20

Requires considerable assistance and frequent medical care Disabled, requires special care and assistance Severely disabled, hospitalization indicated; death not imminent Very sick; hospitalization necessary; active supportive treatment necessary 10 Moribund; fatal processes; progressing rapidly 0 Dead

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

originates from injury to organs and is transmitted via fibers that travel along the sympathetic nervous system.8 Visceral pain is vague in distribution and quality and is often described as a deep, dull, aching, dragging, squeezing, or pressure-like sensation. When acute, it may be paroxysmal and colicky and may be associated with nausea, vomiting, diaphoresis, and alterations in blood pressure and heart rate. Mechanisms of visceral pain include abnormal distention or contraction of the smooth muscle walls (hollow viscera), rapid capsular stretch (solid viscera), ischemia of visceral muscle, serosal or mucosal irritation by analgesic substances and other chemical stimuli, distention and traction or torsion on mesenteric attachments and vasculature, and necrosis.9 The viscera are, however, insensitive to simple manipulation, cutting, and burning.8 Visceral involvement often produces referred pain10,11 (e.g., shoulder pain of hepatic origin). Neuropathic pain is defined as pain due to injury or irritation to some element(s) of the nervous system. Examples of neuropathic pain syndromes include tumor growth around nerve structures; postsurgical pain syndromes, such as post-thoracotomy, postmastectomy, post– radical neck dissection, and posthepatectomy pain; and pain induced by chemotherapeutic agents affecting peripheral nerve structures. Chemotherapeutic agents associated with neuropathic pain include vinca alkaloids (vincristine, vinblastine), cisplatinum, taxol, docetaxel, vinorelbine, and bortezomib. Neuropathic pain often is resistant to standard analgesic therapies and often requires an approach using combinations of opioids, tricyclic antidepressants, anticon-

vulsants, oral or topical local anesthetics, corticosteroids, selective serotonin norepinephrine reuptake inhibitors, and N-methyl-d-aspartate blockers. The temporal aspects of pain, including constant, breakthrough, and intermittent, are an important guide to successful medication management. Constant pain is most amenable to drug therapy administered around the clock, contingent on time rather then symptoms. It is best managed by long-acting analgesics or, in selected cases, infusion of analgesics. Breakthrough pain may be divided in three categories: incident pain, true breakthrough pain, and end-ofdose failure. Incident pain is related to a specific activity, such as eating, defecation, socializing, or walking. This pain is best managed by supplementing the preventive aroundthe-clock regimen with analgesics with a rapid onset of action and a short duration. Once a pattern of incident pain is established, escape or rescue doses of analgesics can be administered in anticipation of the pain-provoking activity. Pain that occurs consistently before the next scheduled dose of around-the-clock opioids is also called end-of-dose failure (plasma concentrations fall below minimum effective analgesic concentrations) and is ideally managed by reducing the interval between doses. In contrast, increasing the doses of long-acting opioids under these circumstances may increase the incidence of side effects. Under a strict definition, breakthrough pain is pain that may occur at any time during the day, increases to a high intensity very rapidly, and has a duration of 30–45 minutes. Intermittent pain is pain that is very unpredictable and is best managed by

neural blockade for cancer pain the administration of as-needed potent analgesics of rapid onset and short duration. Consequently, it is important to recognize the differences among these three types of pain to implement adequate therapy.

Neural blockade for the treatment of cancer pain Neural blockade for the treatment of cancer pain includes intraspinal analgesia, targeted nerve blocks, and neurolysis. Intraspinal analgesia Intraspinal analgesia can be achieved by the epidural or intrathecal administration of an opioid alone (very rarely) or in combination with another agent, such as bupivacaine, clonidine, or ziconotide. With the use of neuraxial analgesia, pain relief is obtained in a highly selective fashion with the absence of motor, sensory, and sympathetic effects, making these modalities highly adaptable to the home care environment.12,13 At its inception, the principle of neuraxial opioid therapy was based on the administration of small quantities of opioids in close proximity to their receptors (substantia gelatinosa of the spinal cord) to achieve a high local analgesic concentration.14,15 Thus, analgesia is potentially superior to that achieved when opioids are administered by other routes, and because the total amount of drug administered is reduced and side effects are minimized. Currently, the biggest advantage is the ability to use multiple agents to target neuropathic, somatic, and visceral components. In general, patients with a life expectancy greater than 3 months are candidates for intrathecal therapy with a permanent intraspinal catheter and an implanted subcutaneous pump. Conversely, patients with survival expectancy less than 3 months require epidural therapy with an implanted system (the Du Pen epidural catheter or the Sims epidural port-a-cath), which is connected to an external pump with PCA capabilities. Either way, patients first need a trial with an epidural catheter placed at the site where nociception is being processed in the spinal cord. This trial is conducted on an outpatient basis and, if successful, then proceeds to implantation of a permanent device. For this purpose, the following protocol is suggested. Epidural trial Catheter position Dermatomal specific, directed under fluoroscopic guidance. Epidural solution components: 1. Opioids: r Morphine: 0.1 mg/mL (60 mg total) to 0.2 mg/mL (120 mg total)

317 or

r Hydromorphone: 0.03 mg/mL (20 mg total) to 0.12 mg/mL (80 mg total) 2. Bupivacaine: 1–2 mg/mL 3. Clonidine: 3–5 ␮g/mL 4. Total volume: 600 mL

Determining epidural opioid doses: 1. If the patient is receiving ⬎300 ␮g/hour of fentanyl, 1200 mg/day of morphine, 600 mg/day of oxycodone, or 160 mg/day of methadone: r Hydromorphone: 0.12 mg/mL 2. If the patient is receiving between 100 and 300 ␮g/hour of fentanyl or equivalent dose: r Hydromorphone: 0.06 mg/mL 3. If the patient is receiving ⬍100 ␮g/hour of fentanyl or equivalent dose: r Hydromorphone: 0.03 mg/mL r Basal infusion: 2 mL/hour r Bolus of 2 mL every 10 minutes r The goal is to determine patient requirements r Trial for 7 days as outpatient If the patient had a successful trial, which is defined as a reduction in pain greater than 80%, proceed to implant an intrathecal system as indicated by the survival expectancy. The following protocol is suggested to achieve more than 80% success: Conditions for success r Place the tip of the intrathecal catheter in the dermatome corresponding to the area of nociception r For severe somatic pain, combinations of local anesthetics plus opioid will be needed r For neuropathic pain: 1. If the tip of the catheter is below L3–4: initial therapy with opioid plus clonidine 2. If the tip of the catheter is above L1–2: initial therapy with opioid plus bupivacaine The medications and dosages used include:16

Drug

Range of doses

Morphine Hydromorphone Sufentanil Bupivacaine Clonidine

1.0–20 mg/day 0.5–25 mg/day 10–100 ␮g/day 6–20 mg/day 250–2000 ␮g/day

318 Thus, compounding by a trained pharmacist is needed. The goal is to concentrate the abovementioned drugs to twice the daily dose so that the pumps may be programmed to deliver 0.5 mL/hour. In this way, patients will need pump refills monthly, and it will not be a burden to their quality of life to have to come frequently to the pain specialist’s office. The following steps are used: Permanent intrathecal therapy r Step 1: r Opioid plus bupivacaine: r Morphine sulfate 3–25 mg/day or hydromorphone 0.5–15 mg/day (25 mg of morphine sulfate/day = 4 mg of hydromorphone/day) r Bupivacaine: 6–20 mg/day r Opioid plus clonidine: r Clonidine: 250–2000 ␮g/day r Step 2: Opioid plus bupivacaine plus clonidine r Step 3: Possible consideration of ziconotide, although a recent controversial document generated by “experts in the field” and funded by Elan, the manufacturer of ziconotide, suggested that ziconotide could be a firstline agent. Because the current literature supporting this recommendation is limited, the authors of this chapter do not support this recommendation. If the patient’s insurance does not pay for hydromorphone, bupivacaine, or clonidine, then the use of morphine plus ziconotide may be an alternative. However, the limitations include the following: r Trial is unpredictable as ziconotide may not be administered in the epidural space. Consequently, the patient will have to have the trial once the implanted system is in place. r Patients may not allow the physician to carry out a titration protocol over 4–6 weeks r Starting dose of ziconotide is 2.4 ␮g/day, with weekly increases of no greater than 2.4 ␮g/day r Therapeutic effects are not usually seen until a dose of 10 ␮g/day is reached

Other issues to consider when initiating ziconotide include: r Rinse the pump with 2 mL of the 25-␮g/mL solution three times r Start low and go slow r Slower titration is better tolerated r Initiate therapy at a dose of 2.4 ␮g/day (0.1 ␮g/hour), and titrate to patient response r Titration increments should not be more than 2.4 ␮g/ day and ideally every week

r. chan and o. de leon-casasola r Maximum recommended dose: 19.2 ␮g/day (0.8 ␮g/ hour)

If in triple therapy with an opioid, bupivacaine and clonidine at optimal doses are not working, then troubleshooting the intrathecal system is a must. In doing so, consider the following: r Pump: Computer program analysis for volume and the volume present within the pump needs to be within 10% of each other, otherwise pump or system failure (e.g., obstruction) is suspected. r Catheter: A myelogram will be needed to determine whether there is an obstruction, and the position of the tip of the catheter. When performing a myelogram through the diagnostic port of the pump, remember that this only accommodates a 25-gauge Huber needle. Moreover, it is important to consider: 1. The dead space of the catheter when injecting the contrast medium 2. The need for a bolus dose after the study is completed

A multicenter prospective randomized clinical trial by Smith et al.17 compared intrathecal therapy with continued medical management, revealing a slight trend toward better analgesia in the intrathecal group (not statistically significant), but an improved side effect profile and increased survival in the intrathecal group. There is also a report from the M. D. Anderson group in abstract form documenting significant improvement in pain scores (numerical rating score from 7.6 to 4.8) and oral opioid intake (mean equivalent daily dose 300 ␮g vs. 80 ␮g) following intrathecal opioid pump implantation.18 The cost of implementing intrathecal therapy is initially high because of equipment acquisition costs. In contrast, the cost of implementing long-term epidural therapy is low. Two studies evaluated the cost of implementing therapy with intrathecal versus the epidural route. These analyses showed a “breakeven” point at approximately 3 months.19,20 Thus, epidural therapy becomes very expensive after 3 months, and is one of the reasons to limit its use in patients with survival expectations of less than 3 months. A consensus panel published current practice data on intrathecal medication management. A survey of 413 physicians managing 13,342 patients showed a variety of medications being used in the intrathecal pump, including morphine (48%), morphine/bupivacaine (12%), hydromorphone (8%), morphine/clonidine (8%), hydromorphone/clonidine (8%), morphine/clonidine/bupivacaine (5%), morphine/baclofen (3%), and others (⬍3%). Other drugs mentioned included fentanyl, sufentanil, ziconotide,

neural blockade for cancer pain meperidine, methadone, ropivacaine, tetracaine, ketamine, midazolam, neostigmine, droperidol, and naloxone.21 Nerve blocks Local anesthetic injections can be implemented for diagnostic and/or therapeutic purposes.22–31 Diagnostic blocks help characterize the underlying mechanism of pain (nociceptive, neuropathic, or sympathetically mediated) and discern the anatomical pathways involved in pain transmission. The main indication is as a preliminary intervention conducted before a therapeutic nerve block or other definitive therapy, which helps the clinician determine the potential for subsequent neurolysis if indicated. Although results often have good predictive value, they are not entirely reliable. Therapeutic injections of local anesthetics, with or without corticosteroid, at trigger points may provide lasting relief of myofascial pain.26 Epidural steroid injections with local anesthetics are unlikely to provide long-lasting relief for neuropathic pain of neoplastic origin. However, they will produce significant analgesia in patients who may not tolerate rapid titration of antineuropathic medications. Local anesthetic injections administered in sympathetic ganglia may contribute to lasting pain relief in patients with complex regional pain syndrome type II, a condition frequently seen in cancer patients.27–29 This condition may arise as a result of tumor invasion of the nervous system structure (e.g., brachial or lumbosacral plexopathy), postsurgical pain syndromes, or chemotherapy-induced peripheral neuropathy. The use of local anesthetic blockade of the stellate ganglion or lumbar sympathetic chain has been used with some success to temporarily relieve pain in these patients. Neurolytic blocks Neurolytic blocks of the sympathetic axis were widely used in the past for control of upper abdominal pain or pelvic pain in patients with cancer. However, recent studies suggest that these blocks are not effective in treating pain that is not visceral in origin. Consequently, when there is evidence of disease outside the viscera – which in the simplest form, translates to lymphadenopathy – the success rate decreases significantly. Moreover, a controlled randomized study has shown that even in the best-case scenario, the length of full pain control is no more than 2 months.32,33 Thus, we should reconsider our indications for these procedures, and when indicated, they should be performed early in the course of the disease.

319 Stretching, compressing, invading, or distending visceral structures may result in a poorly localized noxious visceral pain. Patients experiencing visceral pain often describe the pain as vague, deep, squeezing, crampy, or colicky. Other signs and symptoms include referred pain (e.g., shoulder pain that appears when the diaphragm is invaded with tumor) and nausea/vomiting due to vagal irritation. Visceral pain associated with cancer may be relieved by oral pharmacologic therapy including combinations of NSAIDs, opioids, and coadjuvant therapy. In addition to pharmacologic therapy, neurolytic blocks of the sympathetic axis are effective in controlling visceral cancer pain and should be considered important adjuncts to pharmacologic therapy for the relief of severe visceral pain. These blocks rarely eliminate cancer pain because patients frequently experience somatic and neuropathic pain as well. Therefore, oral pharmacologic therapy must be continued in the majority of patients with advanced stages of disease. The goals of performing a neurolytic block of the sympathetic axis are to maximize the analgesic effects of opioid or nonopioid analgesics and to reduce the dosage of these agents to alleviate side effects. Because neurolytic techniques have a narrow risk–benefit ratio, undesirable side effects and complications from neurolytic blocks can be minimized by sound clinical judgment and assessment of the potential therapeutic effect of the technique on each patient. This section discusses pertinent information regarding neurolysis of the celiac plexus block, superior hypogastric block, and ganglion impar. Celiac plexus block The celiac plexus is situated retroperitoneally in the upper abdomen. It is at the level of the T12 and L1 vertebrae, anterior to the crura of the diaphragm. The celiac plexus surrounds the abdominal aorta and the celiac and superior mesenteric arteries. The plexus is composed of a network of nerve fibers from both the sympathetic and the parasympathetic systems. It contains two large ganglia that receive sympathetic fibers from the three splanchnic nerves (greater, lesser, and least). The plexus also receives parasympathetic fibers from the vagus nerve. Autonomic nerves supplying the liver, pancreas, gallbladder, stomach, spleen, kidneys, intestines, and adrenal glands, as well as blood vessels, arise from the celiac plexus. Neurolytic blocks of the celiac plexus have been used for malignant and chronic nonmalignant pain. In patients with acute or chronic pancreatitis, the celiac plexus block has been used with variable success.34 Likewise, patients with cancer in the upper abdomen who have a significant visceral pain component have responded well to this block.35

320 Three approaches to block nociceptive impulses from the viscera of the upper abdomen include the retrocrural (or classic) approach, the anterocrural approach, and neurolysis of the splanchnic nerves.32 Regardless of the approach, the needles are inserted at the level of the first lumbar vertebra, 5–7 cm from the midline. Then, the tip of the needle is directed toward the upper third of the body of L1 for the and the lower third of the body of L1 for an anterocrural technique. In the case of the retrocrural approach, the tip of the needle is advanced no more than 0.5 cm anterior to the anterior border of L1; in the case of the anterocrural approach, the tip of the needle is advanced through the aorta on the left side until no more blood flow is noted through the needle. This is the reason the anterocrural approach is also known as the transaortic approach. In the case of splanchnic nerve block, the needle is directed toward the body of T12. Perfect needle positioning in this case is achieved when the tip of the needle is at the anterior portion of the T12 vertebral body in the lateral view. More recently, CT and ultrasound techniques have allowed pain specialists to perform neurolysis of the celiac plexus via a transabdominal approach. This approach is frequently used when patients are unable to tolerate either the prone or lateral decubitus position or when the liver is so enlarged that a posterior approach is not feasible. Moreover, CT guidance will allow one to perform an anterocrural technique without piercing the aorta, adding an element of safety in this case (see “Complications”). For neurolytic blocks using the retrocrural or anterocrural approach, 50%–100% alcohol is used. Injected by itself, alcohol can produce severe pain. Thus, it is recommended to first inject 5–10 mL of 0.25% bupivacaine 3–5 minutes before the injection of alcohol or at the time of the injection, by diluting 100% alcohol to a 50% concentration with the same amount of local anesthetic (0.25% bupivacaine). Phenol in a 10% final concentration also may be used; this has the advantage of being painless on injection, and both agents seem to have the same clinical efficacy. The dose of alcohol or phenol administered varies with the approach to be used. For the retrocrural approach, 20–25 mL of alcohol is used on each side. Consequently, the need to inject this high volume precludes the use of phenol in the retrocrural approach. For the anterocrural approach, 8–10 mL of either neurolytic agent is used per side. For the splanchnic nerve blocks, 6–8 mL of phenol per side is recommended. Complications Complications associated with celiac plexus blocks appear to be related to the technique used: retrocrural,36 transcrural,37 or transaortic.38 In a prospective

r. chan and o. de leon-casasola randomized study of 61 patients with cancer of the pancreas, Ischia et al.32 compared the efficacy and incidence of complications associated with these three approaches with celiac plexus neurolysis. Orthostatic hypotension occurred more often when the retrocrural (50%) or splanchnic (52%) technique was used, suggesting an associated sympathetic chain neurolysis. In contrast, the anterocrural approach produced a 10% incidence of hypotension. Conversely, transient diarrhea was more frequent with the anterocrural approach (65%) than with the splanchnic nerve block technique (5%) but not the retrocrural approach (25%). The incidence of dysesthesia, interscapular back pain, reactive pleurisy, hiccups, or hematuria was not statistically different among the three groups. The incidence of complications from neurolytic celiac plexus block (NCPB) was evaluated by Davis39 in 2730 patients having blocks performed from 1986 to 1990. The overall incidence of major complications (e.g., paraplegia, bladder and bowel dysfunction) was one in 683 procedures. However, the report does not describe which approach or approaches were used to perform the blocks. The following are several aspects in the diagnosis and management of specific complications: 1. Malposition of the needle is avoided with radiologic imaging before the injection of a neurolytic agent, as the tip of the needle may be intravascular, in the peritoneal cavity, or in a viscus. Imaging techniques currently used include biplanar fluoroscopy, CT, and ultrasound guidance. However, no study has evaluated the superiority of one technique over the others. Wong and Brown40 suggested that the use of radiologic imaging does not alter the quality of the block or the incidence of complications based on a retrospective study of 136 patients with pancreatic cancer pain treated with a celiac plexus block with or without radiologic control of the position of the needle’s tip. However, it is unclear how many patients had radiologic imaging performed. Assuming that half the patients did not, the upper 95% confidence limit for complications is 5%.41 2. Orthostatic hypotension may occur up to 5 days after the block. Treatment includes bed rest, avoidance of sudden changes in position, and replacement of fluids. Once compensatory vascular reflexes are fully activated, this side effect disappears. Wrapping the lower extremities from the toes to the upper thighs with elastic bandages has been successful in patients who developed orthostatic hypotension, enabling them to walk during the first week after the block.

neural blockade for cancer pain 3. Backache may result from local trauma during the needle placement, resulting in a retroperitoneal hematoma, or from alcoholic irritation of the retroperitoneal structures. Patients with a backache should have at least two hematocrit measurements at a 1-hour interval. If there is a decrease in the hematocrit, radiologic imaging is indicated to rule out a retroperitoneal hematoma. A urine analysis positive for red blood cells suggests renal injury. 4. Retroperitoneal hemorrhage is rare; however, in patients who present with orthostatic hypotension, the possibility of hemorrhage must be ruled out before assuming that it is a physiologic response to the block. Patients who present with backache and orthostatic hypotension after a celiac plexus block should be admitted to the hospital for serial hematocrit monitoring. If the hematocrit level is low or decreasing, patients should undergo radiologic evaluation to rule out injury to the kidneys, aorta, or other vascular structures. A surgical consult should be obtained as soon as feasible. 5. Diarrhea may occur as a result of the sympathetic block of the bowel. Treatment includes hydration and antidiarrheal agents. Oral loperamide is a good choice, although any anticholinergic agent may be used. Matson and colleagues42 reported near-fatal dehydration from diarrhea following this block. In debilitated patients, diarrhea must be treated aggressively. 6. Abdominal aortic dissection also has been reported.43,44 The mechanism of aortic injury is direct damage with the needle during the performance of the block. As expected, the anterocrural approach is more frequently associated with this complication. Thus, this approach should be avoided if atherosclerotic disease of the abdominal aorta is present. 7. Paraplegia and transient motor paralysis have occurred after celiac plexus block.45–51 These neurologic complications may occur as a result of a spasm of the lumbar segmental arteries that perfuse the spinal cord.52 Canine lumbar arteries undergo contraction when exposed to both low and high concentrations of alcohol.52 Thus, these data suggest that alcohol should not be used if there is evidence of significant atherosclerotic disease of the aorta, because the circulation to the spinal cord may also be impaired and entirely dependent on lumbar artery flow. However, there is also a report of paraplegia after phenol use,45 suggesting that other factors (e.g., direct vascular or neurologic injury or retrograde spread to the spinal cord) also may be involved. These complications highlight the importance of the use

321 of radiologic imaging during the performance of these blocks. Efficacy Only three randomized controlled trials32,33,52 and one prospective study54 have evaluated the efficacy of celiac plexus neurolysis in pain due to cancer of the upper abdomen. In a prospective randomized study, Ischia et al.32 evaluated the efficacy of three different approaches to celiac plexus neurolysis in pancreatic cancer. Of 61 patients with pancreatic cancer pain, 29 (48%) experienced complete pain relief after the neurolytic block. The remaining 32 patients (52%) required further therapy for residual visceral pain due to technical failure in 15 patients and neuropathic/somatic pains in 17 patients. The second trial,53 which compared the procedure with oral pharmacologic therapy in 20 patients, concluded that celiac plexus neurolysis resulted in a reduction in visual analogue pain score (VAPS) equal to that of therapy with a combination of NSAIDs and opioids. However, opioid consumption was significantly lower in the group of patients who underwent neurolysis when compared with the group receiving oral pharmacologic therapy during the 7 weeks of the study. Moreover, the incidence of side effects was greater in patients who received oral pharmacologic therapy when compared with those who underwent neurolysis. Regarding the third randomized controlled study by Wong and collaborators,33 the authors are to be congratulated for designing and completing this study. Their results are welcome in light of a lack of properly designed comparative studies between neurolytic techniques and comprehensive medical management (CMM). However, there are several issues in the design and the results of this study that need to be highlighted: 1. Patients enrolled in the study did not have severe pain at study entry. Mean pain scores at baseline were 4.4 ± 1.7 in the NCPB group and 4.1 ± 1.8 in the CMM group. This is a surprising finding in patients with this type of malignancy and may reflect ethnic and racial differences in pain perception and reporting by the population enrolled in the study. 2. Although the authors reported a significant statistical reduction in pain scores 1 week after therapy when comparing the NCPB group with the CMM group, the difference between the two groups may not be clinically important. Patients assigned to the NCPB group reported mean pain scores of 2.1 ± 1.4, whereas those randomly assigned to the CMM group reported pain scores of 2.7 ± 2.1 at that time interval. Further, a statistical difference was found when the percentage reduction from

322 baseline for the NCPB and CMM groups was analyzed separately (53% reduction from baseline for the NCPB group, P = 0.05, vs. the 27% reduction observed in the CMM group, P = 0.01). 3. In analyzing these results, it is critically important to note that most patients (93%) used opiates during the first week of therapy, with similar amounts of opiates being administered to the two treatment groups. In fact, opiate consumption increased over time, with no differences between groups at the different time intervals during the study. Moreover, the incidence of side effects was not different between the two treatment groups at any point in time. 4. Likewise, quality-of-life measurements and the physical and functional well-being subscales of the Functional Assessment of Cancer Therapy – Pancreatic Cancer did not differ between the two groups at any evaluation point. Two important questions stem from the results: 1. Can the authors truly conclude that the major finding of the study was that NCPB significantly improves pain relief in patients with advanced pancreatic cancer compared with those who received optimized CMM? 2. Based on these results, are we justified to submit a patient with advanced pancreatic cancer to an NCPB, considering the potential side effects and complications associated with this procedure? The authors cannot conclude that NCPB significantly improves pain relief in patients with advanced pancreatic cancer. This is because the levels of analgesia achieved by the patients assigned to either group after 1 week of therapy can be considered clinically acceptable. Additionally, the only statistical difference was found when the authors analyzed the percentage reduction of pain from baseline by each of the treatment groups. Thus, based on these results, one should conclude that it is not recommended to perform NCPB in a patient with advanced pancreatic cancer, because in this not-so-perfect world, complications do occur and the risks outweigh the benefits. The aforementioned reservations do not imply that we should not perform NCPB in patients with pancreatic malignancies. As with every clinical study, the results of Wong et al. only applied to the population studied and under the conditions of the study protocol design. The critical issue is that all patients had nonresectable disease, which suggests that patients were likely to have other pain components, such as somatic and/or neuropathic pain, which are not responsive to NCPB.3 This is because neurolytic blocks of

r. chan and o. de leon-casasola the sympathetic axis are effective in treating visceral pain only. Moreover, previous studies have suggested that when there is evidence of disease outside the pancreas, such as celiac and/or portal lymphadenopathy, the success rate of this block decreases significantly. In the study by De Cicco and collaborators,54 long-lasting pain relief was described in nine of nine patients (95% CI, 60–100) when contrast medium was spread in the four quadrants and in 10 of 21 patients (95% CI, 26–70) when contrast was spread in three quadrants. None of the 75 patients with contrast spread in one or two quadrants experienced long-lasting pain relief. Thus, the presence of lymphadenopathy due to metastasis is a poor prognostic factor in success of the block. The results of the study by Wong and collaborators further support the notion that NCPB should not be performed in patients with advanced unresectable carcinomas of the pancreas. This block should be reserved for patients without evidence of disease outside the viscera, in which case one is guaranteed that the patient has a visceral pain component only. A prospective nonrandomized study55 compared 41 patients treated according to the World Health Organization guidelines for cancer pain relief, with 21 patients treated with an NCPB. The authors concluded that this technique may play an important role in managing pancreatic cancer pain. Because one of the three randomized controlled studies compared different approaches to the celiac plexus and had no control group,32 and the other study compared the procedure with an analgesic drug,53 it is not possible to estimate the success rate of this technique. In contrast, the results of a meta-analysis that evaluated the results of 21 retrospective studies in 1145 patients concluded that adequate to excellent pain relief can be achieved in 89% of patients during the first 2 weeks following the block.56 Partial to complete pain relief continued in approximately 90% of the patients who were alive at the 3-month interval and in 70%–90% of the patients during the 3-month interval before death. Moreover, the efficacy was similar in the patients with pancreatic cancer compared with those with other intraabdominal malignancies of the upper abdomen. However, these results are based on retrospective evaluations that may not yield reliable information or may be subject to publication bias. In addition, the statistical techniques used for the analysis must account for the heterogeneity produced by the patients’ selection criteria, technical differences in the performance of the blocks, choice of neurolytic agents and doses used, diversity in the tools for the evaluation of pain, goals of therapy, and other factors. Thus, the meta-analysis

neural blockade for cancer pain must be interpreted with caution as the report may be overly enthusiastic. New perspectives As previously discussed, oral pharmacologic therapy with opioids, NSAIDs, and coadjuvants is frequently used for the treatment of cancer pain. However, the evidence suggests that chronic use of high doses of opioids may have a negative effect on immunity.57 Thus, analgesic techniques that lower opioid consumption may have a positive effect on patient outcomes. Lillemoe and colleagues58 showed in a prospective randomized trial that patients with nonresectable cancer of the pancreas who received splanchnic neurolysis lived longer than patients who did not. These findings may be the result of lower opioid use in the splanchnic neurolysis patients, who not only had better-preserved immune functions, but also experienced fewer side effects (e.g., nausea and vomiting), thus allowing them to eat better. Although the study by Wong et al.33 did not show that patients randomly assigned to the neurolytic arm of the study lived longer, this may be explained by their high intake of opioids during the study period, thus negating the effect of the blocks. Consequently, the effects of this procedure on long-term survival are not clear. Superior hypogastric plexus block Cancer patients with tumor extension into the pelvis may experience severe pain that is unresponsive to oral or parenteral opioids. Also, excessive sedation or other side effects may limit the acceptability and usefulness of oral opioid therapy. Therefore, a more invasive approach is needed to control pain and improve the quality of life of these patients. Pelvic pain associated with cancer and chronic nonmalignant conditions may be alleviated by blocking the superior hypogastric plexus.59,60 Analgesia to the organs in the pelvis is possible because the afferent fibers innervating these structures travel in the sympathetic nerves, trunks, ganglia, and rami. Thus, a sympathectomy for visceral pain is analogous to a peripheral neurectomy or dorsal rhizotomy for somatic pain. A recent study60 suggests that visceral pain is an important component of the cancer pain syndrome experienced by patients with cancer of the pelvis, even in advanced stages. Thus, percutaneous neurolytic blocks of the superior hypogastric plexus should be considered more often for patients with advanced stages of pelvic cancer. The superior hypogastric plexus is situated in the retroperitoneum, bilaterally extending from the lower third of the fifth lumbar vertebral body to the upper third of the first sacral vertebral body. The technique for the blockade

323 has been described elsewhere.59–61 The patient is placed in the prone position with a pillow under the pelvis to flatten the lumbar lordosis. Two 7-cm needles are inserted with the bevel directed medially 45◦ –30◦ caudad so that the tips lay anterolateral to the L5–S1 intervertebral disk space. Aspiration is important to avoid injection into the iliac vessels. If blood is aspirated, a transvascular approach may be used (see “Complications”). The accurate placement of the needle is verified by biplanar fluoroscopy. Anteroposterior (AP) views should reveal the tip of the needle at the level of the junction of the L5 and S1 vertebral bodies. This is an important safety step to avoid potential spread of the neurolytic agent toward the L5 roots (see “Complications”). Lateral views will confirm placement of the needle’s tip just beyond the vertebral body’s anterolateral margin. The injection of 3–5 mL of water-soluble contrast medium is used to verify accurate needle placement and to rule out intravascular injection. In the AP view, the spread of contrast should be confined to the midline region. In the lateral view, a smooth posterior contour corresponding to the anterior psoas fascia indicates that the needle is at the appropriate depth. For a diagnostic hypogastric plexus blockade or for patients with non–cancer-related pain, local anesthetic alone is used. For therapeutic purposes in patients with cancer-related pain, phenol is typically used as the neurolytic solution. Mastering this technique is not easy, as the transverse process of L5 makes it difficult to access the anterior portion of the L5–S1 region. Consequently, a trans-discal approach has been suggested. However, this approach may be associated with the inherent risks of puncturing the intervertebral disk. Complications The combined experience of more than 200 cases from the Mexican Institute of Cancer, Roswell Park Cancer Institute, and M. D. Anderson Cancer Center indicates that neurologic complications have not occurred as a result of this block.61 However, extreme care should be exercised, as placing the tip of the needle in the upper middle of L5 may be associated with retrograde spread to the nerve roots. If the spread is not recognized, the injection of neurolytic agent could result in predicted neurologic deficit. Efficacy The effectiveness of the block was originally demonstrated by a significant decrease in pain via VAPS. In their study, Plancarte et al.59 showed that the block was effective in reducing VAPS in 70% of the patients with pelvic pain associated with cancer. The majority of the enrolled patients had cervical cancer. In a subsequent study,60 69% of the patients experienced a decrease in

324 VAPS. Moreover, a mean daily opioid morphine reduction of 67% was seen in the success group (736 ± 633 mg/day reduced to 251 ± 191 mg/day) and 45% in the failure group (1443 ± 703 mg/day reduced to 800 ± 345 mg/day).60 In a more recent multicenter study,61 159 patients with pelvic pain associated with cancer were evaluated. Overall, 115 patients (72%) had satisfactory pain relief after one or two neurolytic procedures. Mean opioid use decreased by 40% from 58 ± 43 mg/day to 35 ± 18 mg/day of morphine equivalents 3 weeks after treatment in all the studied patients. This decrease in opioid consumption was significant for both the success group (56 ± 32 mg/day reduced to 32 ± 16 mg/day) and the failure group (65 ± 28 mg/day reduced to 48 ± 21 mg/day).61 Success was defined in the two studies as the ability to reduce opioid consumption by at least 50% in the 3 weeks following the block and a decrease in the pain scores below 4/10 in the VAPS.60,61 In another case report, Rosenberg and colleagues62 reported on the efficacy of superior hypogastric plexus block in a patient with severe chronic nonmalignant penile pain after transurethral resection of the prostate. Although the patient did not receive a neurolytic agent, a diagnostic block performed with 0.25% bupivacaine and 20 mg of methylprednisolone acetate was effective in relieving the pain for more than 6 months. The usefulness of this block in chronic benign pain conditions has not been adequately documented. Ganglion Impar Block The ganglion impar is a solitary retroperitoneal structure located at the level of the sacrococcygeal junction. This unpaired ganglion marks the end of the two sympathetic chains. Visceral pain in the perineal area associated with malignancies may be effectively treated with neurolysis of the ganglion impar (Walther’s).63 Patients who will benefit from this block frequently present with a vague, poorly localized pain that is frequently accompanied by sensations of burning and urgency. However, the clinical value of this block is not clear as the published experienced is limited. The ganglion impar is the only unpaired autonomic ganglion in the body. It has gray nerve fiber communication from the ganglion to the spinal nerve, but appears to lack white nerve fibers that communicate the spinal nerves to the ganglion in the thoracic and upper lumbar regions.63 Visceral afferents innervating the perineum, distal rectum, anus, distal urethra, vulva, and distal third of the vagina converge at the ganglion impar. The original technique was described by Plancarte and collaborators.63 The technique calls for the patient to be positioned in the lateral decubitus position with the hips fully flexed. A standard 22-gauge,

r. chan and o. de leon-casasola 3.5-inch spinal needle is bent 1 inch from its hub to form a 30◦ angle. Then the needle is introduced under local anesthesia through the anococcygeal ligament with its concavity oriented posteriorly, and under fluoroscopic guidance, it is directed along the midline at or near the sacrococcygeal junction while a finger is placed in the rectum to avoid puncturing this structure. Retroperitoneal location is verified by observation of the spread of 2 mL of water-soluble contrast medium. An alternative needle geometry, bending the needle to the shape of an arc, has been proposed by Nebab and Florence.64 An easier technique is the trans-sacrococcygeal approach,65 in which the tip of the needle is placed directly in the retroperitoneal space by inserting a 20-gauge, 1.5inch needle through the sacrococcygeal ligament under fluoroscopy guidance so that the tip of the needle is just anterior to the anterior portion of the sacrum. This technique avoids the invasion of more caudal structures (rectum) with the needle and the need to insert a finger in the rectal lumen. For diagnostic blocks, local anesthesia alone is used. For neurolytic blocks, phenol 6% is recommended. Cryoablation of the ganglion impar also has been described for repeated procedures via a trans-sacrococcygeal approach in a patient with chronic benign pain after abdominoperineal resection.66 Complications Although there is always the risk of damaging structures adjacent to the ganglion impar, there are no complications reported from this technique. Plancarte67 has reported one case in which epidural spread of contrast within the caudal canal was observed. In this case, needle repositioning solved the problem. Although published experience is limited and criteria to predict success or failure are not available, patients with poorly localized perineal pain with a burning character are considered candidates for the block. The procedure is safe, and no complications have been reported. Efficacy There are three studies that evaluated the efficacy of ganglion impar block in a prospective nonrandomized, noncontrolled fashion. Plancarte and colleagues63 evaluated 16 patients with advanced cancer (cervix, nine; colon, two; bladder, two; rectum, one; endometrium two) and persistent pain despite treatment (pharmacologic management resulted in a 30% global reduction in pain). Localized perineal pain was present in all cases, characterized as burning and urgent in eight patients and of mixed character in eight patients. Pain was referred to the rectum (seven patients), perineum (six patients), or vagina (three patients). After a neurolytic block with a transsacrococcygeal approach, eight patients reported complete

neural blockade for cancer pain pain relief whereas the remainder experienced significant pain reduction (60%–90%). Blocks were repeated in two patients; the follow-up was carried out for 14–120 days and depended on survival. Swofford and Ratzman,68 reported on the efficacy of the trans-sacrococcygeal approach. Twenty patients with perineal pain unresponsive to previous intervention were studied, 18 with a bupivacaine/steroid block and two with a neurolytic block. In the bupivacaine/steroid group, five patients reported complete (100%) pain relief, 10 patients reported ⬎75% pain reduction, and three patients reported ⬎50% pain reduction. Both neurolytic blocks resulted in complete pain relief. Duration of the pain relief varied from 4 weeks to long term. Vranken and colleagues,69 studied the effect of the ganglion impar block in long-lasting, treatment-resistant coccydynia. Twenty patients, 17 women and 3 men, with a diagnosis of coccydynia (spontaneous, seven; fracture, three; injury, 10) received a 5-mL injection of 0.25% bupivacaine. There was no pain reduction or increase in quality of life associated with the procedure. Thus, based on this study, it would appear that this block is not effective for the treatment of coccydynia. Neurolysis summary Neurolysis of the celiac plexus/splanchnic nerves, superior hypogastric plexus, or ganglion impar may be used in patients with visceral pain of the upper abdomen, pelvis, and perineal region, respectively. The presence of disease in the corresponding lymph nodes is a marker of poor prognosis for these blocks. The incidence of reported complications is low. However, complications may occur and have significant implications for the patient’s quality of life. Thus, strict adherence to the technique is important to prevent potential problems. Again, the use of this technique in patients who do not have a significant visceral pain component is not warranted. Intraspinal neurolysis in the treatment of cancer pain The use of subarachnoid (intrathecal) injections of alcohol or phenol for the management of intractable cancer pain has significantly decreased in the United States since the polypharmacy intrathecal analgesia was implemented. Because alcohol and phenol destroy nervous tissue indiscriminately, careful attention to the selection of the injection site, volume and concentration of injectate, and selection and positioning of the patient is essential to avoid neurological complications,70,71 a risk that is responsible for the decrease in its use. Most authorities agree that neither alcohol nor phenol offers a clear advantage, except insofar

325 as variations in baric properties that may facilitate positioning of the patient.72,73 With the exception of perineal pain treatment, alcohol is usually preferred for intrathecal neurolysis, because most patients are unable to lie on their painful side, as is required for intrathecal phenol neurolysis. In an analysis of 13 published series documenting treatment with intrathecal rhizolysis in more than 2500 patients, Swerdlow72 reported that 58% of patients obtained “good” relief; “fair” relief was observed in an additional 21%, and in 20% of patients, “little or no relief” was noted. Average duration of relief is estimated at 3–6 months, with a wide range of distribution. Reports of analgesia persisting for 1–2 years are fairly common.74 In representative series using alcohol (n = 252) and phenol (n = 151), a total of 407 and 313 blocks were performed, respectively.75,76 In these two series, neither motor weakness nor fecal incontinence occurred, and of eight patients with transient urinary dysfunction, incontinence persisted in one patient. Subarachnoid neurolysis may be performed at any level up to the mid-cervical region, above which the risk of drug spread to medullary centers and the potential for cardiorespiratory collapse increase.77 Hyperbaric phenol saddle block is relatively simple and is particularly suitable for many patients with colostomy and urinary diversion. Until recently, epidural neurolysis was performed infrequently. Results were inferior to those obtained with subarachnoid blockade, presumably because the dura acts as a barrier to diffusion, resulting in limited contact between the drug and targeted nerves.74,78 Peripheral neurolysis for the treatment of cancer pain Peripheral nerve blockade has a limited role in the management of cancer pain.31 Blockade of the ganglion of Gasser, within the foramen ovale at the base of the skull or its branches, may be beneficial for facial pain.79 However, the indications in tumor-related pain are truly minimal, as there usually is a neuropathic pain component. Thus, the risk of deafferentation pain is significantly increased with chemical neurolysis. The use of intraspinal therapy by means of an implanted intrathecal or a cisterna magna catheter for the infusion of bupivacaine has been suggested. Likewise, intraventricular opioid therapy also has been suggested for these patients.80,81

Conclusion Acute and chronic pain is highly prevalent in cancer patients. Inadequate assessment and treatment of pain and other distressing symptoms may interfere with antitumor therapy and markedly detract from the quality of life.

326 Although a strong focus on pain control is important independent of disease stage, it is a special priority in patients with advanced disease who are no longer candidates for potentially curative therapy. Although rarely eliminated, pain can be controlled in the vast majority of patients with the implementation of aggressive CMM. In the small but significant proportion of patients whose pain is not readily controlled with noninvasive analgesics, a variety of alternative invasive and noninvasive measures, when selected carefully, also are associated with a high degree of success. To this end, it is very reassuring to conclude that at this point, we have the appropriate tools to adequately treat cancer-related pain in close to 100% of the patients. References 1. American Pain Society. Principles of analgesic use in the treatment of acute pain and chronic cancer pain, 3rd ed. Skokie, IL: APS, 1992. 2. Jacox A, Carr DB, Payne R, et al. Management of cancer pain: clinical practice guideline 9. Agency for Health Care Policy and Research pub. 94-0592. Rockville, MD: ACHPR, 1994. 3. Zech DFG, Grong S, Lynch J, et al. Validation of the World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain 63:65–76, 1996. 4. Ferrell BR, Wisdon C, Wenzl C. Quality of life as an outcome variable in management of cancer pain. Cancer 63:2321, 1989. 5. Liebeskind JC. Pain can kill. Pain 44:3–4, 1991. 6. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with unresectable pancreatic cancer. Ann Surg 217:447–57, 1993. 7. Sternbach RA. Pain: a psychophysiological analysis. New York: Academic Press, 1968. 8. Newman PP. Visceral afferent functions of the nervous system. London: Arnold, 1974. 9. Procacci P, Maresca M. Pathophysiology of visceral pain. Adv Pain Res Ther 13:123, 1990. 10. Kellgren JH. Somatic simulating visceral pain. Clin Sci 4:303, 1939. 11. Cervero F. Visceral pain. In: Dubner R, Gebhart GF, Bond MR, eds. Proceedings of the VI World Congress on Pain. Amsterdam: Elsevier, 1988, p 216. 12. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 61:276–310, 1984. 13. Crawford ME, Andersen HB, Augustenborg G, et al. Pain treatment on outpatient basis using extradural opiates: Danish multicenter study comprising 105 patients. Pain 16:41, 1983. 14. Yaksh TL. Spinal opiates: a review of their effect on spinal function with an emphasis on pain processing. Acta Anaesthesiol Scand 31(Suppl 85):25, 1987. 15. Snyder SH. Opiate receptors in the brain. N Engl J Med 296:266–71, 1977.

r. chan and o. de leon-casasola 16. Du Pen S, Kharasch ED, Williams A, et al. Chronic epidural bupivacaine-opioid infusion in intractable cancer pain. Pain 49:293–300, 1992. 17. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 20:4040–9, 2002. 18. Burton AW, et al. Reduction in pain and oral opioid intake following intrathecal pump implantation. Presented at the World Congress of Pain. San Diego, CA, August 2002. 10. Bedder MD, Burchiel KJ, Larson A. Cost analysis of two implantable narcotic delivery systems. J Pain Symptom Manage 6:368, 1991. 20. Hassenbusch SJ, Bedder M, Patt RB, Bell GK. Current status of intrathecal therapy for nonmalignant pain management: clinical realities and economic unknowns. J Pain Symptom Manage 14:S36–48, 1997. 21. Hassenbusch SJ, Portenoy RK. Current practices in intraspinal therapy – a survey of clinical trends and decision making. J Pain Symptom Manage 20:S4–11, 2000. 22. Bonica JJ. Management of pain. Philadelphia: Lea & Febiger, 1953. 23. Cousins MJ. Anesthetic approaches in cancer pain. Adv Pain Res Ther 16:249–73, 1990. 24. Raj P, Ramamurthy S. Differential nerve block studies. In: Raj P, ed. Practical management of pain. Chicago: Year Book, 1986, pp 173–7. 25. Abram SE. The role of nonneurolytic nerve blocks in the management of cancer pain. In: Abram SE, ed. Cancer pain. Amsterdam: Kluwer, 1989, pp 67–75. 26. Travel JG, Simons DG. Myofascial pain and dysfunction: the trigger point manual. Baltimore: Williams & Wilkins, 1983. 27. Payne R. Neuropathic pain syndromes, with special reference to causalgia and reflex sympathetic dystrophy. Clin J Pain 2:59– 73, 1986. 28. Gerbershagen HU. Blocks with local anesthetics in the treatment of cancer pain. In: Bonica JJ, Ventafridda V, eds. Advances in pain research and therapy, vol. 2. New York: Raven Press, 1979, pp 311–23. 29. Warfield CA, Crews DA. Use of stellate ganglion blocks in the treatment of intractable limb pain in lung cancer. Clin J Pain 3:13, 1987. 30. Evans PJD. Cryoanalgesia. Anaesthesia 36:1003–13, 1981. 31. Doyle D. Nerve blocks in advanced cancer. Practitioner 226:539–44, 1982. 32. Ischia S, Ischia A, Polati E, et al. Three posterior percutaneous celiac plexus block techniques: a prospective randomized study in 61 patients with pancreatic cancer pain. Anesthesiology 76:534–40, 1992. 33. Wong G, Schoeder DR, Carns PE, et al. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer. JAMA 291:1092– 9, 2004. 34. Rykowski JJ, Hilgier M. Continuous celiac plexus block in acute pancreatitis. Reg Anesth 20:528–32, 1995.

neural blockade for cancer pain 35. Regional anesthetic techniques for the management of cancer pain. In: Urmey W, ed. Techniques in regional anesthesia and pain management, vol. 1, no. 1. Philadelphia: W. B. Saunders, 1997. 36. Singler RC. An improved technique for alcohol neurolysis of the celiac plexus block. Anesthesiology 56:137–41, 1982. 37. Hilgier M, Rykowski JJ. One needle transcrural celiac plexus block: single shot, or continuous technique, or both. Reg Anesth 19:277–83, 1994. 38. Ischia S, Luzzani A, Ischia A, et al. A new approach to the neurolytic block of the coeliac plexus: the transaortic technique. Pain 16:333–41, 1983. 39. Davis DD. Incidence of major complications of neurolytic coeliac plexus block. J R Soc Med 86:264–6, 1993. 40. Wong GY, Brown DL. Celiac plexus block for cancer pain. In: Urmey W, ed. Tech reg anesth pain manage, vol. 1, no. 1. Philadelphia: W. B. Saunders, 1997. 41. Hanley JA, Lippman-Hand A. If nothing goes wrong, is everything all right? Interpreting zero numerators. JAMA 249:1743– 5, 1983. 42. Matson JA, Ghia JN, Levy JH. A case report of a potentially fatal complications associated with Ischia’s transaortic method of celiac plexus block. Reg Anesth 10:193–6, 1985. 43. Sett SS, Taylor DC. Aortic pseudoaneurysm secondary to celiac plexus block. Ann Vasc Surg 5:88–91, 1991. 44. Kaplan R, Schiff-Keren B, Alt E. Aortic dissection as a complication of celiac plexus block. Anesthesiology 83:632–5, 1995. 45. Galizia EJ, Lahiri SK. Paraplegia following coeliac plexus block with phenol. Case report. Br J Anaesth 46:539–40, 1974. 46. Lo JN, Buckley JJ. Spinal cord ischemia a complication of celiac plexus block. Reg Anesth 7:66–8, 1982. 47. Cherry DA, Lamberty J. Paraplegia following coeliac plexus block. Anaesth Intensive Care 12:59–61, 1984. 48. Woodham MJ, Hanna MH. Paraplegia after coeliac plexus block. Anaesthesia 44:487–9, 1989. 49. van Dongen RT, Crul BJ. Paraplegia following coeliac plexus block. Anaesthesia 46:862–3, 1991. 50. Jabbal SS, Hunton J. Reversible paraplegia following coeliac plexus block. Anaesthesia 47:857–8, 1992. 51. Wong GY, Brown DL. Transient paraplegia following alcohol celiac plexus block. Reg Anesth 20:352–5, 1995. 52. Brown DL, Rorie DK. Altered reactivity of isolated segmental lumbar arteries of dogs following exposure to ethanol and phenol. Pain 56:139–43, 1994. 53. Mercadante S. Celiac plexus block versus analgesics in pancreatic cancer pain. Pain 52:187–192, 1993. 54. De Cicco M, Matovic M, Bortolussi R, et al. Celiac plexus block: injectate spread and pain relief in patients with regional anatomic distortions. Anesthesiology 94:561–5, 2001. 55. Ventafridda GV, Caraceni AT, Sbanotto AM, et al. Pain treatment in cancer of the pancreas. Eur J Surg Oncol 16:1–6, 1990. 56. Eisenberg E, Carr DB, Chalmers TC. Neurolytic celiac plexus block for treatment of cancer pain: a meta-analysis. Anesth Analg 80:290–5, 1995.

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57. Yeager MP. Morphine inhibits spontaneous and cytokineenhanced natural killer cell cytotoxicity in volunteers. Anesthesiology 83:500–8, 1995. 58. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with unresectable pancreatic cancer: a prospective randomized trial. Ann Surg 217:447–57, 1993. 59. Plancarte R, Amescua C, Patt RB, et al. Superior hypogastric plexus block for pelvic cancer pain. Anesthesiology 73:236–9, 1990. 60. de Leon-Casasola OA, Kent E, Lema MJ. Neurolytic superior hypogastric plexus block for chronic pelvic pain associated with cancer. Pain 54:145–51, 1993. 61. Plancarte R, de Leon-Casasola OA, El-Helaly M, et al. Neurolytic superior hypogastric plexus block for chronic pelvic pain associated with cancer. Reg Anesth 22:562–8, 1997. 62. Rosenberg SK, Tewari R, Boswell MV, et al. Superior hypogastric plexus block successfully treats severe penile pain after transurethral resection of the prostate. Reg Anesth Pain Med 23:618–20, 1998. 63. Plancarte R, Amescua C, Patt RB. Presacral blockade of the ganglion of Walther (ganglion impar). Anesthesiology 73:A751, 1990. 64. Nebab EG, Florence IM. An alternative needle geometry for interruption of the ganglion impar. Anesthesiology 86:1213– 14, 1997. 65. Wemm KJ, Sabersky L. Modified approach to block the ganglion impar (ganglion of Walther). Reg Anesth 20:544–5, 1995. 66. Loev MA, Varklet VL, Wilsey BL. Cryoablation: a novel approach to neurolysis of the ganglion impar. Anesthesiology 88:1391–3, 1998. 67. Plancarte R, Velazquez R, Patt RB: Neurolytic blocks of the sympathetic axis. In: Patt RB, ed. Cancer pain. Philadelphia: Lippincott-Raven, 1993, p 419. 68. Swofford JB, Ratzman DM. A transarticular approach to blockade of the ganglion impar (ganglion of walther). Reg Anesth Pain Med 23(3 Suppl):103, 1998. 69. Vranken JH, Bannink IMJ, Zuurmond WWA: Invasive procedures in patients with coccygodynia: caudal epidural infiltration, pudendal nerve block and blockade of the ganglion impar. Reg Anesth Pain Med 25(2 Suppl):25, 2000. 70. Peyton WT, Semansky EJ, Baker AB. Subarachnoid injection of alcohol for relief of intractable pain with discussion of cord changes found at autopsy. Am J Cancer 30:709, 1937. 71. Smith MC. Histological findings following intrathecal injections of phenol solutions for relief of pain. Br J Anaesth 36:387– 406, 1963. 72. Swerdlow M. Intrathecal neurolysis. Anaesthesia 33:733–40, 1978. 73. Katz J. The current role of neurolytic agents. Adv Neurol 4:471– 6, 1974. 74. Swerdlow M. Subarachnoid and extradural blocks. Adv Pain Res Ther 2:325–37, 1979. 75. Hay RC. Subarachnoid alcohol block in the control of intractable pain. Anesth Analg 41:12–16, 1962.

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76. Stovner J, Endresen R. Intrathecal phenol for cancer pain. Acta Anaesthesiol Scand 16:17–21, 1972. 77. Holland AJC, Youssef M. A complication of subarachnoid phenol blockade. Anaesthesia 34:260–2, 1979. 78. Racz GB, Heavner J, Haynsworth R. Repeat epidural phenol injections in chronic pain and spasticity. In: Lipton S, Miles J, eds. Persistent pain, vol. 5. Orlando: Grune & Stratton, 1985, pp 157–79.

r. chan and o. de leon-casasola 79. Madrid JL, Bonica JJ. Cranial nerve blocks. In: Bonica JJ, Ventafridda V, ed. Advances in pain research and therapy, vol. 2. New York: Raven Press, 1979, pp 463–8. 80. Waldman SD, Feldstein GS, Allen ML, et al. Cervical epidural implantable narcotic delivery systems in the management of upper body pain. Anesth Analg 66:780–2, 1987. 81. Lobato RD, Madrid JL, Fatela LV, et al. Intraventricular morphine for intractable cancer pain: rationale, methods, clinical results. Acta Anaesthesiol Scand 31:68–74, 1987.

17

Neurosurgical treatment of cancer pain robert w. hurleyb a and fred a. lenz b a University of Florida and Johns Hopkins Hospital

Over the past 30 years, there have been significant changes in neurosurgical approaches to the treatment of cancer pain. Specifically, there has been a substantial decrease in the number of ablative procedures and an increase in the number of interventional pain and implantation procedures for treatment of chronic pain. The application of ablative surgery has been diminished in part because of the increasing recognition that some types of persistent pain are the result of injuries to the nervous system.1,2 In the treatment of pain of malignant origin in patients with a life expectancy of less than 3 months, this is often less of a concern, as the pain relief provided by the procedure is often good for the patient’s remaining life.3 The indications for all pain treatment, particularly neurosurgical treatments, are dependent on the type of pain. Nociceptive pain refers to pain arising from the activation of peripheral nociceptors and transmitted to the central nervous system through intact somatic sensory pathways. Examples of nociceptive pain include acute cancer pain secondary to invasion of bone. This pain has been said to respond well to opiates.4 Neuropathic pain refers to pain arising from injury to the nervous system either peripherally, such as malignant invasion of pancreatic cancer into the celiac plexus or diabetic peripheral neuropathy, or centrally, such as post-stroke pain.5 It has been suggested that central pain does not respond to opiates,4 although this is certainly not universally accepted.6,7

Ablative procedures Peripheral ablative procedures Dorsal rhizotomy or dorsal root ganglionectomy is the transection of the dorsal roots of a spinal nerve that interrupts sensory axons from the periphery passing preferentially through the dorsal roots, including A␦- and C–fibers

signaling pain. The ventral root preferentially contains the axons of anterior horn cells activating somatic muscles. However many axons in the ventral roots are sensory A␦and C–fibers that may run from the periphery into the ventral root and loop back into the dorsal root to enter the dorsal horn or enter the spinal cord directly through the ventral root.8–10 Cell bodies may be located in the dorsal root ganglion (DRG) or along either root. The rationale of dorsal root ganglionectomy is the surgical interruption of all afferent axons with cell bodies in the DRG, including those that enter the cord through the anterior root. Therefore, ganglionectomy may be superior to dorsal rhizotomy, which interrupts only fibers in the dorsal roots. One theoretical disadvantage of ganglionectomy is that it leads to wallerian degeneration of peripheral afferents and target tissue denervation, which may contribute to the pain and dysesthesias of neuropathic pain.11,12 Indications, results, and complications Dorsal rhizotomy or ganglionectomy can be carried out throughout the neuraxis up to C2 for treatment of occipital neuralgia and cervicogenic headache. It may be used for the treatment of pain of malignant origin in the neck, thorax, abdomen, and pelvis/perineum. Dorsal root ganglionectomy of S2 and S3 results in neurogenic bowel and denervation of the anal sphincter; therefore, patients should be counseled regarding these adverse results. Part of the preoperative evaluation includes psychological counseling, an evaluation of more conservative medication and interventional pain procedures, and selective nerve root or DRG local anesthetic block.13 Although a positive nerve root block may isolate a pain syndrome to a single root, even when placebo controlled, it is not an infallible predictor of the outcome of the subsequent ablative procedure.14 Injectate volumes used in this study were very large and lacked external validity; therefore, the criticisms of the 329

330 technique need to be tempered. The surgical procedure requires a laminectomy and foraminotomy for adequate exposure. Commonly, three to four levels are addressed during the operation. Most patients receiving this therapy have a limited life span secondary to their underlying malignant disease; therefore, long-term results of these procedures are limited. The level of scientific evidence for this procedure in cancer pain is not high. The majority of manuscripts are case reports or retrospective reviews. In a case series, 14 patients underwent thoracic dorsal rhizotomy for pain of malignant etiology.15 Thirteen of the 14 had good to excellent results, with a median time of pain relief of 22 weeks. The duration of response, however, was highly variable. Some patients had relief for less than 6 weeks, and others had 45 weeks of relief. Unfortunately, symptoms of deafferentation were not discussed in the patients who obtained limited duration of pain relief. Saris and colleagues16 reported a series of patients treated for cancer-related perineal pain who were followed up for an average of 3 years. Fifty-three percent of the patients (10/19) had good pain relief for that duration. Ablation of the dorsal root entry zone Dorsal root entry zone (DREZ) lesions are indicated in patients suffering from cancer-related pain in extremities that remain motorically functional. Although the dorsal roots are heterogenous with regard to the fiber type location, as they pass into the DREZ, they segregate. The large fibers (A␤) tend to enter medially, and the medium (A␦) and small (C) fibers, which are responsible for the majority of nociceptive transmission, enter laterally and ventrally into the spinal cord dorsal horn. These small C- and A␦-fibers form Lissauer’s tract as they ascend or descend up to four levels superficially lateral to the fibers of the dorsal root. These fibers terminate in laminae I, II, and V. Destruction of fibers afferent to, or circuitry of, the DREZ is understood to produce the therapeutic benefit of this procedure17 and therefore has been used as a treatment modality for neuropathic pain syndromes caused by deafferentation (central pain) or peripheral denervation resulting from tumor infiltration. Techniques Lesions bracketing the painful dermatomes have been carried out using incision with a knife or coagulation with laser, ultrasound, or bipolar electrode. In the absence of visible spinal cord pathology, the extent of the lesion is determined by using the dermatomal level of the pain to select the vertebral level of the involved roots. Alternately effected levels

r.w. hurley and f.a. lenz can be identified by somatic sensory potentials recorded in the DREZ following stimulation of the painful part. Lesions are made at 1-mm intervals along and into the DREZ to a depth of 2 mm by radiofrequency coagulation to a temperature of 80◦ C.18,19 For the caudalis DREZ procedure, lesions are made at the junction of the medulla and cord.18–20 The lesion includes two rows: one along the rootlets from C2 to 5 mm above the obex, and the other parallel to the first but 1 mm dorsal. Intraoperative monitoring may be used to refine the lesioning of the DREZ.21 Indications, results, and complications Spinal and nucleus caudalis DREZ-lesioning procedures may be an effective means of treating peripheral neuropathic pain syndromes in carefully selected patients. Brachial or lumbar plexus avulsion is the best indication for the DREZ procedure. The best results are observed in patients with incomplete neurologic deficits and in those with “electric” pain. Pain occurring below the level of injury, especially constant, burning pain in the sacral dermatomes, may not respond well to DREZ procedures.22 DREZ procedures for lumbosacral pain should include a limited number of segments to minimize the risks or somatic motor hypotonia and sphincter dysfunction, particularly if lesions are made bilaterally. The caudalis DREZ procedure may be indicated in patients with cancer-related craniofacial pain, either nociceptive or neuropathic, such as that caused by tumor invasion of the trigeminal nerve. The caudalis DREZ procedure has a relatively high risk of postoperative deficits and a relatively high rate of recurrence of the pain;23 therefore, it should be reserved for patients with limited life expectancy. In a large retrospective series by Sindou,24 DREZ was used to treat cancer-related pain in the lung apices, brachial plexus, axilla, and pelvic floor. In this series, he found a success rate of approximately 85% 10 months following the procedure. Deafferentation pain secondary to peripheral nerve compression or invasion has been successfully treated with thoracic and lumbar DREZ procedures.25 Caudalis DREZ procedures for posterior fossa microglioma, a lacrimal gland carcinoma, a temporal meningioma, a parasellar tumor (craniopharyngioma), and an orbital fibrosarcoma were found to provide good to excellent pain relief in all five patients immediately after the procedure; however, the pain returned and limited two of the five patients’ activities of daily living 14 months after the procedure.26 Radiation-induced brachial plexopathy and radiation-induced trigeminal neuropathy are the result of the treatment of cancer but also may be treated with the DREZ procedure or the analogous trigeminal caudalis

neurosurgical treatment of cancer pain nucleotractotomy. In a case series of eight patients with brachial plexopathy (n = 6) or trigeminal neuropathy (n = 2) treated with DREZ or trigeminal tractotomy, all patients received “complete” relief through a 1-year followup period.27 Unfortunately, the authors included preoperative pain scores but no postoperative or follow-up pain scores for comparison. These data were consistent with the first report of DREZ lesioning for postirradiation brachial plexus pain, in which two patients treated with DREZ received very good to excellent pain relief for 29 and 48 months.28 Complication rates may be significant, particularly in the case of DREZ lesions for brachial plexus avulsion pain, which is associated with sensory or motor deterioration in 40% of patients each.29 Overall, permanent sensory and motor deficits occurred in about 10% of patients who underwent spinal or caudalis DREZ. Non-neurologic complications, such as infection, cerebrospinal fluid (CSF) leak, and epidural hematoma, occur in about 7% of patients. The caudalis DREZ procedure has a higher rate of complications. Postoperative ataxia occurred in about 45% and diplopia or corneal anesthesia in about 20%. Caudalis DREZ has been reported with physiologic monitoring intraoperatively, including trigeminal, median, and tibial nerve somatosensory evoked potentials and electromyograms. This technique was reported to result in 70% pain relief at 1 year in noncancer patients, and no permanent neurological deficits. These favorable results were attributed to the smaller number of DREZ lesions per patient and may therefore be less applicable to cancer patients requiring an extensive number of lesions.21 Cordotomy Cordotomy produces relief of pain by interrupting the transmission of signals in the spinothalamic tract (STT) from below the level of intervention.30,31 Historically, cordotomy was usually carried out as an open bilateral procedure at T1–2 for relief of pain secondary to cancer. This procedure requires general anesthesia, a laminectomy at two levels, and manipulation of the spinal cord to visualize the anterolateral component of the cord. A lesion of the entire anterolateral quadrant of the spinal cord is then made with a sharp blade. Percutaneous cervical cordotomy under local anesthesia minimizes the anesthetic risks, spares sick patients a general anesthetic, and facilitates physiological confirmation of the location of the STT.30 Percutaneous cordotomy can be done by the dorsal approach at the C1–2 interspace, the low anterior cervical approach (C5–6), or the lateral cervical approach at C1–2. The high

331 lateral cervical approach seems to be the most popular at present. Technique The technique of percutaneous, high cervical cordotomy has been developed over decades.31 Percutaneous cordotomy usually is carried out using intravenous sedation, with myelography or CT to identify the STT anatomically.32 Macro-stimulation carried out through the lesioning electrode identifies ascending and descending tracts in the cord, including the STT.33 The lesion is made with radiofrequency coagulation.34 The percutaneous procedure also may be done under general anesthesia, but this procedure relies entirely on anatomic criteria for STT localization because the description of stimulation-evoked sensations is not possible and therefore does not provide less benefit over the open technique. A insulated electrode with a 2-mm bare tip is introduced through a thin wall lumbar puncture needle at the C1–2 interspace.31 The spinal cord is penetrated at the anteroposterior midpoint indicated by the dentate ligament, as illustrated by myelography. Recently, CT guidance has been used to provide anatomic guidance during cordotomy.35 Impedance monitoring identifies the pial surface of the cord based on an impedance increase from 400 ohms in spinal fluid, up to 1200 ohms in cord.36 When the electrode is in the STT and stimulated at 2 Hz, muscle contractions in time with the stimulation appear in the ipsilateral trapezius, shoulder, and arm, but not in the lower limb. Following this, a 50-Hz electrical stimulus is applied. If the needle is well placed in the STT, the patient should feel temperature sensations (warm or cold) on the contralateral body half. During lesioning, contralateral analgesia is tested with pinprick and begins at 35 mA (60◦ –75◦ C) and is enlarged in 10-mA steps to a maximum of 50 mA (90◦ C). Indications, results, and complications The efficacy of this technique to relieve severe cancer pain makes it a viable procedure in patients with limited survival and pain refractory to other medical and interventional techniques. Percutaneous cordotomy should be considered for the relief of somatic nociceptive pain located below the level of the cordotomy. Although the percutaneous cordotomy may be performed at C1–2, the nature of the STT limits the dermatomal relief, usually to below C4–5. In the case of neuropathic pain, cordotomy may relieve the allodynia, hyperpathia, and neuralgic pain but is less effective against the steady burning component of neuropathic pain.37,38 In a large series, the indication for cordotomy included pain from cancer of the cervix in approximately 20%, rectum

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332 in 15%, colon in 10%, lung in 10%, breast in 5%, and other cancers in 30%, and central pain of spinal cord origin in 10%.39,40 Patients received 60%–80% complete pain relief and 70%–95% significant contralateral pain relief. Complete pain relief was found in 90% of patients immediately postoperatively, 85% after 3 months, 60% at 1 year, 40% between 1 and 5 years, and 40% at 5–10 years. In one large retrospective series from the Netherlands, 43 patients with cancer-related pain of the shoulder, chest, pelvis, groin, rectum, or leg received C1–2 percutaneous cordotomy under intravenous sedation.41 All patients in this study had received maximal medical and interventional pain therapy, some with intrathecal drug delivery, without significant relief of their pain. The median numerical rating score of pain was 8 before the procedure, 0 immediately post procedure, and 2 the final time the score was recorded before the patient’s death from cancer. The reduction in pain score was accompanied by a significant decrease in opioid medication intake. Four of the 43 patients (9.3%) received inadequate relief from the procedure, three of whom had significant pain reduction after the procedure was repeated. The overall failure rate was 2%. If the pain is not isolated to one side of the body, a bilateral procedure is often proposed. The two procedures should be staged at least one week apart. Because the rate of immediate significant pain relief with unilateral cordotomy is 80%, the success of the bilateral procedure may be estimated by 80% 80%, or 64%. If the first procedure of a proposed bilateral cordotomy interferes with ipsilateral automatic respiration, then the second side should be approached with caution. Urological complications are common after unilateral cordotomy, and the risk is increased after a bilateral procedure. The complications of cordotomy are related to damage of nearby structures in the cord. The chief complication is respiratory failure related to loss of involuntary respiration (Ondine’s curse). This is the result of lesioning of the ipsilaterally distributed reticulospinal tract that lies among the axons of the cervical STT. Significant reversible respiratory complications occur in up to 10% and death due to respiratory complications occurs in 0%–5% of patients after unilateral cordotomy. Persistent paresis of the ipsilateral leg or ataxia occurs in up to 10%, and dysfunction of micturition in up to 15%. It has been suggested that any patient who has strength of three of five muscles in the affected limb will recover and not suffer sufficient disability.31 Postcordotomy dysesthesia affects less than 10%. Ipsilateral ptosis from sympathetic tract damage in the intermediolateral cell column is a frequent but well-tolerated complication.

Myelotomy Anterior commisural midline myelotomy is a procedure whose intention is to disrupt the decussating second-order neurons of the dorsal horn before joining the STT and ascending to supraspinal structures. Destruction of these crossing fibers produces effects similar to those of bilateral anterolateral cordotomy; however, it is associated with a higher complication rate.42 A dorsal column midline myelotomy is a procedure that involves sectioning of pathways at particular “segmental” levels in the spinal cord, rather sectioning of an ascending pathway, as in the case of cordotomy. It interrupts a multisynaptic pathway to the brain43,44 that may be the postsynaptic dorsal column visceral pain pathway.45,46 Recent anatomical and physiologic studies may have identified this pathway, which arises from cell bodies near the central canal and ascends in the dorsal column midline.45 Technique The procedure is performed under general anesthesia. A laminectomy is performed one to two vertebral levels above the innervating segments of the spinal cord – for example, T3–4 for the pancreas, liver, and spleen. Anatomic midline is identified after the dura is opened longitudinally and the dorsal vein is mobilized and displaced. A microdissector is then placed to a depth of 5 mm, and maintaining absolute midline, a needle is placed to destroy the surrounding fibers. Maintaining midline position is essential to make sure that only the medial fibers of nucleus gracilis are disrupted. Indications, results, and complications An optimal patient for this procedure is thought to be one with prominent visceral pain who is otherwise in good condition and can tolerate a surgical procedure. Nauta et al.47 demonstrated that a small midline lesion above the painful level could be effective for medically intractable pelvic pain. A similar myelotomy at the upper thoracic level was reported to be effective for pain of stomach cancer.12 In the most recent series, Hwang and colleagues48 reported a decrease in pain and opioid dose in patients with epigastric and right upper quadrant pain treated with dorsal column midline myelotomy. Although none of these patients suffered from recurrent pain in other unrelated sites, this represents one of the possible complications of the procedure. The most common complication is diminution of effect. The median duration of benefit is approximately 2 months (range, 2 weeks to 31 months). Other complications include bowel and bladder dysfunction, paresthesias, and loss of

neurosurgical treatment of cancer pain somatic sensation from collateral damage to the dorsal columns. Intracranial ablative procedures Brainstem tractotomy, thalamotomy, hypophysectomy Brainstem tractotomy includes mesencephalic tractotomy, in which the STT fibers are sectioned at the level of the mesencephalon, providing pain relief similar to that of midline anterior commissure myelotomy or anterolateral cordotomy.37 However, analgesia is also observed after lesions of the mesencephalic central gray, through the interruption of the spino-mesencephalic pathway.49 In the latter case, the lesion is reported to relieve chronic pain without analgesia to pinprick.50 These two types of lesion effects also are reflected in the intracranial procedures that lesion either the parts of the somatosensory system subserving pain or lesions of the limbic system. Other central analgesia targets include the spino- and trigeminothalamic tracts. Historically, these tracts were lesioned by open procedures at sites where they lie close to the surface of the brainstem, at the lateral edge of the tectal plate.51 Another technique, the dorsolateral medullary tractotomy, is a lesion of the descending tract of the trigeminal nucleus, which subserves nociception for head and neck pain. The localization of these tracts relative to landmarks on the surface of the brainstem is variable, which led to a high incidence of both failure of the procedures and neurological side effects. The technique of these procedures was dramatically changed by the application of CT- or magnetic resonance–based stereotaxis. Indications, results, and complications Intracranial procedures include lesions of the STT by stereotactic mesencephalotomy and lesions of the mesencephalic central gray. When the STT was first interrupted stereotactically in the midbrain – that is, by mesencephalotomy – hemisensory loss of pain sensation or analgesia could be achieved throughout the entire contralateral body, face, and head, often with good but temporary relief of pain. Unfortunately, a high incidence of postoperative central pain was observed. This procedure also is associated with a 5% risk of mortality and a 37% risk of morbidity, but it provides long-term pain relief in 75%–85% of cancer patients.52 The spino-reticulo-thalamic pathways may project to the more medial thalamic nuclei, including the posterior intralaminar, central median, posterior medial dorsal, and posteriorly adjacent nuclei.53 These pathways project to the limbic system, including the anterior cingulate cortex. These intracranial ablative procedures are indicated for patients with pain involving the head and/or neck or

333 upper extremities or pain that is widespread throughout the body.54 Ablation of these thalamic nuclei has been used primarily for the management of medically refractory neuropathic pain.55 In this series of patients with neuropathic pain treated by lesions of the posterior intralaminar nuclei, 69 patients were followed an average of 13 months (range, 1–48 months).56,57 Subjective rating by the patients was reported to show an improvement of 50%–100%, depending on the diagnosis. Outcomes were reported to show 70% relief in peripheral and 60% relief in central neuropathic pain. Overall, 67% improved, including 20% with complete relief. It is sometimes observed that lesions in the intralaminar or centromedian nuclei may produce successful pain relief and may minimize symptoms of opiate withdrawal.54 This techniques also may be a useful adjunct in the treatment of malignant pain that is nonresponsive to all other medical and interventional therapies in patients with a limited life span.58 The morbidity and mortality of medial thalamotomy are difficult to assess because some large series do not report complications.56,57 Hypophysectomy is recommended for the treatment of pain related to metastatic lesions of the bones from prostate and breast cancer. In patients treated with percutaneous hypophysectomy for metastatic prostate cancer, 94% received pain relief following the procedure.59 This procedure is associated with significant medical morbidity, producing a patient with pan-hypopituitarism and all its attendant medical complications. This technique is now little used in the treatment of cancer pain. Most of these procedures are carried out stereotactically, which carries a risk of complications independent of the diagnosis. There is a risk of hemorrhage of between 1% and 6%.60 Lesions of the STT-thalamocortical projection zone are associated with a risk of central pain, as in the case of mesencephalic tractotomy. These procedures have been reported using radiosurgical ablation, with good to excellent relief of pain in 55% (11/20).61 The recent series of gamma knife medial thalamotomy reports complications in four of 17 cases followed up over 3 months. There were four cases of hemiplegia, one of which resolved and two of which were improving at the time of the report; the fourth patient died of radiation necrosis following a contralateral, medial thalamotomy.61 This is consistent with the risk of neurologic complications of such procedures when used for treatment of movement disorders and pain.62 Cingulotomy Cingulotomy deserves separate mention as the sole descendent of frontal lobotomy used to treat chronic pain.63 This

334 procedure lesions the anterior portion of the cingulate bundle as it wraps around the anterior end of the corpus callosum.64 In the Massachusetts General Hospital (MGH) series, the largest, a total of 123 patients with pain were treated. Procedures were judged to be successful if the patient reported no pain without any analgesic medication or was comfortable on non-narcotic analgesics. Among 35 patients with cancer, 57% benefited from cingulotomy; among the 61 patients with chronic back pain, 74% benefited. Improvement was reported in patients with chronic abdominal pain (83%, 5/6) and phantom limb (60%, 3/5) but in none of the patients with post-stroke or postherpetic neuralgia. Another recent series of cingulotomy for pain included patients with cancer and nociceptive (n = 6) and neuropathic pain (n = 2). Results were judged by the patient’s activity level and by the patient’s subjective rating of pain and of pain relief overall. Among these patients, four had an excellent result and four had a poor to fair result.65 The remaining patients had pain secondary to neurofibromatosis and central pain secondary to an infarct, leading to excellent and poor results, respectively. There do not appear to have been complications in this series. In the most recent series, Yen et al.66 described a series of 15 patients with medically intractable pain from cancer who underwent stereotactic bilateral anterior cingulotomy. Of these 15 patients, significant or meaningful pain relief was achieved in 67% at 1-month follow-up, which decreased to 58% at 3 months and 50% at 6 months. There was no surgical mortality or permanent neurological morbidity. Two patients developed transient confusion, but no clinically evident personality or emotional changes were noted. The rate of reported complications has been variable. In one recent series, two of 28 patients had seizures intraoperatively and five had late seizures. Four of those patients were placed on phenytoin, with good control of their seizures.67 Neuropsychological testing of patients with bilateral cingulotomy for chronic pain displayed worse executive function, attention, and self-initiated behavior, whereas language, motor control, and memory were not affected.67 Other side effects of cingulotomy may be less deleterious. Cohen and colleagues68 studied the emotional changes that result from the surgical intervention in a large number of patients after cingulotomy. Patients had lower anxiety and expressed less anger than those who had intractable pain and did not have the surgery. Although interesting, it is hard to determine whether the anxiolytic effect was the result of the surgical lesion or the reduction in pain from the surgical lesion.

r.w. hurley and f.a. lenz A lower incidence of complications was reported in the large MGH series (714 cingulotomies, 414 patients) performed for either chronic pain or psychiatric disease. There were no deaths and no infections. Two patients became hemiplegic secondary to acute subdural hematomas, one developed a chronic subdural hematoma, and five patients had seizures controlled by phenytoin.64

Neural stimulation and intrathecal drug delivery Since the 1970s, stimulation of the nervous system or intrathecal drug delivery has largely supplanted lesioning of the nervous system for control of pain. The term augmentative refers to modulation of nervous system activity by implanted stimulators and drug pumps, which are not destructive. Neuroelectrical stimulation (e.g., motor cortex, deep brain, or spinal cord stimulation), in its current state, has limited application to the treatment of medically refractory cancer pain because of the high cost associated with the therapy and the commonly limited life span of the cancer patient. Intrathecal drug delivery for the treatment of pain Medication delivery to the spinal cord or the dorsal nerve roots via the intrathecal or epidural route exploits the endogenous pharmacology of the neuraxis to produce pain relief in cancer patients. These methods of delivery require a certain degree of expertise and are commonly used by neurosurgeons and Accreditation Council for Graduate Medical Education board-certified interventional pain management specialists. The modern era of intrathecal drug delivery began in 1942, when Manalan69 used a catheter to administer medication continuously for labor analgesia. Several years after the discovery of the endogenous opioid receptors and their respective agonists, Wang70 reported treating cancer pain with intrathecal morphine. The main advantage of intrathecal pumps over oral drug delivery is the decrease in systemic side effects as a result of lower blood levels secondary to the restriction of hydrophilic opioids and other medications to the intrathecal CSF.71 Administration directly into the CSF is considered superior to administration into the epidural space. Epidural administration requires higher doses and frequent refills, which increase the risk of adverse systemic effects such as respiratory depression and infection. In addition, there is the risk of catheter misplacement or migration into the subdural space, again with a risk of ineffective therapy, overdoses, and/or fatal respiratory depression. Neuraxial analgesics were

neurosurgical treatment of cancer pain discussed in greater detail in a previous chapter; therefore, this chapter contains only a brief review of the recent literature. Pump technology and surgical technique Before the development of drug pumps, opioids were infused directly via an implanted Ommaya reservoir-type device with a catheter in the CSF space. The catheter was placed in the lateral ventricle or lumbar intrathecal space. Ventricular infusion produced longer-lasting analgesia compared with infusion into the lumbar subarachnoid space, which was a benefit in the era of single-dose reservoirs. However, these reservoirs and the associated medication administration one to two times a day was time consuming and associated with complications such as CSF leaks, respiratory depression following injection, and infection related to the necessarily frequent percutaneous access of the administration port.72 Therefore, this therapy was considered a “last resort” for palliation.73 Implantable pumps with larger-volume reservoirs that could slowly infuse medications and could be completely internalized were developed and were safer and more effective. Currently, the most commonly used design is a variablerate infusion pump; constant-infusion systems are still in production and are used rarely. The great advantage of a variable-rate system is that the dosage of the medication delivered can be altered without having to alter the concentration of the medication in the reservoir. This lessens the number of times the operator has to access the pump percutaneously and therefore reduces patient discomfort and risk of infection. Variable-rate infusion pumps also have the capability of functioning as patient-controlled pumps within physician-programmed, safe parameters. Using a handheld computer (personal data assistant), the patient can deliver bolus infusions or different constant infusion rates. However, programmable and patient-controlled pumps have some disadvantages, including cost and the use of battery power, which may lead to more frequent pump changes. The average life of a programmable intrathecal pump is 5–7 years. These programmable pumps used to be reserved for patients with neuropathic pain, who have a longer life expectancy than patients with pain secondary to cancer;72 however, the ease of use and increased patient satisfaction with these pumps mandates their use. The intrathecal route of medication delivery currently is the most common method. First, a lumbar puncture is performed between L2 and L5 to avoid the conus of the spinal cord. A silastic catheter is then threaded through the needle rostrally to the level of the spinal cord segment consistent

335 with the dermatome/viscerotome associated with the patient’s greatest pain. In patients with widespread pain, the catheter tip most often is placed in the mid-thoracic region in an effort to cover the greatest area of pain. For upper extremity and/or thoracic pain, the catheter tip may be placed at the cervical level. The choice of the final location of the catheter tip also depends on the properties of the intended medications. For instance, ziconotide or morphine can be placed at the low lumbar level and still achieve good analgesia for arm and neck pain, but fentanyl must be delivered close to the dermatomal level of the pain. However, placement of the catheter into the cervical region carries an increased risk of respiratory depression. Following catheter placement, the location of the tip is confirmed with myelography. The catheter then is tunneled into a subcutaneous pocket for the implantable pump on the anterolateral aspect of the abdominal wall. The pump is implanted, and the intrathecal catheter is connected to the pump and secured to prevent pump and catheter migration. Results and complications Intraventricular delivery is as efficacious as intrathecal subarachnoid delivery but is more invasive and carries significantly greater risk (vide supra). It is usually considered in the case of patients who fail to respond to intrathecal delivery or in cases of refractory craniofacial pain. Ballantyne et al.74 reviewed studies comparing intraventricular with intrathecal morphine delivery in cancer patients. They found that 73% of patients with intraventricular morphine drug delivery achieved excellent pain control, compared with 62% of patients who received intrathecal morphine.74 There were fewer technical problems with intraventricular therapy, although adverse effects of sedation and confusion were more common.74 Smith et al.71 described the benefits of intrathecal analgesia in patients with refractory cancer pain compared with benefits in those managed with comprehensive medical management. The patients who received intrathecal opioid therapy had a reduction in pain scores, systemic opioid consumption, and opioid-related complications, such as sedation and constipation. Rauck et al.75 demonstrated that 91% of patients enrolled in an intrathecal trial experienced a 50% reduction in refractory pain (P ⬍0.01). They also showed that the most common complications (sleep disorders, daytime drowsiness, constipation, nausea) and the most frequent complication (urinary retention) significantly improved after intrathecal analgesia. Most likely, these results reflect the opioid-sparing effect when changing

336 from the systemic to the intrathecal route of opioid delivery. Gilmer-Hill et al.76 administered intrathecal analgesia in nine advanced pancreatic cancer patients. All patients receiving intrathecal opioids experienced good to excellent pain relief on a Likert 5-point scale. With regard to the visual analogue scale, there also was a significant and clinically relevant decrease from 9/10 to 2/10. Importantly, all patients reported improvements in their quality of life and improved function in activities of daily living. No patient developed loss of pain control that could not be resolved with increased doses. Souter and colleagues77 reported on a patient who had no benefit from intrathecal opioids, local anesthetics, and clonidine but had a successful result with meperidine. This patient experienced no deleterious side effects from the infusion. The patient’s plasma meperidine and normeperidine levels were measured and found to be well under concerning levels. Although this may be an appropriate choice in terminal patients, the long-term deleterious effects of intrathecal meperidine on the spinal cord are unknown. Although the majority of cases or studies have reported on the administration of opioids to the intrathecal space, there are case reports and a few case series of patients receiving a combination of medications or a nonopioid alone. The most recent medication to receive U.S. Food and Drug Administration approval for intrathecal use is ziconotide, the marine snail venom–derived conotoxin used by Aborigines for hunting fish, which acts on the spinal N-type voltage-gated calcium channels. In a randomized controlled trial mostly including patients with cancer pain, patients were randomly assigned to the ziconotide or inactive placebo group. The author noted that 43% of patients receiving treatment had a significant reduction in pain, compared with 18% in the placebo group.78 Unfortunately, this trial has been criticized for numerous protocol, statistical, and procedural issues.79 Another single agent that has been tried is ketamine. In two case reports of terminal cancer patients who no longer responded to any other intrathecal or oral agent, continuous ketamine was infused, with good results.80,81 Although there are no preclinical safety data available for this agent, no untoward side effects were noted from this treatment strategy. Combinations of opioid and local anesthetic also have been found to be beneficial in cancer patients suffering from pain. In a case series review, Mercadante82 reported that the addition of levobupivacaine to intrathecal morphine produced a significant decrease in pain as well as a reduction in patient drowsiness and confusion. The only side effect appeared to be increased urinary retention. Clonidine also has been used alone or

r.w. hurley and f.a. lenz in combination with an opioid for intrathecal administration; unfortunately, there are few data on the effectiveness of this strategy in cancer patients. In a mixed population that contained two cancer patients, single-agent clonidine was found to be ineffective in reducing pain scores, and in combination with opioids, clonidine was of short-lived (⬍18-month) benefit.83 Infection, either subcutaneous at the pump site or subarachnoid (meningitis), is the most common complication, resulting in removal of the pump and long-term intravenous antibiotics. CSF leaks are treated with an epidural blood patch, that is, epidural injection of the patient’s blood followed by flat bedrest or, if necessary, catheter revision and placement of additional pursestring sutures around the catheter as it exits the intrathecal/epidural space and instillation of fibrin glue. A variety of catheter problems (migration, disconnection, obstruction, kinking) are common occurrences that often require surgical revision. Intrathecal pumps (from Medtronic) are MRI compatible to 1.5 T and can therefore be left unchanged before imaging. As a safety feature, the pump itself shuts down for the duration of the MRI so that an overdose cannot be administered inadvertently. Although post-MRI pump failure is an extremely rare occurrence, it should be interrogated within 48 hours of the MRI procedure to assure continued appropriate function. Long-term catheter use may lead to the development of an inflammatory mass at the tip of the catheter. Recently, a review of the literature described 41 cases, all in patients with morphine pumps.84 Fourteen of these patients suffered complete, irreversible spinal cord lesions at the level of the mass. Intrathecal medications, including morphine, may be more responsible than the catheter because this complication is not described with lumbar–peritoneal shunt catheters.84 Although it was initially believed that morphine was the sole causative agent, further reports have implicated other opioid and nonopioid agents, including baclofen. Experimental animal studies found that all opioids, with the exception of fentanyl, were associated with granuloma formation.85 The etiology of this difference is not understood. Patients must be warned of the occurrence of this rare but potentially devastating complication. Transient respiratory depression may occur with morphine pumps at any site but is most common with intraventricular delivery74 and appears to be less common with less hydrophilic compounds, such as hydromorphone and sufentanil. Symptoms of withdrawal also may occur with pump depletion or malfunction and usually can be ameliorated by oral opioid therapy. Other adverse effects are

neurosurgical treatment of cancer pain similar to those of systemic opioid administration: pruritus, hypotension, constipation, confusion, drowsiness, and urinary retention. Painful myoclonus is a rare, mysterious complication.86

Conclusions At present, ablative procedures are becoming less common whereas intrathecal drug delivery is becoming more common. Intrathecal drug delivery has been improved by refined indications and has demonstrated efficacy in intractable cancer pain. It seems likely that the future will reflect the chemical basis of chronic pain.87 Surgical treatment of these conditions may use refinements of the currently available drug pump technology. Refinement of the indications has led to selective intrathecal administration of a drug or drugs88 specific to the condition being treated. Examples of such tailored drug administration in noncancer states are found in the case of patients with pain due to spasticity14 or pain following spinal cord injury, or in patients with opiate withdrawal.89 The possibility of anatomic as well as chemical approaches to surgical targets within the forebrain is within reach. Neuraxial administration may become practical for delivery of drugs to anatomically or physiologically defined structures. The intracerebral delivery of neurotransmitters or proteins, such as growth factors, into defined structures also may be accomplished by stereotactically placed catheters or by implantation of other novel drug delivery systems.90,91 These technologies promise to revolutionize the neurosurgical treatment of cancer pain in the future.

Acknowledgments This work is supported by grants from the National Institutes of Health to F.A.L. (RO1:NSRO1:39498, RO1: NS40059) and to R.W.H. (MH075884) and by the International Association for the Study of Pain Trainee Fellowship, funded by the Scan/Design by Jens and Inger Bruun Foundation. References 1. Gybels J, Erdine S, Maeyaert J, et al. Neuromodulation of pain. A consensus statement prepared in Brussels 16–18 January 1998 by the following task force of the European Federation of IASP Chapters (EFIC). Eur J Pain 2:203–9, 1998. 2. Tasker RR, Organ LW, Hawrylyshyn P, Bonica JJ. Deafferentation and causalgia. In: Pain. New York: Raven Press, 1980, pp 305–29.

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r.w. hurley and f.a. lenz 40. Tasker RR, Schmidt R, Willis WD. Percutaneous cordotomy. In: Lenz FA, ed. Encyclopedia of pain. Berlin: Springer Verlag, 2004. 41. Crul BJ, Blok LM, van Egmond J, van Dongen RT: The present role of percutaneous cervical cordotomy for the treatment of cancer pain. J Headache Pain 6:24–9, 2005. 42. Hong D, Andren-Sandberg A. Punctate midline myelotomy: a minimally invasive procedure for the treatment of pain in inextirpable abdominal and pelvic cancer. J Pain Symptom Manage 33:99–109, 2007. 43. Hitchcock E. Stereotactic myelotomy. Proc R Soc Med 67:771– 2, 1974. 44. Nauta HJ, Schmidt R, Willis WD. Midline myelotomy. In: Lenz FA, ed. Encyclopedia of pain. Berlin: Springer Verlag, 2004. 45. Christensen MD, Willis WD, Westlund KN. Anatomical evidence for cells of origin of a postsynaptic dorsal column visceral pathway: sacral spinal cord cells innervating the medial nucleus gracilis [abstract]. Soc Neurosci 22:109, 1996. 46. Willis WD, Coggeshall RE. Sensory mechanisms of the spinal cord. New York: Plenum Press, 1991. 47. Nauta HJ, Soukup VM, Fabian RH, et al. Punctate midline myelotomy for the relief of visceral cancer pain. J Neurosurg 92:125–30, 2000. 48. Hwang SL, Lin CL, Lieu AS, et al. Punctate midline myelotomy for intractable visceral pain caused by hepatobiliary or pancreatic cancer. J Pain Symptom Manage 27:79–84, 2004. 49. Willis WD. The pain system. Basel: Karger, 1985. 50. Shieff C, Nashold BS Jr. Stereotactic mesencephalotomy. Neurosurg Clin N Am 1:825–39, 1990. 51. Gybels JM, Sweet WH. Neurosurgical treatment of persistent pain. Physiological and pathological mechanisms of human pain. Basel: Karger, 1989. 52. Frank F, Fabrizi AP, Gaist G, et al. Stereotactic mesencephalotomy versus multiple thalamotomies in the treatment of chronic cancer pain syndromes. Appl Neurophysiol 50:314–18, 1987. 53. Gildenberg PL, Schmidt R, Willis WD. Intracranial ablative procedures. In: Lenz FA, ed. Encyclopedia of pain. Berlin: Springer Verlag, 2004. 54. Gildenberg PL, DeVaul RA: The chronic pain patient. Evaluation and management. Basel: Karger, 1985. 55. Jeanmonod D, Magnin M, Morel A. Thalamus and neurogenic pain: physiological, anatomical and clinical data. Neuroreport 4:475–8, 1993. 56. Jeanmonod D, Magnin M, Morel A. Low-threshold calcium spike bursts in the human thalamus. Common physiopathology for sensory, motor and limbic positive symptoms. Brain 119:363–75, 1996. 57. Jeanmonod D, Magnin M, Morel A, et al. A thalamic concept of neurogenic pain. In: Proceedings of the 7th World Congress on Pain. Progress in Pain Research and Management, vol. 2. Seattle: IASP Press, 1994, pp 767–87. 58. Whittle IR, Jenkinson JL. CT-guided stereotactic antero-medial pulvinotomy and centromedian-parafascicular thalamotomy for intractable malignant pain. Br J Neurosurg 9:195–200, 1995.

neurosurgical treatment of cancer pain 59. Takeda F, Uki J, Fuse Y, et al. The pituitary as a target of antalgic treatment of chronic cancer pain: a possible mechanism of pain relief through pituitary neuroadenolysis. Neurol Res 8:194– 200, 1986. 60. Favre J, Taha JM, Burchiel KJ. An analysis of the respective risks of hematoma formation in 361 consecutive morphological and functional stereotactic procedures. Neurosurgery 50:48–56, 2002. 61. Young RF. Gamma knife radiosurgery as an alternative form of therapy for movement disorders. Arch Neurol 59:1660–2, 2002. 62. Kondziolka D. Gamma knife thalamotomy for disabling tremor. Arch Neurol 59:1660–4, 2002. 63. Cosgrove GR, Rauch SL. Psychosurgery. Neurosurg Clin N Am 6:167–76, 1995. 64. Ballantine HT Jr, Giriunas IE, Schmidek HH, Sweet WH. Treatment of intractable psychiatric illness and chronic pain by stereotactic cingulotomy. In: Operative neurosurgical techniques. Indications, methods, and results. Philadelphia: W. B. Saunders, 1988, pp 1069–75. 65. Pillay PK, Hassenbusch SJ. Bilateral MRI-guided stereotactic cingulotomy for intractable pain. Stereotact Funct Neurosurg 59:33–8, 1992. 66. Yen CP, Kung SS, Su YF, et al. Stereotactic bilateral anterior cingulotomy for intractable pain. J Clin Neurosci 12:886–90, 2005. 67. Cohen RA, Kaplan RF, Zuffante P, et al. Alteration of intention and self-initiated action associated with bilateral anterior cingulotomy. J Neuropsychiatry Clin Neurosci 11:444–53, 1999. 68. Cohen RA, Paul R, Zawacki TM, et al. Emotional and personality changes following cingulotomy. Emotion 1:38–50, 2001. 69. Manalan SA. Caudal block anesthesia in obstetrics. J Indiana Med Assoc 35:564–5, 1942. 70. Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology 50:149–51, 1979. 71. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 20:4040–9, 2002. 72. Simpson RK Jr. Mechanisms of action of intrathecal medications. Neurosurg Clin N Am 14:353–64, 2003. 73. Siegfried J. [Intracerebral neurosurgery in the treatment of chronic pain]. Schweiz Rundsch Med Prax 87:314–17, 1998. 74. Ballantyne JC, Carr DB, Berkey CS, et al. Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer. Reg Anesth 21:542–56, 1996. 75. Rauck RL, Cherry D, Boyer MF, et al. Long-term intrathecal opioid therapy with a patient-activated, implanted delivery

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SECTION VI

REHABILITATION AND PSYCHOLOGICAL INTERVENTIONS

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Psychological interventions for cancer pain francis j. keefe, a amy p. abernethy, a jane l. wheeler, b and tamara j. somers a b a Duke University Medical Center and Duke University School of Medicine

Over the past 15 years, psychological interventions have emerged as a useful adjunct to medical approaches to cancer pain management.1–3 Psychological interventions offer several advantages in cancer pain management.3 First, they can enhance patients’ sense of self-efficacy (i.e., confidence) in their own abilities to control pain. Increased self-efficacy for pain control has been linked to lower psychological distress, less interference of pain with daily activities, and improved quality of life. Second, psychological interventions teach patients skills that can be applied to many of the day-to-day challenges of living with persistent pain, such as coping with pain flares, managing emotional reactions to pain (e.g., anxiety, fear, depression), and maintaining an active and rewarding life despite having pain. Third, psychological interventions and pain medications may have synergistic effects for cancer patients and produce an array of benefits (e.g., decreased pain, improved mood, enhanced interpersonal interactions) that may not be achieved by alone. Finally, psychological interventions may offer a viable pain management option for patients who respond poorly or have difficulty tolerating pain medications. This chapter provides an introduction to psychological approaches to managing cancer pain. The chapter is divided into three sections. The first section highlights the challenges of cancer pain. This section emphasizes the fact that psychological interventions for pain are delivered in the context of multiple ongoing challenges faced by persons having cancer pain. The second section provides an overview of four psychological interventions currently being used in cancer pain management: pain coping skills training (CST), partner-assisted coping skills interventions, hypnosis/guided imagery, and comprehensive yoga-based interventions. For each intervention, we describe basic treatment components, illustrate outcome studies, and briefly comment on their utility for cancer

patients. The third section of this chapter addresses controversies related to the use of psychological interventions in cancer pain management, including the therapist’s background and level of training needed, the amount of ongoing supervision/treatment monitoring needed to ensure treatment fidelity, and the importance of skills rehearsal as a treatment component.

Challenges of cancer pain Afflicting millions of cancer patients worldwide, pain is one of the most common, and most dreaded, cancer-related symptoms. Cancer pain is a heterogeneous phenomenon comprising acute pain, chronic pain, tumor-specific pain, and treatment-induced pain.4 Paradoxically, improvements in treatment agents and methodologies, and correspondingly, higher survival rates for many cancer types have resulted in a larger population afflicted by pain during active treatment, in early survivorship, and over the long term. World Health Organization estimates and numerous national and international surveys support the contention that three quarters of advanced cancer patients and one third to one half of cancer patients in active treatment experience cancer pain.5–8 More than 80% of cancer patients with pain report pain at two or more sites.9 The nature of cancer pain changes over the course of disease, further challenging both patients and clinicians seeking to understand and manage it. As cancer advances, pain is more prevalent and also may become more severe, especially as developing tumor masses impinge nerves, expand the liver capsule, or erode bone. Cancer pain does not occur as a discrete event, rather it arises as one element in a complex web of experiences. Most patients undergoing active treatment suffer a multiplicity of symptoms; among the most common disease- and treatment-related effects are pain, fatigue, nausea, cognitive 343

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impairment, sexual dysfunction, insomnia, and neuropathy.10 Meuser et al.11 conducted a longitudinal study of 593 advanced cancer patients receiving treatment at a pain service and found that, in addition to pain, the most frequent symptoms during treatment were impaired activity (74% of days), mood changes (22%), constipation (23%), nausea (23%), and dry mouth (20%). In the posttreatment phase, many cancer survivors continue to experience pain and one or more symptoms to varying degrees. Among breast cancer patients, for example, Ganz et al.12 reported that the majority of women at the conclusion of primary treatment experienced significant symptoms, which included aches and pains (60%) and cognitive dysfunction (56%). Specific symptoms vary by cancer diagnosis. Hammerlid et al.,13 in a study of head and neck cancer patients, examined longitudinal scores on a quality-of-life instrument. They found significant worsening of general symptoms that persisted at least 3 years post diagnosis, such as pain, fatigue, dyspnea, insomnia, and loss of appetite, as well as disease-specific symptoms – dry mouth and difficulty with senses, teeth, and opening the mouth wide. It now is well recognized that cancer symptoms tend to co-occur in clusters. The cluster comprising pain, fatigue, and sleep disturbance represents a common profile of cancer patients;14,15 additionally, loss of appetite and emotional distress often complicate this symptom cluster.16,17 Cancer-related symptoms, including pain, can contribute to long-term challenges faced by cancer patients and survivors. Using self-reported data from the 1998–2000 National Health Interview Survey, Hewitt et al.18 found that significantly more cancer survivors (n = 4878) than individuals without current cancer or history of cancer (n = 90,737) reported fair or poor health (29.8% vs. 10.5%), three or more other chronic medical conditions (3.2% vs. 0.9%), psychological problems (5.4% vs. 2.8%), functional limitations (58.1% vs. 28.5%), and inability to work because of health issues (16.8% vs. 5.0%). The psychological functioning of cancer patients is influenced by several factors: emotional distress associated with the diagnosis, treatment-related distress, fear of recurrence, impact on relationships, and stress associated with physical and emotional challenges of the disease. The magnitude of the psychosocial toll exacted by this combination of stressors has gained increasing recognition over recent years, culminating in the 2007 publication of an Institute of Medicine (IOM) report, Cancer Care for the Whole Patient: Meeting Psychosocial Needs.8 The prevalence of psychological distress among cancer patients varies depending on cancer type, time since diagnosis, prognosis, degree of impairment, and amount of pain.8 Zabora et al.19 reported

a 35.1% overall prevalence of psychological distress in a broad sample of cancer patients (n = 4496); prevalence rates ranged from 43.4% for lung cancer to 29.6% for gynecological cancers. The manifestation of cancer patients’ psychosocial distress is diverse and includes clinical diagnoses of depression,20 adjustment disorders,21 and anxiety disorders (e.g., posttraumatic stress disorder22,23 ). Subclinical psychological symptoms frequently experienced by cancer patients include anxiety, mood disturbance, fear, body image concerns, communication strain, and interpersonal issues with family members.24 There is a clear relationship between cancer pain and psychological distress; in a systematic review, Zaza and Baine25 identified a consistent literature linking the symptoms with 14 of 19 studies demonstrating that higher levels of distress were associated with higher levels of pain, regardless of scales used or setting. Interestingly, in a logistic regression analysis using multiple possible predictors of quality of life, emotional functioning, and pain at 3 years post diagnosis, pain was the only predictor of emotional functioning.13 Cancer pain confronts patients in the context of both multiple co-occurring symptoms and various psychosocial concerns, making it more difficult to navigate issues and often compounding psychological distress. Pain intensifies patients’ distress and suffering; in patients with lifethreatening diseases such as cancer, pain may exacerbate the debilitating effects of the disease, foster hopelessness and fear, and diminish the patient’s ability to adhere to treatment plans.26

Four psychological interventions for cancer pain Pain coping skills training The hallmark of pain CST is its insistence that learning to cope with pain is a skill that can be acquired and mastered like any other skill.27 These protocols structure the course of treatment in ways that maximize opportunities for skill development.3 The training is conducted over a series of sessions. It begins with an introductory session that provides an educational rationale (e.g., the gate control theory) that helps participants understand that cancer pain is a complex experience that can influence and be influenced by thoughts, feelings, and behaviors. Patients are then introduced to a menu of coping skills that can be used to enhance their abilities to control pain by changing their thoughts, feelings, and behaviors. Coping skills frequently included on a menu include relaxation training, imagery, activity pacing methods, pleasant activity scheduling, problem solving, and cognitive restructuring. In each

psychological interventions for cancer pain subsequent session, systematic instruction and practice are provided, with a specific skill drawn from the menu. For each skill, a rationale is given that explains the basics of the skill and how it can be applied to maximize pain control. This is followed by therapist-guided practice with the skill and immediate, corrective feedback. The session ends with patient and therapist setting goals for home practice with the skill. Home practice goals can be divided into two basic groups: 1) goals focused on basic skills building (e.g., practicing at home with a relaxation tape for 30 minutes each day), and 2) goals related to practicing in challenging pain-related situations (e.g., applying what one has learned about relaxation to control pain that occurs while climbing stairs at the local mall). Patients’ experiences with home practice goals are systematically reviewed during subsequent training sessions, and successes and problems are noted. To enhance patients’ confidence in their abilities to control pain, patients are taught problem-solving methods for identifying and overcoming obstacles to implementing learned coping skills. At the end of training, patients typically develop a coping skills maintenance plan that outlines, for example, goals for weekly practice, a plan for dealing with pain flare-ups, and key short- and long-term goals. Dalton et al.28 tested the efficacy of two pain CST protocols (standard and tailored) in managing pain in 131 patients suffering from persistent cancer pain. In this study, patients were randomly assigned to a standard pain CST protocol (similar to that described earlier), a tailored pain CST protocol (that attempted to match specific skills taught to the needs of the patients), or a standard care control condition. All training was carried out in five 1-hour face-to-face treatment sessions. During the study, patients continued to receive the pain medications provided as part of their typical care. Data analyses revealed that both CST protocols were found to be beneficial when compared with standard care. The timing of these benefits, however, differed in the two CST conditions. When compared with the standard pain CST protocol, the tailored coping skills protocol produced a broader range of immediate benefits (i.e., posttreatment improvements in pain, pain interference with sleep and other activities, and confusion). When compared with the tailored coping skills protocol, the standard pain CST protocol patients showed greater long-term improvements (i.e., improvements at 6 months’ follow-up) in terms of reduced pain, lower symptom distress, mental quality of life, and Karnofsky performance status. Taken together, these findings suggest that, when compared with usual care, either standard or tailored pain CST protocols can have beneficial effects in managing persistent cancer pain.

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CST can be incorporated into more comprehensive rehabilitation programs for cancer patients. Berglund et al.,29 for example, conducted a randomized clinical trial of a comprehensive intervention that combined information, physical training, and training in coping skills. Among the skills included in the training were training in relaxation, distraction, cognitive techniques, and problem solving. When compared with a standard care control group, patients receiving the comprehensive intervention showed significant improvements in pain at 6 months’ follow-up. They also showed significant long-term improvements in terms of strength. Of the psychological interventions used to manage cancer pain, pain CST is probably the most widely available. This training often is provided by psychologists trained in cognitive–behavioral therapy who are affiliated with pain treatment centers. Although some studies have shown pain CST to be effective for cancer pain, not all have.2 The overall number of randomized clinical trials of pain CST, however, is small, and a definitive conclusion regarding the efficacy of this approach remains to be determined. Partner-assisted interventions for cancer pain Cancer pain is a major concern not only for the cancer patient, but also for the patient’s loved ones. Partners of patients with cancer pain worry about their ability to help the patient manage cancer pain30 and are more likely to experience tension, depression, and mood disturbance than partners of cancer patients without pain.31 Challenges of caregiving for patients with chronic illnesses may put partners at risk for impaired immune responses, hypertension, and other health challenges.32 Understandably, these caregiver responses to a patient’s cancer pain may, in turn, influence the patient’s responses and adjustment to his or her own pain. Fortunately, several novel psychologically based cancer pain treatments have been developed in recent years that include both the cancer patient and his or her partner. Two major approaches have been used to integrate partners into psychosocial interventions for controlling cancer pain and distress: partner-assisted and couples-based interventions.33 A partner-assisted approach focuses on the patient, and the partner’s role is to serve as a coach who assists the patient in learning symptom management skills. A couplesbased approach focuses on both the patient and partner, and treatment is designed to improve the couple’s interactions around a specific concern, such as pain. Partner-assisted and couples-based psychosocial interventions for cancer pain have the potential to provide benefits to the patient and

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partner through biological pathways (e.g., reduction in pain, physiological arousal, and stress hormones), psychological pathways (e.g., changes in thoughts, attitudes, and beliefs), or social pathways (e.g., interactions with the partner and others).1 To date, most partner-assisted and couples-based interventions for cancer pain and other symptoms have been based on CST (as described earlier) and tailored to include both the patient and the partner. Several preliminary studies have provided data suggesting that these interventions are promising, and several large randomized studies are currently underway to examine the efficacy of partner-assisted and couples-based interventions for cancer pain. In an early study of partner-assisted intervention for cancer pain, Keefe and colleagues34 tested the feasibility of a partner-assisted pain management protocol in terminally ill cancer patients (N = 78). The protocol integrated information about cancer pain with systematic training in cognitive and behavioral pain coping skills. Three sessions were delivered by a registered nurse to the patient and partner in their own home. The patient–partner dyads were given a rationale for training in partner-guided pain management techniques and then systematically trained in three coping skills: relaxation, pleasant imagery, and activity pacing. Partners were trained how to serve as a coach to help them better guide the patient in his or her use of the learned skills and to prompt and encourage the patient’s use of pain coping skills. Patients in this study were very sick, many were actively dying, and a number were unable to complete the study because they were too sick or had died. Despite the severity of the patients’ condition and the demands experienced by the partners during this time, data analyses showed that the protocol produced significant increases in partners’ ratings of their self-efficacy for helping the patient control pain and for controlling other cancer symptoms, and a trend (P = .06) toward reporting lower caregiver strain compared with those in the usual care control condition. Although patients showed improvements in their usual pain and social/family well-being, the small sample size in this pilot study provided insufficient power to detect statistically significant effects on these outcomes in these terminally ill patients. Taken together, these results suggest that partner-guided pain management training may be beneficial in the context of cancer pain at the end of life. They also suggest that enrolling and training patients at the very end of their lives, when they are very sick, is challenging and that interventions are required earlier in the disease trajectory. Investigators in our laboratory are involved in several ongoing studies to examine how dyad-based interventions

can decrease cancer pain and cancer-related distress for both cancer patients and their partners. One of these trials is evaluating the efficacy of a comprehensive partner-assisted CST intervention in managing treatment-related symptoms, including pain, in early-stage lung cancer patients and their partners. This five-session intervention systematically trains partners and patients in coping skills for managing pain, including relaxation, imagery, calming selfstatements, activity pacing, symptom monitoring, and communication skills. Participants are taught to problem solve for current problems, and also to anticipate future problems that might arise during the course of their cancer. Patients and their caregivers are then encouraged to jointly practice the skills they have learned in their daily lives. Baseline data from this study suggest that patients and partners generally have low self-efficacy for managing pain and that higher self-efficacy is related to better adjustment to the disease.35 It is expected that patients and partners who receive pain CST will increase their self-efficacy and thus report better adjustment to disease and cancer pain. A second ongoing trial being conducted in our laboratory is testing the efficacy of a partner-assisted emotional disclosure protocol for patients with advanced gastrointestinal cancer in improving patient outcomes (e.g., pain), partner outcomes (e.g., emotional distress), and relationship outcomes (e.g., marital satisfaction). This protocol trains the patient and partner in methods to help patients disclose their cancer-related concerns and to help patients and partners increase the level of emotional support they receive from their partner. The partner-assisted emotional disclosure protocol consists of four weekly 45-minute face-toface sessions attended by the patient, the partner, and a therapist. The first session focuses on skills to facilitate the patient’s disclosure, and the subsequent sessions include therapist-facilitated communication in which the patient is encouraged to spend 30 minutes talking to his/her partner about his/her cancer-related concerns. Couples-based intervention has been applied widely and successfully to several problem areas (e.g., alcohol abuse, agoraphobia, smoking cessation36,37 ). Despite the challenges faced by partners of patients with cancer pain, limited work has been done examining the efficacy of couples-based interventions targeting cancer pain. Baucom and colleagues38 have developed a couples-based intervention entitled “CanThrive” and have applied it to breast cancer patients and their partners. CanThrive is based on cognitive–behavioral interventions and teaches patients and partners relationship skills that can help them cope with the significant challenges, including pain, associated with a breast cancer diagnosis. A key

psychological interventions for cancer pain component of CanThrive is to assist couples in providing each other with emotional and practical support by teaching important communication and problem-solving skills. Pilot work that has applied this intervention suggests that it has a positive impact on pain and other physical symptoms experienced by breast cancer patients.39 Persistent cancer pain is psychologically and physiologically stressful for patients and their partners. Interventions that either 1) provide partners with additional caregiving skills, such as pain management (e.g., partner-assisted interventions), or 2) provide both the patient and partner with pain coping skills (couples-based interventions) may decrease the impact of cancer pain for both the patient and the partner. To date, there has been limited empirical investigation of partner- and couples-based interventions for cancer pain. However, available evidence and results from other areas of chronic pain (e.g., osteoarthritis1 ) have prompted several rigorous trials of dyad-based cancer pain interventions. Preliminary results from these trials provide some support for these interventions, and it is expected that long-term data will provide important information on how best to implement these interventions so as to enhance their effects on patients with cancer pain and their partners. Hypnosis and guided imagery for cancer pain Documented reports of the use of hypnosis in pain management date back to the mid-1800s.40 Over the past several decades, reports of the use of hypnosis to relieve pain have appeared in the areas of obstetrics,41 dentistry,42 burn care,43 and cancer.44 During the past 5 years, hypnosis has become more widely used by clinical psychologists who specialize in pain management. When hypnosis is used for pain control, a trained hypnotist suggests that the patient experience changes in sensation, perception, or cognitions that can alter the experience of pain.45 The process of hypnosis is designed to heighten patients’ ability to focus their concentration and reduce peripheral awareness. Patients having pain who are hypnotized typically experience relaxation, an attitude of nonjudgment, and dissociation from the pain. Hypnosis sessions for pain management generally entail an induction phase and a suggestion phase. During induction, the patient is guided through a sequence of calming images or statements. A common induction image is that of the staircase; the hypnotist instructs the patient to imagine him/herself at the top of a staircase and steps him/her slowly down the stairs so that by the time he/she reaches the bottom, he/she is at a level of relaxed awareness. Following

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induction, the hypnotist makes suggestions to the patient, such as that he/she will experience less pain, lower stress, greater vitality, and increased self-efficacy.46 Syrjala et al.,44 studying the use of hypnosis for cancer pain, provided a basic template for hypnosis in the research environment. In a pre-hospital training session, the therapist explained hypnotic induction, described the benefits of hypnosis for pain control, and addressed patients’ concerns about hypnosis. Hypnosis sessions were conducted during two pre-hospital sessions, taped, and given to the patient to use in daily practice. Sessions combined relaxation with visual, auditory, and kinesthetic imagery tailored to each patient’s preferences; no single standardized imagery protocol was used. Inpatient sessions were taped for the patient’s use between sessions. Suggestions targeted reduction of treatment-related pain, as well as of nausea and emotional response to symptoms. Throughout all sessions, the hypnotist interspersed phrases related to health, well-being, self-control, and coping. Patterson et al.43 described a 25-minute hypnosis protocol for pain in burn patients, in which patients were instructed to rest comfortably in their beds and to imagine a staircase with 20 steps. They were directed to see themselves descending the staircase; suggestions for increasing comfort and relaxation were interspersed with instructions to descend another step. When they reached the bottom of the staircase, participants listened to statements intended to elicit confusion and amnesia, and then were given posthypnotic cues for relaxation and comfort during subsequent procedures expected to be painful. At the end of the suggestion phase, the hypnotist touched the patient’s shoulder or forehead in a specific way; participants received the instruction that when their nurse touched them similarly during a procedure, they would experience a deep level of comfort. The hypnotist then counted back up the steps to return the patient to normal consciousness. Although the evidence base until recently has been scant, largely comprising pediatric studies and assorted low-quality trials, recent investigations are demonstrating improved methodology and examining applications of hypnosis in adult populations. A trial by Schnur et al.47 randomly assigned excisional breast biopsy patients (n = 90) to receive either a 15-minute presurgery hypnosis session or attention control session. Patients in the hypnosis group had significantly lower mean values for emotional upset, depressed mood, and anxiety and significantly higher relaxation levels than did controls. Montgomery et al.46 conducted a meta-analysis of controlled studies of hypnosis for surgical patients (n = 20) and reported that participants

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in hypnosis treatment groups had better outcomes, including pain and pain medication, than did 89% of patients in control groups. Guided imagery is another way of using verbal directions to gently encourage the patient to refocus his/her attention away from a symptom, such as cancer pain, to cultivate a relaxed state of mind and to achieve a sense of physical and emotional well-being.3 In guided imagery, the patient, rather than the therapist, creates the specific visual or perceptual images. Commonly used techniques are picturing oneself in a favorite place and imagining the sounds, sights, smells, and feelings associated with being there; visualizing a cool blue light erasing the hot red pain of inflammation and pain; forming a mental picture of the cause of the pain, such as a tumor pressing on a nerve, and imagining the change that would relieve the pain, such as the tumor shrinking away from the nerve; or picturing oneself in a situation in which he/she is totally pain-free and well, such as mentally reenacting the pleasure, well-being, and positive sensations of one’s wedding day. In the clinical or research setting, guided imagery sessions involve a trained practitioner verbally leading the patient through an imagery technique or script, either one on one or in a group context. Audiotaped recordings of guided imagery scripts also are readily available through standard media sources and are used frequently by individuals in the home setting. Lyrical or poetic wording, fantasy and imagination, and background music often are incorporated into imagery sessions to amplify the patient’s sense of relaxation and to help free his/her mind from other thoughts.48,49 Guided imagery interventions in oncology have focused on four areas: pain management, surgical outcomes, quality of life, and immunity.50 Techniques tailored for the cancer patient with pain might direct his/her thoughts to the location of pain and instruct him/her to visualize a healing scenario; specific images will vary from one patient to another, depending on the individual’s personality and preferences. Scripts associated with guided imagery sessions may address the patient’s fears and concerns, provide positive affirmations to bolster self-efficacy for pain management, and encourage new pain coping behaviors.51 The duration of guided imagery audiotapes that have elicited a response in research studies has ranged from 12.5 to 21.5 minutes;52,53 a standard study duration is 6 weeks. Although anecdotal evidence suggests that cancer patients respond well to guided imagery, it is difficult to attribute specific outcomes to this modality because it is usually implemented in combination with other therapies, such as relaxation exercises or analgesics. A 2005 systematic review of randomized controlled trials using guided

imagery as the sole adjuvant therapy identified only six studies; poor methodological quality and discrepant results prevented the drawing of definitive conclusions.48 However, certain data intriguingly suggest that guided imagery may have effects worth exploring. Functional MRI studies have found that individuals may show affective, behavioral, and/or psychophysiologic responses when using imagery in the absence of a physical stimulus.54 A small uncontrolled study (n = 20) of diverse medical patients, including cancer patients, reported that all participants who followed a guided imagery intervention experienced a significant decrease in white blood cell count.55 Comprehensive yoga-based interventions Although yoga is a comprehensive philosophy, lifestyle, and approach to physical health and fitness, most Western styles of yoga emphasize the latter aspect. Controlled trials of such physically based yoga interventions suggest that the gentle poses and stretches they entail can help patients suffering from persistent pain. These sorts of yoga interventions have been demonstrated to positively affect pain and range of motion in patients with osteoarthritis of the hand;56 pain, functional disability, and pain medication usage in chronic low back pain patients;57,58 and pain and grip strength in patients with carpal tunnel syndrome.59 Recently, there has been growing interest among psychologists in comprehensive yoga interventions that comprise a wider range of yogic philosophy and practices – such as meditation, breathing techniques, inward gaze, selfawareness, mindfulness, and service. Such comprehensive yoga-based interventions have proven efficacious in alleviating diverse concerns such as chronic pain,60,61 asthma,62 caregiver distress,63 and anxiety disorders.64 A recent randomized controlled study conducted in our laboratory tested the effects of a comprehensive yoga-based protocol for pain management in a sample of metastatic breast cancer patients.65 The study protocol was built on traditional yogic philosophy, embodied in Kripalu and other schools of yoga, which views the body as a vehicle for accessing spirit and seeks to exert profound effects on the mind and emotions through integrated physical/mental practice. The protocol combined gentle stretching postures (asana) with breathing exercises (pranayama), meditation techniques (dhyana), self-study (swadhyay; e.g., cultivation of a nonjudgmental attitude or observation of one’s reactions to life events and challenges), and group discussions (satsang; e.g., discussion of experiences with a home-based yoga practice). The yoga-based pain management intervention was conducted in eight 120-minute weekly group

psychological interventions for cancer pain sessions (four or five patients per group) jointly led by a certified yoga instructor and a clinical health psychologist; a physician assistant or nurse attended each session to address any medical concerns that might arise. Participants were encouraged to spend at least 10 minutes per day practicing yoga at home, and applications of yoga to daily living (e.g., repeating affirmations of acceptance during intervals of pain) were assigned each week. Patients attended a mean of seven of eight sessions (range, five to eight) and reported practicing 21 minutes per day (standard deviation, 11 minutes). Data from this pilot study revealed significant improvements in daily invigoration and acceptance as well as trends toward improvement in pain and relaxation. Same-day assessments indicated that greater yoga practice was significantly associated with decreased pain, increased invigoration, and increased acceptance. Next-day assessments indicated that on the day after a day during which participants practiced more, they experienced significantly lower levels of pain and fatigue and higher levels of invigoration, acceptance, and relaxation. Several aspects of this pilot study protocol make it an instructive case example for clinicians interested in applying yoga as a pain management strategy and maximizing its benefit for their patients. First, use of a comprehensive yoga training protocol, as compared with a solely physical yoga protocol, not only results in better pain management, but also improves other major symptoms, such as distress and fatigue, that may moderate the pain experience. Second, the yoga-based pain management protocol used illustrated handbooks and CDs to facilitate regular home yoga practice, thus exploiting the dose/response relationship that has been demonstrated between the quantity of patients’ home yoga practice and improvements in their symptoms.65 Third, as should be the case in any highquality yoga instruction, asanas (yoga poses) were selected and adapted in consideration of the needs, challenges, and capacities of participants. Asanas can be tailored for use in virtually any setting and population; an example of adaptation of yoga for specific populations is the use of chairbased exercises to accommodate the physical limitations of hospital patients or of individuals attending classes at senior centers; yoga-based routines are available for people as diverse as airplane travelers, office workers, and athletes. Yoga props – chairs, blankets, blocks, and straps – afford the instructor a high degree of latitude in modifying poses for a range of individual circumstances and challenges. Fourth, the pilot study intervention was based on a standardized manual.65 Yoga materials have proliferated during recent years as the popularity of yoga has mushroomed; the public now

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has access to an abundance of yoga videotapes, audiotapes, books, magazines, classes, programs, and retreats. For clinicians seeking to assist their patients through incorporation of yoga into treatment plans, the challenge may lie in knowing which yoga options best suit their patients and how a yoga practice can be implemented in a safe and effective manner. In working with cancer patients experiencing pain, it is best to refer to or engage only well-trained and certified yoga instructors; those who have graduated from a yoga therapy program may be particularly well suited, and protocols that have proven effective for cancer pain management are available.

Controversies In this section, we review three controversial issues that arise in applying psychological interventions to cancer pain management. These include the therapist background and level of training needed to provide these treatments, the amount of ongoing supervision/treatment monitoring required to ensure treatment fidelity, and the importance of skills rehearsal as a critical treatment component. Therapist background and training One of the most controversial questions is, Who should deliver psychological interventions to patients having cancer pain? Psychological treatments for pain are typically delivered by individuals with an educational background and training in psychology.3 Most often, this means they are delivered by experienced doctoral-level clinical psychologists working in specialized pain treatment centers. Arguments for using highly trained psychologists include the fact that psychologists are familiar with the theoretical underpinnings and research literature on these interventions, often have done postdoctoral training in how to apply them to medical populations, and are equipped to deal with psychological problems that might arise in the patients being treated.3 There also is evidence that the effect sizes for psychosocial treatments delivered by psychologists are larger than when the same treatments are delivered by nonpsychologists.66 The problem is that most cancer patients with pain have limited to no access to psychologists with expertise in pain management. Unless a patient has a significant psychological problem (e.g., diagnosable psychiatric disorder), insurance carriers rarely cover the cost of psychological interventions for pain control in cancer patients.3 There is growing interest among nurses in using psychological interventions in cancer pain management. Many of

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the randomized clinical trials of psychological pain protocols cited in this chapter have been conducted by nurses and feature the use of nurses as interventionists. There are a number of reasons that nurses may be particularly appropriate providers of psychological interventions for cancer pain management. First, nurses are routinely involved in educating cancer patients about how to manage their cancer pain. Incorporating education about psychological pain management approaches fits well with this role. Second, nurses have much greater access to cancer patients with pain than do psychologists. This means that many more cancer patients could receive psychological interventions. Third, with increased access comes the opportunity to introduce psychological interventions much earlier in the course of a patient’s pain trajectory. Such early intervention could prevent maladaptive responses to pain from becoming more entrenched and thus more difficult to modify. Finally, having nurses deliver psychological interventions is much less costly than having the same intervention delivered by psychologists. Problems in relying on nurses to deliver psychological treatments also are apparent. These include the fact that they typically lack depth of background and training in these interventions, do not have access to ongoing supervision, and may be ill equipped to recognize and manage adverse psychological effects that might occur. At this point, it seems fair to conclude that if psychological interventions are to have a major impact in cancer pain management, they will need to be delivered not only by psychologists, but also by nonpsychology providers. It may be that nurses or other nonpsychology providers will be most successful if they restrict their focus to certain interventions (e.g., training in relaxation, imagery, activity pacing, yoga) that require less formal training in psychology. Psychologists should play a more active role in either directly providing services or intensively supervising the delivery of psychological interventions such as hypnosis, cognitive restructuring, and partner-assisted interventions. Ongoing supervision/treatment monitoring and treatment fidelity Another controversial issue is how much ongoing supervision and monitoring of treatment sessions is needed to ensure that psychological interventions show high treatment fidelity.1 Treatment fidelity refers to delivering a treatment as it was intended to be delivered. Treatment fidelity may be compared with the quality control procedures put in place by a drug company to ensure that the pill taken by a patient contains the proper formulation of ingredients.

One would not expect a pill that contains only half of the active ingredient to have the same effect as one that contains 100% of the active ingredient. Likewise, the argument is made that psychological interventions that are delivered in a fashion that is not fully true to the original protocol might not be expected to have as strong an effect. When psychological interventions are used, the primary quality control procedures involve tracking what goes on in sessions (usually by means of audiotaping treatment sessions) and providing feedback to interventionists in supervision sessions. In the absence of such procedures, the phenomenon of therapist drift (i.e., therapists reverting back to their usual style of providing treatment) tends to occur. Optimal approaches to quality control involve having a supervisor review audiotapes of every treatment session, having independent raters code a portion of audiotapes (e.g., 20% is common) and rating whether each of the treatment components was delivered and whether the delivery was done in a competent fashion, and then providing feedback to therapists on the information gathered. Such procedures are routinely incorporated into methodologically rigorous clinical trials of psychological interventions. The controversy arises when psychological interventions for pain management are delivered in a clinical setting where it may seem unnecessary to implement such quality control procedures. In many settings, the only supervision in these methods takes place during an initial training phase (often a 2-day workshop). Interventionists are then left on their own to apply the intervention protocol as they see fit. Although some scrupulous interventionists may be able to maintain a high level of treatment fidelity after such brief training, most cannot. The end results are therapist drift, a treatment protocol that can be considered a “watered-down” version of the original, modest benefits for the patient in terms of improvements in pain and other outcomes, and a sense among treatment providers and others that the treatment is not that effective In this era of concerns about treatment costs, it is rare that arrangements are made to provide funds for procedures designed to enhance the fidelity of psychological treatments for cancer pain. This is unfortunate and wastes valuable therapist and patient time. Those involved in delivering and reimbursing treatments for cancer pain need to be aware of this problem. No one would consider administering pain medications to a patient if it was unclear whether the drugs had been subjected to rigorous quality control procedures. Why should we settle for psychological interventions for cancer pain being delivered in a way in which quality control is not being considered?

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Skills rehearsal

Conclusions

Another controversial issue is how central a role skills rehearsal should play in psychological interventions for cancer pain. Some argue that the essence of psychological interventions for cancer pain is acquiring and mastering specific skills (e.g., skills in relaxation, skills for managing one’s emotions in the face of increased pain, and skills for altering activity patterns to better regulate pain).1 If this is the case, then one should maximize the amount of treatment time that is devoted to the behavioral rehearsal of learned skills. In behavioral rehearsal,1 patients are provided with brief therapist instruction and modeling of the skill, a chance to practice the skill several times while being observed by a therapist, and therapist feedback on performance. The goal of behavioral rehearsal is to shape and reinforce patients’ abilities to apply the skill and to help them develop a sense of confidence that the skill can be useful in controlling pain. Most of the studies on psychological interventions in this chapter incorporated behavioral rehearsal as part of their pain treatment protocol. However, in some clinical settings, psychological interventions are being used for cancer pain management in a way that does not emphasize skills rehearsal as an essential component. By and large, these represent examples of “blended” interventions in which educational information on the medical management of cancer pain is combined with a brief introduction to one or more psychological techniques for pain control. The basic format of these interventions tends to be one of presenting information to patients with the goal of helping them become more informed and involved in their pain treatment. Because these interventions tend to be brief, it is often felt that little or no time is available for skills rehearsal. As a result, patients are typically provided with information, handouts, or possibly an audiotape on psychological techniques for pain control rather than actual skills rehearsal with these methods. A key factor driving the controversy about skills rehearsal is treatment cost.1 As the time available for treatment is compressed, therapists tend to focus on what they view as essential to treatment success. Taking time to rehearse a skill (e.g., imagery) may be viewed by some as less important than simply giving a patient information about that skill. Others would argue that skills rehearsal should be the focus because it is more likely to enhance self-efficacy for pain, which appears to be a key factor related to short- and long-term treatment gains in patients with persistent pain conditions. Future research is needed to determine how critical skills rehearsal is to the outcome of psychological interventions for cancer pain.

As evidenced by the release of, and publicity associated with, the IOM 2007 report Cancer Care for the Whole Patient: Meeting Psychosocial Needs,8 the importance of developing effective methods of psychosocial cancer care is now widely recognized. Likewise, subjective outcomes that are largely affected by psychological pain treatments, such as quality of life, are now accepted as important outcomes in oncology. Improvement in cancer pain outcomes likely will occur more rapidly when psychological interventions are incorporated into state-of-the-art medical/surgical treatment. A growing evidence base demonstrating the efficacy of a broad range of psychosocial interventions supports this contention. As in other areas of medical research, the field now faces the task of translation, that is, of advancing evidencebased psychosocial interventions for cancer pain into mainstream practice. Translation of evidence into practice will require 1) investigation of barriers to uptake, 2) strengthening of the evidence basis through additional studies, and 3) publication of research findings in well-respected and broadly circulated journals. The increasing availability of information on such interventions through print and online digests, as well as through traditional journal sources, will help clinicians learn of promising therapies. Nonetheless, psychological interventions will and should remain adjuvants in the overall cancer pain management plan; medications are and will remain the mainstay. Several factors warrant consideration when promoting psychological interventions for cancer pain in particular settings, patients, or populations. First, it is not yet clear whether groups with different sociodemographic characteristics may be differentially receptive to psychosocial interventions; this area deserves investigation. Choice of intervention, although founded on consideration of the evidence regarding efficacy, must take account of feasibility issues, including logistics and cost. Many psychosocial interventions initially can be taught to a patient and then continued by the patient on a self-management basis. Audiotapes and videotapes, print manuals, and electronic education and monitoring systems all present methods of achieving continuity and sustaining a psychosocial intervention without the need for additional clinic visits, clinician time, or cost. Interestingly, even for pain management interventions that seem dependent on the physical presence of the interventionist, home-based practice is critically important. Finally, it bears noting that psychological interventions for pain management often are used in combination; for example, guided imagery often is used to facilitate hypnosis. Studies

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exploring the potential amplification of effect through combining psychosocial interventions would provide interesting and clinically meaningful results.

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Rehabilitation medicine interventions jack b. fu, a ki y. shin, a and theresa a.b gillis b a

The University of Texas M. D. Anderson Cancer Center and The Helen F. Graham Cancer Center

Introduction Rehabilitation has become an increasingly prominent tool for cancer pain management. Generally speaking, rehabilitation may be defined as the process of restoration and maximization of quality of life through enhancing function and mitigating disability. A person’s function is influenced by abilities and limitations, and includes domains of physical health, emotional status, intellect/cognition, vocation and vocational activity, social activity, and role fulfillment. The burden of pain is manifested in an individual through suffering but also through impaired function, activity, and alterations in social roles and self-image. Successful pain management can improve mobility, function, and quality of life. Pain management is an important component in the successful rehabilitation of the cancer patient. Pain can limit one’s function. Conversely, rehabilitation techniques help reduce and manage pain. The pain management and functional improvement goals are never exclusive and frequently coexist for cancer patients throughout the course of the disease. Functionally oriented efforts may involve the application of strengthening, coordination, balance, and other training exercises; use of therapeutic equipment; and adaptive education. This chapter focuses on interventions directed toward pain management. Some movement-based therapies are used for pain management, although their more frequently recognized benefits are strength, coordination, endurance, and balance.

spinal cord injury, or amputation. This model is widely accepted in both lay and medical professional populations, and the course of functional recovery is somewhat predictable (Fig. 19.1). However, rehabilitation also plays a crucial role in chronic disease models, for which disability is more gradual, fluctuant in severity, and difficult to predict. Pertinent examples of these include rheumatologic disorders such as rheumatoid arthritis, neurologic disorders such as multiple sclerosis and Parkinson’s disease, and cardiopulmonary and vascular abnormalities, all of which may have waxing and waning courses of functional impairment requiring intensive rehabilitation or maintenance programs. Increasingly, rehabilitation is becoming recognized as an important part of cancer patient care. However, there is still lack of availability. The diagnosis of cancer still holds a mystique for many rehabilitation professionals, who equate it to a death sentence despite an overall improving survival rate. During their training, many therapists and physiatrists have limited exposure to patients receiving cancer treatment

Rehabilitation philosophy The rehabilitation physician’s expertise is based on musculoskeletal and neurological anatomy and pathophysiology. Rehabilitation has traditionally been viewed as an intervention used after a chronologically discrete onset of disability, such as may follow a cerebrovascular accident, traumatic 354

Fig. 19.1. Rehabilitation intervention following a discrete pathophysiologic event such as traumatic spinal cord injury, cerebrovascular accident, traumatic brain injury, or amputation.

rehabilitation medicine interventions and therefore have little experience to refute their erroneous beliefs. Anxieties provoked by these beliefs and awareness of their own knowledge deficits lead some rehabilitationists to exclude those with cancer diagnoses. A recent survey found that half of American rehabilitation hospitals treat fewer than 10 brain tumor patients each year.1 There is increasing interest in adding specific oncology training to therapy school curricula and physical medicine and rehabilitation physician residency education. Oncology professionals and rehabilitationists may be hesitant to offer rehabilitation because of concerns that a “poor” prognosis negates the need for rehabilitation concepts. Because “cancer” encompasses a multitude of tumor pathologies and patient-specific factors, such as stage at diagnosis, tumor response to prior treatment, and morbidity from prior treatment, as well as perhaps change in tumor behavior over time, rehabilitation performance may be difficult to predict. The typical functional ability curve, as shown in Fig. 19.2, often does not apply to the cancer patient. However, cancer rehabilitation patients have been shown in numerous studies to benefit to the same degree as traditional rehabilitation patients.2–4

Fig. 19.2. Variability in functional abilities after cancer diagnosis compared with more predictable functional recovery after traumatic brain injury. Cancer diagnosis, histopathological factors, and individual patient characteristics create much more uncertainty in rehabilitative management. In traumatic brain injury and many other rehabilitative diagnoses, the severity of functional limitation may vary, but the recovery course and stability of function are more consistent.

355 Understanding these factors as much as possible for a specific patient remains necessary to create a rehabilitation plan that takes into account the whole patient. In cancer rehabilitation, life expectancy, quality of life, home setting, support system, current and expected functional status, and physical strength are all taken into account. When a patient with stage IV carcinoma of the lung with liver metastasis develops a thoracic paraplegia secondary to a spinal cord metastasis, rehabilitation efforts should be pursued. Typical nononcologic spinal cord injury rehabilitation goals that include gait training, planning for work reentry, and prescription of an electric wheelchair and van lift to allow a return to employment would usually be inappropriate because of the length of time required to reach those goals relative to expected survival. In a cancer rehabilitation patient with short life expectancy, the emphasis is placed on how to get the patient home, into a safe environment. Appropriate rehabilitation efforts might include training in safe transfers from bed to a wheelchair to avoid injury, patient or family/caregiver education regarding protection of insensate skin, bowel and bladder management, and bathing strategies. Independent mobility within the home might include an electric wheelchair if resources permit; more often, a lightweight, well-fitted wheelchair with removable arm and leg rests may be rented. An understanding of the patient’s available resources and disease process can aid the cancer physiatrist in formulating and prioritizing a rehabilitation plan. There also are biases and misconceptions regarding cancer-related disability among patients, caregivers, and the general public. Many cancer patients are unaware that functional decline is a very real possibility with cancer and its treatments. Often patients and their families simply focus on survival and may overlook quality of life. Functional decline and pain often are accepted as part of the cancer diagnosis. Improved patient and family education regarding the functional consequences on the part of the medical community and the media is necessary. Oncology health care professionals also often overlook functional declines for many reasons. Many oncologists and surgeons have minimal exposure to rehabilitation during their training and careers. Understandably, for many oncologists the primary focus is survival and the patient’s disease rather than one’s functional deficits caused by the disease and treatments. Conversely, many patients are more focused on survival during their physician visits and may not mention functional problems. Rehabilitation interventions may be inaccurately perceived as expensive care, despite the fact that a therapeutic joint injection or a series of physical therapy treatments may cost less than a 1-month supply of an

356 analgesic medication for a painful joint. These treatments usually are less expensive than “routine” diagnostic studies, many of which are obtained serially during the course of treatment. Most frequently, however, the oncology treatment team fails to recognize a problem that is amenable to rehabilitation in their patient.5 As cancer treatments improve and patients survive longer as a result of slower disease progression, better disease management, or cure, a chronic disease model for cancer rehabilitation will become more widely understood. This model entails use of rehabilitation interventions in gradually increasing proportions as impairments increase because of cancer or cancer treatment.6 A second appropriate model incorporates repeating and, in some cases, cyclical, brief bursts of rehabilitation after acute exacerbations of disability (Fig. 19.3). Particularly challenging to oncologists, physiatrists, and other rehabilitation professionals, and especially to patients, is the reality that cancer pain, functional impairment, and large systemic tumor burden often go hand in hand. These functional impairments are multifactorial. Tumor metastases to the neurological and musculoskeletal systems

Fig. 19.3. Patterns of rehabilitation intensity between time of cancer diagnosis and end of life. Rehabilitation interventions are defined as functional restoration (mobility, activities of daily living, therapeutic exercise), education, adaptive equipment, ambulatory aids and orthoses, and pain management.

j.b. fu, k.y. shin, and t.a. gillis create direct and severe functional impairments. Other compromised systems (e.g., respiratory, gastrointestinal, integumentary) also limit function through symptoms of discomfort or inconvenience. Impairments also may arise as a consequence of medical treatments (e.g., steroid myopathy and chemotherapy-related neuropathy) and surgical procedures (e.g., spinal fusion, cordotomy, or use of epidural anesthetics). Patients with cancer often face disability as a direct result of their treatment. Limb salvage procedures, amputations, laryngectomies, and other surgical procedures leave readily identifiable deficits. Less frequently identified but often equally disabling consequences of treatment include joint contractures, lymphedema, leg length discrepancy, and osteoporotic fractures. The cancer patient’s comorbidities also must be considered. Peripheral vascular disease, fibromyalgia, diabetic neuropathy, osteoarthritis, visual and auditory losses, and cognitive fragility are frequently encountered. Although unrelated to the cancer diagnosis, recovery of independence may be slowed or prevented by these factors. In other cases, the underlying comorbidity is exacerbated by the cancer and/or its treatments. For example, a patient with a history of osteoarthritis undergoes a prolonged hospital intensive care unit stay with steroid and chemotherapy treatment for his lymphoma. He develops steroid myopathy, deconditioning, and peripheral neuropathy. Because of the weakening of his leg musculature, his osteoarthritic knee pain actually becomes more prominent.7 A rehabilitation plan may include strengthening exercises and training the patient and caregiver regarding the safe use of ambulatory aids (e.g., walkers, canes, crutches), orthoses and prostheses, adaptive equipment (e.g., bath bench, elevated commode seat), wheelchairs, and transfer assist devices (e.g., lifts, sliding boards). Medical professionals such as physiatrists, physical therapists, and occupational therapists typically provide rehabilitation interventions. Nurses, oncologists, and many other care providers also use and reinforce these and related strategies. Ultimately, patients and caregivers learn to use these strategies, with some modification, in a self-maintenance program. The ultimate goal of all rehabilitation interventions is to maximize knowledge, self-care, and health so that the patient is empowered to function as autonomously as possible. Furthermore, it must be noted in cancer rehabilitation that functional improvement has quality-of-life ramifications, but decisions as to whether to pursue further cancer treatment often are based on a patient’s current functional status. A bedridden patient in most circumstances would not be offered further chemotherapy or aggressive surgeries.

rehabilitation medicine interventions Rehabilitation and pain management Rehabilitation care often has much to offer in the management of cancer pain. Over the past 10 years, pain management and musculoskeletal medicine have become more prominent in physiatry (rehabilitation medicine). A physiatrist (rehabilitation medicine physician) can assist in pain management in a number of ways. Although physiatrists frequently treat pain with medications, the nonpharmacological treatments physiatrists have to offer, the focus on the big picture, and the physiatrist’s knowledge of both musculoskeletal and neurological conditions provide this specialty with a unique approach to pain management. Physiatrists and therapists may use range of motion and stretching of specific soft tissue and muscle groups to relieve contractures, improve mobility and posture, and thus reduce discomfort. Restoring muscle balance and joint or spine kinetics enhances muscular efficiency and thus reduces fatigue. Modalities can generate beneficial effects on local areas of pain and may also serve as powerful pain modulators at both the spinal and cerebral levels. Massage, transcutaneous electrical nerve stimulation (TENS), acupuncture and acupressure, and thermal modalities (ultrasound, microcurrent, topical heat and cold) are postulated to influence pain perception through endogenous pain-modulating systems, as originally described in the gate-control theory.8 Direct effects on local tissues also are presumed to occur via alterations in blood flow and inflammatory cascades (see later). A physiatrist may also inject medications to assist with local pain relief. For patients with pain caused by direct tumor invasion, physical interventions are generally adjuncts to pharmacological management. Patients with advancing cancer who prefer rehabilitation approaches over opioid analgesic medications may have anxieties about drug use that must be explored by their physicians. Some nonpharmacologic interventions, however, may ease pain perception and aid patients even with the most severe cancer pain. Music, movement, and touch are recognized by patients as helpful in coping with discomfort, and although research in these areas is not robust, it is encouraging. Because of their simplicity and ease of use, these techniques tend to be overlooked. However, taking the time to introduce these to patients and families often results in a significant contribution to their quality of life throughout their course of disease, whether cancer is cured or controlled or death is drawing near. Musculoskeletal pain not related to tumor involvement is frequently very amenable to rehabilitation techniques and

357 often can correct the abnormality occurring. For example, physical therapy with an emphasis on core strengthening exercises can often cure a patient with muscular low back pain. Unfortunately, pharmacologic analgesia, which typically does not address the origin of the pain, is often used before rehabilitation in the medical community.

Skeletal pain Skeletal pain can be defined as pain that arises from the bone and articular surfaces. Examples of nonmalignant pain syndromes include fractures, rheumatoid arthritis, spondyloarthropathies (e.g., ankylosing spondylitis), spondylolisthesis, osteomyelitis, and osteoarthritis including spinal facet degeneration. These syndromes may occur in the patient with cancer. Cancer-related skeletal pain usually is related to bone metastasis. Radiotherapy and other primary treatments may be effective, and rehabilitative approaches should be considered as part of the overall strategy. In the cancer population, skeletal pain also may occur as a result of osteoporotic compression fractures of the spine and insufficiency fractures of the pelvis, which may be late sequelae of hormonal ablation (both estrogen and testosterone); long-term or frequent corticosteroid treatment of cancer; the use of FK506, cyclosporine, and other immunosuppressive medications;9–11 and/or local radiation treatment. Many cancer patients encounter more than one of these risk factors, and such fractures are not uncommon. Avascular necrosis is also an etiology of treatment-related pain. Rehabilitative options for management of these painful conditions may include use of bracing or casting to immobilize painful segments and cooling modalities to reduce acutely inflamed joints (although often poorly tolerated by rheumatoid patients). Therapists can teach patients how to reduce the amount and frequency of weight on a painful extremity and to use ambulatory aids such as crutches and walkers when lower extremities are affected. For patients with joint pain, bracing, isometric strengthening exercises of surrounding musculature, joint conservation techniques, and cooling modalities may be of benefit. Intra-articular injections of steroids and hyaluronate agents (such as hylan [Synvisc] for osteoarthritic patients) may be highly effective for severely affected joints. Osteoporosis management may require treatment with calcium, vitamin D, estrogen replacement for women and testosterone for men when not contraindicated, and/or bisphosphonate therapy (e.g., alendronate sodium). Alendronate has been shown to normalize the rate of bone turnover and increase bone mass.12 Essential rehabilitation

j.b. fu, k.y. shin, and t.a. gillis

358 treatments for osteoporotic patients include postural correction exercises; strengthening of the spine extension musculature; stretching of the anterior chest, neck, and abdominal muscles; and weightbearing exercises. Weight training, with weights gradually increasing from as little as 1–2 pounds, and weightbearing exercises (e.g., walking, tai chi)13 are also helpful for maintaining strength, enhancing bone density, and lessening the risk for fractures or additional fractures.14 Spinal flexion exercises and forceful forward bending or lifting of heavy weights from a flexed position must be avoided.15 A rigid spinal orthosis to prevent spinal flexion may be used to reduce the risk of vertebral fractures.

Neuropathic pain Neuropathic pain in a cancer patient is common and may be associated with direct tumor invasion, surgical damage, chemotherapy, radiation, compression neuropathies, paraneoplastic syndromes, infections such as zoster, or comorbidities. The pain is usually characterized as burning, electrical, shooting, or tingling. Neurological damage may occur at the spinal cord, nerve root, plexus, and peripheral nerves. Nerve conduction studies are useful when the cause of the neuropathic pain is unclear. Neuralgia is not uncommon among cancer patients, and phantom pains after amputation or mastectomy16 are recognized. Interventions include desensitization techniques such as massage, tapping, and patting the affected area, and TENS in hopes of modulating the pain at the spinal level. Compression by tight garments can ease perceptions of pain and are particularly useful for peripheral neuropathy and phantom limb sufferers.

Soft tissue pain Soft tissue pain is often ligamentous, tendinous, or muscular in origin. Nonmalignant pain may originate within muscles as a result of injury, inflammation, or overuse. Frequently, this cause of pain is overlooked in cancer patients. After ruling out bone metastasis, spinal cord compression, plexopathy, and other diagnoses detectable with imaging studies, the oncologist may be puzzled about how to proceed. Several diagnoses have been overused in a “wastebasket” manner because of this dilemma, including postthoracotomy syndrome and postmastectomy syndrome. In fact, many of these patients have rib or scapular motion limitations and not primarily neuropathic pain, and their pain may be resolved through rehabilitative treatment alone. The practitioner’s knowledge of musculoskeletal anatomy,

diagnostic skills, and knowledge of treatment options are key to formulating a successful treatment plan. Diagnosis of muscle dysfunction may be difficult, relying on palpatory skills to detect tissue texture changes and sometimes subtle range-of-motion limitations or postural deviations. However, thorough history taking and physical examination in association with knowledge of muscular anatomy and function can usually lead to the correct diagnosis. Research does support the notion that patients in pain experience changes in muscle activation. Surface electromyography (EMG) studies of patients in pain revealed failure of the dysfunctioning muscle to return to a quiet baseline electrophysiologic activity at the conclusion of movement, or a higher peak level of activity compared with paired nonpainful muscles.17 However, experimentally produced muscle pain causes suppression of EMG resting activity.18 When pain is thought to originate within a discrete muscle unit with a trigger point and its associated referred pain pattern, injection or dry needling may be chosen. If the pain is muscular, with dull, aching characteristics but without trigger point findings, and postural changes or range-ofmotion limitations are found, stretch or massage may be chosen. Aching pains thought to originate within a spinal segment’s sclerotome (vertebral body and its costal processes or neural arch) or its associated myotome may be treated through manipulation interventions.

Trigger points Myofascial trigger points have been described as hyperirritable spots, which are generally within taut bands of skeletal muscle or the muscle’s fascia.19–21 They give rise to referred pain (which differentiates them from the tender points of fibromyalgia) and often have associated autonomic phenomena, such as lacrimation, salivation, sweating, and erythema.22 They possess fairly uniform characteristics on examination (Table 19.1).23

Table 19.1. Trigger point characteristics

r r r r r r r r r

Sharply circumscribed spot of exquisite tenderness Local twitch response with snapping palpation Recoil or flinching (“jump sign”) with pressure Painful active or passive stretch of affected muscle Reduced range of motion or distensibility of affected muscle Painful contraction of affected muscle Reduced maximal contractile force Deep tenderness and dysesthesia referral Autonomic disturbance in reference zone (pallor, hyperemia, sudomotor, pilomotor activity with stimulation

rehabilitation medicine interventions Pain refers from an active trigger point into contiguous or noncontiguous structures, often but not necessarily within the same dermatome, sclerotome, or myotome innervated by a posterior spinal root.23 It is theorized that trigger points arise in areas of increased metabolic demand, reduced circulation, and local ischemia or in areas of focal nociceptor or mechanoreceptor hyperirritability after an initial injury to muscle fibers. The injury may be secondary to a traumatic event or to repetitive microtrauma. Trigger points may be activated directly by acute muscular overload or overuse, direct trauma, or cold. Activation also may occur indirectly through 1) protective postural responses to nearby intra-articular inflammation, arthritides, or other active trigger points; 2) referred visceral pain, with the trigger point found in the myotome shared by the same visceral innervation; and 3) emotional distress. Trigger points cause pain and stress in muscle fibers. When the stress increases, other trigger points may be activated. This is known as the “injury pool” theory.23 Trigger points are self-sustaining in that they do not resolve spontaneously, although they may become “latent” or less symptomatic with time, awaiting the next triggering event. They often are accompanied by sleep disturbance as well. Trigger points also may arise within scars, with different symptomatology; these refer burning, prickling, or lancinating pains locally and without referral patterns. There is no palpable neuroma or discrete mass at these sites.

Muscular imbalance and shortening In the absence of trigger points, pain also may arise from shortened muscles or soft tissues, which change the muscular balance of a joint. Any given muscle has an optimal resting length and an optimal dynamic length and must work harmoniously with surrounding muscles for movement. A muscle may be overstretched because of contracted soft tissues in its accompanying nearby joint or contracted antagonist muscles. Common causes in cancer patients include radiation and muscle spasms. An overstretched muscle fibril has poor actin–myosin cross-bridging within its sarcomere and, therefore, reduced contractility, resulting ultimately in reduced strength. Muscular injury and inflammation may arise with attempts to use the overstretched muscle against resistance. Foreshortened muscle also fails to have optimal actin–myosin cross-bridging and thus also has reduced strength. Foreshortened muscles place their antagonist counterpart muscles at suboptimal resting and active lengths, and restrict joint range of motion; this increases the risk of tendinous, ligamentous, and articular injury. Stretching encompasses manual techniques applied

359 by physical therapists, osteopathic physicians, chiropractors, and patients themselves. These interventions seek to move joints and muscles to restore optimal muscular length and joint mobility, thereby reducing pain and maximizing strength and function.

Somatic dysfunction Somatic dysfunction is a concept used by practitioners of manual medicine, including osteopathic physicians, chiropractors, and some physical therapists and allopathic physicians. It is defined as impaired or altered function of related components of the somatic (body framework) system; skeletal, arthrodial, and myofascial structures; and related vascular, lymphatic, and neural elements. The diagnostic criteria for somatic dysfunction include asymmetry of structure or function, impaired range of motion of a joint or region (either hypermobile or hypomobile), and tissue texture abnormality within the skin, fascia, muscle, ligament, or other structure.24 Treatment of somatic dysfunction is through manipulative or manual therapy, and its goal is the restoration of maximal, painfree movement of the musculoskeletal system in postural balance. Muscle strength testing, observation of physical symmetry during patient motion and at rest, and a thorough neurological examination are of critical importance to eliminate malignant etiologies for pain before use of manipulative therapy, owing to its high risks of severe injury.

Capsulitis, ligamentous and tendinous injuries Intrabursal and intra-articular injections frequently are helpful for temporary relief of pain from adhesive capsulitis of the shoulder as an adjunct to a physical therapy program,25 but should not be given more than once. Heating of musculature with ultrasound or more superficial methods promotes stretch of the capsule. Management of chronic bursitis also may warrant intrabursal corticosteroid injection. An acutely inflamed bursa may indicate a septic joint, and fluid analysis, including cell count, culture, and crystal detection, is warranted. Shoulder pain in plegic or paretic upper extremities (whether spastic or flaccid)26 is poorly understood. Anterior and inferior subluxation of the humeral head, shoulder– hand syndrome (complex regional pain syndrome), adhesive capsulitis or frozen shoulder, rotator cuff impingement syndrome, and bicipital tendonitis are common causes and frequently coexist. Modalities, orthosis and taped support of

360 the joint, gentle stretching of tight muscles, shoulder intraarticular injections, and antispasticity medications may be used. Ligamentous and tendinous pain usually arise through acute strains or tears. Diagnosis is usually made by history and sometimes MRI; joint instability is generally not apparent because of edema and protective subconscious inhibition (splinting) by the patient. Rest, ice, and immobilization are commonly used, and compression and elevation help reduce edema formation and accompanying pain.

Lymphedema Secondary lymphedema is a common cause of pain in cancer patients as a result of radiation treatments, lymph node surgical dissections, and/or lymphatic metastasis. The most common malignancies associated with secondary lymphedema include breast, melanoma, gynecologic, lymphoma, and urologic. Lymphedema can contribute to skeletal, neuropathic, and soft tissue pain. Rehabilitation treatment options include isometric exercises, manual lymph drainage, external pneumatic compression devices, compression stockings and multilayered bandage wraps. Decongestive lymphatic therapy and complete (complex) decongestive physiotherapy (CDP) incorporate these options into lymphedema management. In one study, lymphedema reduction using CDP averaged 59.1% in the upper extremity and 67.7% in the lower extremity.27 CDP reduction of excess lymphedema volume has been shown to improve pain.28

Hypertonia and spasticity Decreased function and pain are two interrelated sequelae in patients with central nervous system (CNS) disease. The etiology of CNS insult in cancer patients frequently is directly related to the tumor, procedures, and strokes. Spastic hemiparesis, spastic paraparesis, and cervical dystonia are frequently the result. Spasticity management may be indicated for function, hygiene, positioning, contracture prevention, and pain. Medications are often used but frequently are associated with undesirable side effects, most notably sedation. Therapists can perform serial casting and range-of-motion exercises and create special splints and orthotics to minimize the hypertonia with success in a motivated patient. In patients who have failed conservative treatments, botulinum toxin injections and nerve blocks have been shown to decrease spasticity while minimizing systemic side effects.29

j.b. fu, k.y. shin, and t.a. gillis Manual interventions Trigger point management Practitioners have found that needling a trigger point, with or without injections of saline or anesthetic agents, relieves the focal pain as well as the referral. Many clinicians also follow injections with stretch of the affected muscle and related muscle groups. Some clinicians apply forceful localized pressure to these points during massage, or use acupressure or acupuncture needle insertion in these areas. There is a correlation of 70% between classically defined acupuncture points and trigger points.30 The diagnosis of trigger points is specific to the characteristics described previously. It is intuitive but sometimes forgotten by rehabilitationists and pain management physicians that an area of tenderness and palpable nodularity may originate from metastatic foci within soft tissues. Therefore, needling techniques must be used with caution when the possibility of soft tissue metastasis is present, and avoided when the classically defined examination findings are absent. The risk of severe hemorrhage caused by needling also must be noted if the primary cancer is hypervascular in nature, as in the case of renal cell carcinoma. Compared with needling, directed stretching of the affected muscle(s) is more successful in obtaining relief and more useful for patients with numerous trigger points or multiple affected muscles, and it is noninvasive. Vapocoolant spray and ice massage may be used to distract the patient from the discomfort of the stretch and to reduce local blood flow and inflammation, as discussed later. Scar manipulation via massage, needling with acupuncture, ultrasound, or injections may inactivate these points.23 Injections may consist of short-acting anesthetic agents, botulinum toxin, corticosteroids, or simply dry needling. A randomized controlled trial compared ultrasound, massage, and exercise against sham ultrasound, massage, and exercise. After a 4-week treatment period, no benefit was detected for the ultrasound group, although both groups were improved over the control group. This study’s findings gave mild support to the role of massage in trigger point management.31 Further study comparing modalities, massage, and specific stretching interventions is needed, as massage alone is not the primary means of trigger point treatment.

Stretch and manipulation Osteopathic medicine was founded on the theory that disease arises from mechanical pressure on the nerves and

rehabilitation medicine interventions blood vessels of the spine, and that this pressure is caused by malalignment of vertebrae or the associated musculature and laxity or shortening (contracture) of those muscles. Chiropractic practice attends more specifically to the vertebral segments. Manipulative therapy may be defined as movement of a bone or joint in an attempt to improve its range of motion or its alignment with other structures. Practitioners of manual medicine identify and treat somatic dysfunction (see previously). The goal of manipulation is to restore maximal, pain-free movement of the musculoskeletal system in postural balance. Manipulation has been well accepted by the public.32 Despite a paucity of randomized controlled trials,33 these manual techniques are gaining acceptance among allopathic practitioners for the treatment of selected painful conditions. A recent small study of patients who underwent posterolateral thoracotomy for lung cancer, showed improvement in pain after manual therapy.34 However, osteopathic and chiropractic manipulation in the cancer population is controversial. Most literature from these disciplines describes cancer as an absolute contraindication to manipulative therapy because of concerns about metastatic involvement in the spine or epidural space.35 Little mention is made in the literature of actual examples of manipulation-induced complications in cancer patients, but theoretically the risks of neurological injury or skeletal injury exist. Because of these safety considerations, manipulative therapy should be considered appropriate for neuromyotomal or myofascial pains that arise from maladaptive, compensatory postural changes in areas not directly involved with primary or metastatic disease. In most manipulative therapy schemata, a painful joint is moved to its physiological tissue barrier and then beyond it to gain realignment and proper motion. The patient’s presentation and the practitioner’s skills and training philosophy dictate the direction of movement, choice of direct or indirect (leveraged) technique, and the force used. Anecdotally, gentle, nonthrust, low-velocity movements are well tolerated by patients when the treated areas are not directly or indirectly compromised by tumor. Muscle energy techniques use patient movements against the resistance of the practitioner in isometric or near-isometric contractions. Because the force and duration of effort are completely controlled by the patient, muscle energy techniques can be used safely in body segments in which no tumor is present and no risk of fracture is detected. Manual and mechanical traction also may be used to achieve soft tissue and muscular stretch. Patients are generally passively stretched by these interventions. Stretch

361 may relieve an acute episode of pain, but rehabilitation is incomplete until the opposing musculature is strengthened sufficiently to reduce recurrence of the painful process. Massage Evidence of massage for therapeutic purposes can be traced to ancient Chinese, Japanese, Greek, and Indian ayurvedic health practices, and massage was well established as a health-maintaining activity by the Romans. After the decline of the Roman Empire, little was known about its use until “Turkish massage” was reintroduced to Europe through the writings of de Chauliac in the 1300s and Par´e in the 1500s;36 Par´e coined the stroke names effleurage, p´etrissage, and tapotement.37 Interest in the West was heightened after French missionary work in China in the early 19th century. Ling in Sweden, followed by Metzger in Holland, as well as Tissot and Georgii in France spread the use of massage through Europe. “Swedish massage” has grown in popularity; it and other forms of massage are now among the most commonly used complementary medicine interventions.32 The most common uses of massage are promotion of relaxation and reduction in pain and anxiety or stress. Feelings of well-being are elicited, which may arise from a feeling of companionship or care from the practitioner, or a change in self-image or ability to communicate. Direct mechanical physiological changes, including transiently increased local blood and lymphatic flow and venous return, also are thought to occur.38–40 Edema is mobilized and venous return is increased, allowing enhanced arterial flow into the tissue capillary beds.41 Some authors have proposed reflexive physiological changes, such as increased sympathetic activity with increased systolic blood pressure, heart rate, peripheral skin temperature, and decreased respiration rate.42 Others have found no consistent effects on autonomic functions.43 One study found that beta-endorphins increased in subjects for 1 hour after massage, peaking at a 5-minute postmassage test;40 however, Day et al.44 found no significant changes in endorphin levels after massage. Deep friction massage, although uncomfortable, may be used to release fascial limitations when these inhibit range of motion. A recent review of randomized trials of massage therapy for nonmalignant low back pain suggested that it might be a beneficial therapy but that few unflawed studies have been published.45 In three studies, massage was compared with chiropractic manipulation or electrostimulation,46 manipulation,47 and balneotherapy (spa treatments), traction, or nontreatment;48 in all cases, no significant

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362 differences were obtained between massage and the alternate therapy approaches. The case can be argued, however, that the subjects in these studies had quite heterogenous biomechanical derangements and chronicities. If study designs incorporated these more specific diagnostic descriptions and subjects were stratified accordingly, different subject diagnostic groups may have responded more favorably to specific treatments. Although used successfully in the treatment of trigger points, myofascial pain, lymphedema, and the pain and spasm related to upper motor neuron injuries, massage has the potential to worsen inflammatory or traumatic arthritis, bursitis, phlebitis, and entrapment neuropathies. It may be associated with bleeding in patients with hemophilia or a coagulopathy.49 There have been some promising results from several studies performed specifically in cancer patients. A study of massage therapy with 1290 cancer patients at Memorial Sloan-Kettering Cancer Center showed symptom scores, including those for pain, reduced by 50%.50 Two other, smaller studies also showed improved cancer-related pain after massage.51,52 Ferrell-Torry and Glick53 identified significant reductions in pain perception on a visual analogue scale (VAS) immediately after a 30-minute massage. The intervention included effleurage, p´etrissage, and trigger point massage. Another study found that a very brief (10-minute) massage had brief benefit in VAS pain intensity only for the male subjects. Detailed description of the massage method was not included.54 Massage generally is not done directly over the tumor site.55 Acupuncture More than 2 million Americans are estimated to use acupuncture annually.56 Acupuncture needles are believed to stimulate type II and III muscle afferent nerves or A␦fibers, sending impulses to the spinal cord. In the spinal cord, acupuncture-induced release of enkephalin and dynorphin presynaptically block transmission of pain signals into the spinothalamic tract. Input to the midbrain periaqueductal gray matter and raphe nucleus may lead to the release of norepinephrine and serotonin in the spinal cord to inhibit pain presynaptically and postsynaptically in the spinothalamic tract. Pituitary stimulation releases beta-endorphins into the blood from the pituitary.57 In Oriental medicine, acupuncture needles are placed to correct deficiencies in qi, loosely interpreted by Westerners as one’s vital energy or life force and defense against illness and disease. The location, pattern, and order of needle placement influence the balance of yin and yang within the

patient, adding to or dissipating the “energy” in the organs and functions influenced by specific meridians where qi circulates. Electroacupuncture combines use of acupuncture needles and high-frequency (100–200 Hz) or low-frequency (2–4 Hz) electrical stimulation. High-frequency stimulation has been shown to have a rapid onset and a noncumulative, nonopioid, receptor-mediated effect. Its analgesia does not outlast the treatment.58 Conversely, low-frequency stimulation has a slow onset, cumulative benefit, and a naloxonereversible effect that persists after the treatment. Use of electrical therapy is determined by the practitioner’s experience. As mentioned previously, there is considerable overlap between trigger points and acupuncture points. Many acupuncture points are also palpably detectable hollows or anatomical tissue planes, which, in Western theory, may signify easily influenced zones of lymphaticoneurovascular bundles in the subcutaneous tissue. Peripheral endings of cranial and spinal nerves and penetrations of neurovascular bundles through superficial fascia have been cited as morphological findings of acupuncture points.59 Acupuncture treatment protocols are highly individualized to patient characteristics and the practitioner’s style and interpretation of findings, making randomized controlled trials exceptionally difficult to perform. The results of studies analyzing acupuncture and cancer pain have been mixed.60 Many Oriental cultures have developed their own methods of qi manipulation. Acupressure is the use of fingers, thumbs, and hands to stimulate acupuncture points. It has shown benefit in managing postoperative pain.61 Shiatsu, which means “finger pressure” in Japanese, is the use of heavy perpendicular pressure applied with the fingers, palm of the hand, or heel of the foot. The treating practitioner’s “energetic” characteristics are also thought to influence the degree of benefit for the patient. Mention in scientific literature is extremely limited, although mention has been made of its use in palliative care.62 Touch Massage and stretch use touch as a means to enact the activity, whereas simple touch is an end in itself. Laying on of hands has been understood across the centuries as a healing intervention. Companionship, compassion, and empathy are communicated by this interaction and can benefit the patient through this emotional validation. Intuitively, touch is beneficial for many patients through its influence on the suffering, emotional component of the painful experience. Obviously, its use is not limited to the health care team.

rehabilitation medicine interventions Reiki is a practice ranging from the laying on of hands to healing at a distance. Its origins are also within Asia. An interesting uncontrolled pilot study of patients experiencing cancer and noncancer pain showed significant improvements in VAS and Likert scale ratings of pain after a single reiki treatment.63 Obviously, much more work is needed in this area before it can be identified as an effective adjuvant means of pain management.

Modalities Humans have used modalities since the earliest times to decrease pain and return a person to optimal physical functioning. In rehabilitation medicine, these modalities have included diathermy, spa therapy, hydrotherapy, use of cold and heat, and ultrasound. Traditionally, therapists have been taught not to use heat or ultrasound in cancer patients as these allow for increased blood flow to and from a tumor site, possibly potentiating metastases. Unfortunately, the data supporting or refuting this claim are insufficient. Some of these modalities have gained widespread acceptance despite few well-designed supportive studies. Superficial heat and cold Superficial heat is recognized as a means of increasing collagen extensibility and decreasing joint fluid viscosity, as well as enhancing local metabolic activity. Superficial cold has opposite effects; its desirable effect is to reduce metabolic activity in areas of acute inflammation and pain. Modalities effect temperature change via conduction, convection, or conversion. Hydrocollator packs are segmented canvas sacks filled with silica dioxide, which absorbs heated water (70◦ –80◦ C) and then conducts heat in a therapeutic range for as long as 30 minutes. Hot packs should be wrapped in towels to absorb moisture and protect the skin. They may be quite heavy and thus difficult to tolerate on painful areas. Patients should not lie on packs because of increased temperatures generated at bony prominences and increased risk of injury focally. Commercially available gel packs can be heated in a microwave or in hot water at the stovetop. Heating is obviously more difficult to control, with heightened risk of burns, and the duration of heat is much shorter. However, gel packs are easy to use and well accepted by patients. Heating lamps use tungsten or quartz heating elements to generate infrared energy. In the home, incandescent bulbs also can generate heat. Changing the distance between the bulb and the patient controls the maximum heat and rate of heating.

363 Heating pads may have electrical heating elements or circulating fluid. Electrical heating pads have been shown to generate peak temperatures as high as almost 52◦ C even on the lowest setting, and temperature oscillations of up to 5◦ C also were found.64 The dipping or immersing of distal extremities into liquefied paraffin is another form of superficial heating. Mineral oil and paraffin are combined in a 1:7 ratio and maintained at 52◦ –54◦ C; the reservoir should be cool enough to have a rim of congealed wax at its edges to prevent burns during immersion. Home units are available but are somewhat expensive. For many patients, warm-water baths are just as comfortable and have less associated mess. Traditionally, paraffin baths have been used for contracted joints in the hands or feet resulting from rheumatoid arthritis. Superficial heat obviously is not completely free of the risk of injury. Blood flow to the heated area increases in an attempt to dissipate heat more rapidly. Inflammatory edema and bleeding increase as a result. There also is an increased production of lymphatic fluid, which may lead to lymphedema in at-risk individuals. Heat over insensate skin can easily create severe burns. Irradiated skin dissipates heat poorly owing to changes in microcirculation and loss of sweat glands or local lymphatic glands and can easily be injured. Because of a theoretical risk of metastasis, superficial heat generally is not placed directly over a known tumor site. Cryotherapy may be used to raise pain thresholds,65 temporarily diminish muscular tone and spasticity,66,67 decrease synovial collagenase activity,68 minimize formation of edema, and diminish inflammation.69 Cooling of the skin below about 15◦ C70,71 acutely causes vasoconstriction. Gradual vasodilation appears to reflexively follow vasoconstriction in an attempt to rewarm the cooled area. In the presence of sustained cold, skin temperature drops rapidly, slows in its decline, and reaches equilibrium 12◦ –16◦ C below its initial point in roughly 10 minutes, whereas subcutaneous tissue temperature falls only 3◦ –5◦ C during this time.66,72 Muscle temperatures after 5 minutes of ice massage at 2 cm below the skin surface have been reduced by as much as 15◦ C at the biceps brachii.73 Insulation by subcutaneous fat creates individual variability in effect. When a limb is packed in ice, vasoconstriction occurs within 5 minutes and can produce decreases of blood flow as great as 30% in soft tissue and 20% in skeletal muscle by 25 minutes.70 Ice massage involves direct stroking of tissues with ice wands or chunks, often for 5–10 minutes at a time. Ice packs cool more gradually through toweling and are helpful in improving tolerance in some patients. Vapo-coolant sprays

364 produce local analgesia and are used frequently in the treatment of trigger points (see earlier).74 Spray is applied in a linear fashion and parallel to the muscle fibers. Skin temperature may drop as much as 20◦ C during application75 as a result of evaporation. Ice and cold water frequently are used in the home or in therapy. Gel packs are commercially available, conform to joint shapes, and are quickly refrozen. Immersion of any tissue in water cooler than 15◦ C is poorly tolerated. Injuries may occur quickly; responses such as Raynaud’s phenomenon, cold urticaria, frostbite and frost burn, and abrupt hypotensive changes must be watched for. Ultrasound Most therapeutic ultrasound is between 0.8 and 3 MHz; higher frequencies attenuate more rapidly and have poor tissue penetration, whereas lower frequencies are difficult to focus. Pulsed waveform (PW) or continuous waveform (CW) may be used. CW generates heat and is limited by patient comfort and risk of injury to 2.0–2.5 W/cm2 . PW alternates higher intensities of ultrasound with absence of signal, which avoids the heating limitations caused by CW. PW also creates streaming and cavitation movements of molecules within tissue, which dominate at higher intensities than are tolerable in CW. The benefits of PW are not universally acknowledged, and CW has been investigated more thoroughly. Generally, treatment is applied in overlapping sweeping or circular motions for 10 minutes using a conducting gel or mineral oil. Nonthermal effects such as cavitation and standing waves may cause tissue damage. To avoid injury, the applicator head should be kept in constant motion and fluid-filled cavities, such as the eye and gravid uterus, should be avoided. As described previously, appropriate intensities also should be maintained. Metal prostheses or implants of any nature may create interfaces where heat could potentially build up. The spinal cord, heart, and brain also should be avoided. Ultrasound use in cancer patients is not without its controversy. It is not used frequently in cancer patients because of a theoretical risk of metastasis. Unfortunately, no studies have examined whether there is an increased risk of metastasis from ultrasound in cancer patients. Ultrasound often is used in areas of tendon and bursa inflammation, particularly at the shoulder, elbow, and knee. Some controlled studies in this patient population have found lack of benefit or lack of superiority to oral antiinflammatory medications regarding the desired outcome of increased joint range of motion.76,77 Study designs were

j.b. fu, k.y. shin, and t.a. gillis hampered by murky diagnostic criteria, lack of blinding, variations in the treatment protocols, and limited numbers of subjects. Definitive conclusions could not be reached. Ultrasound is commonly used in the treatment of joint contractures and reduced range of motion. It has been shown to be capable of heating the deep structures of the hip joint, which cannot be achieved through other superficial heating modalities.78–80 The combination of heat with stretching results in superior tendon extensibility compared with either agent alone.81 Unfortunately, the efficacy of ultrasound for the treatment of osteoarthritis and joint inflammation is not fully established. Many studies fail to adequately separate chronic joint pain patients from acute injury, and CW or PW and dosing often are not standardized. Water-based therapy Water is a popular means of pain management throughout the world. Water-based therapies are effective for several reasons. The buoyancy of water reduces pain associated with weightbearing and axial loading. Water is an effective means of heat transfer, via either convection with agitation or conduction when static. Finally, water also may serve as a medium for exercise, providing resistance in all planes of motion. Several studies have found that aquatic exercises are beneficial for fibromyalgia and osteoarthritic patients.82,83 Research of aquatic exercises with respect to cancer pain is very limited. Water temperatures between 33◦ C and 36◦ C are most commonly used and are well tolerated by most patients. Precautions against heat or cold injury, as described earlier, are just as important in water therapies. Systemic hyperthermia and hypothermia and drowning are additional risks. Hydrotherapy is the immersion of a limb or body region in warmed, agitated water. Whirlpool baths and specialized immersion tanks such as the Hubbard tank use pumps to agitate water. Temperatures below 33◦ C or above 38◦ C usually are not used for total body immersion; the higher the percentage of body surface immersed, the lower the temperature should be within this range. Systemic hyperthermia and cardiovascular injury may occur at temperatures above 38◦ C. Extremities can be treated in water as warm as 45◦ C for short periods. Hydrotherapy is helpful for irrigation and d´ebridement of wounds, often with handheld sprays or directional jets for better penetration and cleansing. The warm water encourages movement in painful or stiff joints. Water movement creates a sensation of massage that may relax muscle spasms and reduce overall anxiety. Facilitated stretch can be

rehabilitation medicine interventions performed on a limb within the whirlpool or tank, although heat penetration to medium and large joints may not be as effective as ultrasound.

365 theoretical risk of metastasis, TENS is generally not placed directly over a known tumor site.

Orthoses and ambulatory aids Transcutaneous electrical nerve stimulation TENS is infrequently mentioned as a treatment for cancer pain. Ventafridda84 reported the use of TENS among cancer patients. Relief was noted to be significant but of short duration in 70%–80%. By the 10th day of treatment, 58% of those with initially good relief found TENS no longer effective. Pain diagnoses (e.g., visceral, neuropathic, or bone metastasis) and stimulation characteristics were not well described, however. Application of electrical stimulation to the skin has been shown to effect analgesia for a variety of painful conditions. High frequencies (80–100 Hz) stimulate largediameter myelinated afferent nerve fibers, producing analgesia within the stimulated region with rapid onset. This analgesia also is not reversible by the opioid antagonist naloxone.85 This sensory input appears to influence the transmission of pain messages within the spinothalamic tract, either by direct inhibition of an abnormally or inappropriately active nerve or by activation of pain modulatory systems. Low-frequency stimulation (1–4 Hz) at higher intensities (≥10 amperes) activates sensory afferents and produces a localized muscle twitch. The analgesic response in this case is slower in onset, provides more generalized relief, persists after the conclusion of stimulation, and has cumulative effects.58 This mechanism is endorphin dependent and thus reversible with naloxone.85 It is much more common to use TENS for the more indirect causes of cancer-related pain, such as myofascial pain, muscle spasm, and chronic postsurgical neuropathic pain. Studies of TENS for these pain diagnoses also are mixed in their findings. In a double-blind study, acute and chronic low back pain patients, with presumably a variety of musculoskeletal pain etiologies, were treated with either high-intensity TENS or mechanically administered massage. Pain relief was noted to be significantly greater in the TENS group in this study.86 However, TENS was not significantly superior to ice massage among a group of patients with chronic low back pain.87 Chronic neuralgic pain often responds well to low-frequency, high-amplitude stimulation, although duration of relief is variable. Subjects with postherpetic neuralgia and peripheral nerve lesions88 appear to achieve more sustained relief than those with pain from plexus89 or radicular origins.90 TENS also has been used to effectively relieve acute postoperative pain after laparotomy, thoracotomy, and laminectomy.91 Because of a

The function of an orthosis is to support an anatomical structure to enable function or reduce pain. Many orthoses are used in the supportive management of cancer pain, particularly pain that is exacerbated or intensified by movement. An optimal orthosis relieves pain but enables function as much as possible. Thus, although casting may completely immobilize a limb and thereby avoid movement-related pain, the ability to use the limb is so compromised that generally it is a poor choice. Skin integrity also is a consideration in cancer patients. Nutritionally depleted patients with poor subcutaneous fat stores may tolerate skin pressure poorly, necessitating careful fitting of the device. Skin may be friable and easily injured because of the effects of steroidal medications. Irradiated skin often has a reduced ability to dissipate heat buildup underneath an orthosis. Irradiated skin may have fibrotic changes that prevent normal glide over subcutaneous structures and is thus predisposed to friction injury. Once injured, these areas heal with difficulty and with a higher risk of infection. Spinal orthoses may be prescribed when primary or metastatic lesions affect the vertebral column or adjacent soft tissues. Orthoses may support patients before and after surgical resection and stabilization of the spine, or be offered when advanced disease or other comorbidities prevent patients from being surgical candidates. In a patient with a vertebral compression fracture, a brace helps unload the fractured vertebrate, leading to decreased paraspinal spasms and pain.92 Excellent discussions of spinal stability and surgical rationale and techniques are found in the literature.93 The thoracolumbosacral orthosis (Fig. 19.4) provides the greatest restriction in motion in lower thoracic and lumbar segments. Higher thoracic levels and cervical involvement may require use of a sternal–occipital– mandibular immobilization brace (Fig. 19.5). Halo fixation provides the most complete immobilization of most cervical levels but is used infrequently in cancer patients. When frank spinal instability is not a concern, orthoses may be chosen for pain relief and ease of application and use. The Jewett orthosis provides three-point contact at the sternum, pubis, and lumbar region and is useful for compression fractures in the thoracic and lumbar spine, when kyphosis and flexion forces on the spine need to be minimized. Rigid and soft cervical collars provide postural cues and slight reduction in range of motion, as rotation

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Fig. 19.4. Rigid thoracolumbosacral orthosis.

and lateral bending are not well controlled. Soft corsets provide comfort to some patients; however, those with rib metastasis may not tolerate the pressure these corsets exert on the thoracic cage (Fig. 19.6). Extremity orthoses generally hold the limb in a position of function, which may be done for pain relief and improvement in safety or fatigue. An ankle–foot orthosis (AFO) creates a stable walking surface for patients with severe peripheral neuropathy and foot drop, but also may be helpful in those with weakness caused by lumbosacral plexopathy or paraparesis. The AFO reduces the energy cost of gait; without it, the patient with foot drop must hike the leg and/or excessively flex the knee during swing-through phase (steppage gait). The device also enhances proprioceptive awareness in patients with reduced sensation. Upper-extremity devices may strive to decrease the load of the limb on a painful shoulder joint and to control planes of motion. The shoulder immobilizer (Fig. 19.7) or abduction pillow (Fig. 19.8) fulfills both these goals, and although the limb position is not one of optimal function, at least it

Fig. 19.5. Sternal–occipital–mandibular immobilization.

can serve as a stable base of support for the contralateral limb to manipulate or hold items against. Several orthosis designs have been attempted to immobilize the scapula against the chest wall for patients with spinal accessory nerve loss or neuropraxia after cervical lymph node dissection. Without the function of the trapezius, scapular instability prevents overhead use of the ipsilateral arm. Ambulatory aids permit transfer of the center of gravity away from painful lower extremities and decreased transmission of force through the painful limb. A wide range of devices are available (Fig. 19.9) and are prescribed by rehabilitationists based on patient-specific characteristics. Devices are fit to a patient based on height and girth, and patients require instruction by therapists for safety. Insurers and other health care payers may permit only one ambulatory aid and may not pay for revisions or changes when an improper device has been prescribed.

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Fig. 19.7. Shoulder immobilizer.

Fig. 19.6. Thoracic orthosis. Corset with rigid stay inserts.

Compression Compression has long been used as an intervention for acute injury, along with rest, ice, and elevation. In this use, compression retards the soft tissue swelling that accompanies the inflammatory cascade. This edema itself may be painful and may excessively slow the recovery of mobility. Compression also is often helpful in chronic conditions in which there is pain or altered sensation or in which edema persists. In the example of a humeral fracture brace (Fig. 19.10), the device provides mechanical stability through compression. Use of compression garments or devices often helps patients with allodynia or dysesthesias related to peripheral neuropathies, plexopathies, or radicular or other peripheral nerve injuries. Activation of endogenous pain modulatory systems may explain the diminished pain perception anecdotally experienced by these patients. However, while donning tight garments or custom-fitted sleeves or stockings, some patients experience exacerbation of pain. Although

tight garments also may enhance sensory perception in the presence of peripheral neuropathies, possibly improving kinesthetic awareness, insensate skin must be evaluated for the development of pressure injury, and patients and caregivers must monitor and inspect skin at least twice daily. Compression garments, sleeves, and stockings frequently are used to attempt to control lymphatic edema. Lymphedema is not reversed but may accumulate more slowly in the presence of these garments. Optimal lymphedema treatment combines manual lymphatic drainage massage, a specific and superficially directed form of massage, with low-stretch compression bandaging and exercises for the affected limb. Treatment continues on a daily basis for several weeks until limb measurements have reached a stable degree of reduction and/or a caregiver can demonstrate independence in performing basic massage and bandaging techniques for the patient. Once limb size stabilizes, patients take on a more independent means of measuring and caring for the limb, including daytime wear of an appropriately sized or custom-fitted compression garment and nighttime bandaging, if possible.

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infection. Descriptive studies of palliative treatment for malignant lymphedema are needed.

Energy conservation The concept of “energy conservation” is frequently misunderstood, but may prove helpful to some patients experiencing cancer pain. Rather than resorting to bedrest and inactivity, the intervention encourages activity toward pleasurable or purposeful goals. Fundamental components include planning and pacing to prevent overexertion and redundant, wasteful efforts. Prioritization of tasks can reduce distress when pain or fatigue limits a patient’s endurance. Adaptive equipment items, such as those shown in Fig. 19.11, also may reduce the number and severity of “energy sinks,” which occur during painful or inefficient activities. Energy conservation techniques have been shown to improve quality of life in lung cancer patients undergoing chemotherapy.94 Commonly used as a therapeutic intervention in chronic neurological diseases (multiple sclerosis, postpolio syndrome) and rheumatoid arthritis, it is gaining familiarity among oncology professionals.

Therapeutic exercise

Fig. 19.8. Shoulder abduction pillow.

Pneumatic compression pumps have been used for many years in the treatment of chronic lymphedema of the extremities. Sequential, gradient pressure air chambers within the pneumatic sheath push lymphatic fluid into the axilla or groin. Concerns have been voiced about the potential for exacerbation of lymphatic injury through their use. Critics suggest that compression pumps force lymph into already overwhelmed proximal lymphatic vessels, promoting further injury and inflammation with repeated use. The presence of tumor in the axilla or groin is a general contraindication to the use of pneumatic pumps or lymphatic massage, owing to fears of tumor dissemination. Clinical experience has shown that pumps may exacerbate malignant pleural or pericardial effusions because of the rapidity of fluid shifting. Compressive bandaging often is used for palliation of malignant lymphedema, particularly if the edema causes pain, immobility, and/or recurrent

Exercise may be prescriptive or self-initiated. Prescriptive exercise is directed toward enhancement or restoration of function, generally in strength, coordination, or speed. Exercise has been shown to improve fatigue, quality of life, self-esteem, and patient mood.95 Specific muscle groups and joints may be targeted as well as overall performance. The mode (e.g., weightlifting, bicycling), frequency, duration, and goals are all components of the prescription. Among those with pain related to cancer, prescriptive exercise may be warranted after surgery or other treatments when function is compromised. A variety of self-initiated exercises may benefit patients with cancer-related pain through enhancement or maintenance of endurance, coordination, or postural control or promotion of a sense of well-being. Some exercises may increase cardiopulmonary fitness or flexibility. Studies indicate that some patients use exercise to combat fatigue. Exercise is well recognized to benefit pain management for patients with primary fibromyalgia syndrome, osteoarthritis, and other painful chronic conditions. Progressive resistive exercises improved pain, endurance, quality of life, and strength in cancer survivors.96 Use of these interventions may be limited in patients with severe pain or advanced/metastatic disease that directly affects mobility, such as bone metastasis, spinal cord

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Fig. 19.9. A: Rolling walker with brakes and seat. B: Single-point cane. C: Forearm crutch. D: Quad-base cane with forearm cuff.

compression, or brain metastasis. Elderly patients often are less familiar or experienced in movement therapies, may be more sedentary or less inclined toward exercise, are generally less flexible, and are therefore at higher risk of injury. With instructors who are able to modify and adapt programs

for a patient’s specific needs, however, almost all but those in severe pain or very near the end of life can participate in these therapies to some extent. Walking, swimming, stationary bicycling, and other familiar means are not specifically discussed. For patients

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Fig. 19.10. Humeral fracture brace.

with sedentary lifestyles before the diagnosis of cancer, traditional exercises may be intimidating or unrealistic. Other movement therapies, such as those described in this section, can provide novel, group-oriented activity and perhaps enhanced compliance or lifestyle changes. It is important to note that the positive effects of exercise may vary significantly as a function of the type of cancer; the stage of disease; the medical treatment; the nature, intensity, and duration of the exercise program; and the lifestyle of the patient.97

Tai chi Tai chi, or tai chi chuan, is a practice of movement with origins during the late Ming and early Qing dynasties more than 3000 years ago. Initially a martial art, it has gradually become popularized in China as a means of maintaining health and well-being. Its 108 movements, or forms, are used to balance yin and yang and to strengthen qi, the life force or vital energy, which wards off illness and disease. An emphasis is placed on relaxing unnecessary tension in the body, controlled but fluid weight shifting from one leg to another, maintaining a flexed-knee position, and heightened but relaxed kinesthetic and breathing awareness. Increased popularity in the West has led to an impressive array of literature, including randomized controlled trials. Tai chi has been shown to have impressive and significant benefits over cycle ergometry in ventilatory frequency and ratio of dead space ventilation to tidal volume. When compared with sedentary matched individuals, tai chi practitioners had significantly higher oxygen uptake, pulse oximetry, and work rate98 and experienced less decline in maximal oxygen uptake and pulse oximetry than control subjects at

Fig. 19.11. A and B: Tub transfer bench used over commode and in tub. C: Bedside commode that also may be placed in a shower. D and E: Dressing stick. F: Long-handled shoe horn. G: Sock aid.

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372 a 2-year follow-up evaluation.99 Other comparison studies showed practitioners to have significantly greater peak oxygen uptake, greater flexibility, and lower percentage of body fat compared with sedentary subjects.100 There have been a limited number of controlled clinical trials of tai chi in cancer patients, all of which have been in breast cancer patients. A recent systematic review of these controlled clinical trials concluded that further research is needed in this area.101

Yoga Yoga is a practice of specific postures and breathing techniques, accompanied by mental quietude, concentration, or focus. It is used as a means of achieving well-being for its participants, and in healthy volunteers, it has been associated with higher life satisfaction; less excitability, aggressiveness, and emotionality; and fewer somatic complaints.102 Yoga has been shown to help depression, anxiety, insomnia, pain, and fatigue in cancer patients. A pilot study of metastatic breast cancer patients revealed significantly lower levels of pain and fatigue and higher relaxation and invigoration 1 day after yoga practice.103

Pilates Joseph Pilates (1880–1967) developed a form of therapy emphasizing kinesthetic awareness, particularly in the pelvic and truncal muscles, and the notion of a “stable core” from which movement must arise. Areas of injury are weak links in the body’s kinetic chain and must work in harmony with the entire structure. Awareness and strength are developed through specific exercises, often using eccentric muscle contractions. Exercise equipment uniquely designed to facilitate this development also is incorporated. Strength and coordination are progressively increased through more challenging tasks on these devices.

Mind–body techniques Although not within the usual scope of practice for many rehabilitationists, mind–body techniques are commonly practiced but little discussed or researched. They are included as reminders of their adjunctive but often helpful role in pain management.

Music It has been postulated that music may diminish the awareness of pain by the distraction it provides. In another theory,

j.b. fu, k.y. shin, and t.a. gillis pleasant and uplifting music may stimulate the brain to release endorphins that relieve pain centrally. Music can elicit the relaxation response, lessen anxiety, and reduce muscle tension. For some, it is a means to facilitate guided imagery techniques. Music can evoke memories, increase or decrease emotional states, and change moods. Although most clinicians are intuitively aware of the effects music holds for them personally, the notion of prescriptive music is still not widely accepted. In the United States, the National Association for Music Therapy and the American Music Therapy Association are striving for increased recognition of formalized music interventions. Two reviews of music for pain relief concluded that music therapy reduces pain intensity by small amounts.104,105 A randomized controlled clinical trial of 60 patients with chronic pain suggested that patients who received music therapy had less pain, depression, and disability than a control group.106 Incorporating appropriate music into treatment areas and home environments seems a natural enhancement that frequently is overlooked. In fact, some studies have investigated the addition of soothing music to chemotherapy infusion and found reductions in the incidence of nausea and emesis.107 Music therapy also has been recommended for the control of postoperative nausea and vomiting.108 Case reports109 and anecdotal experience suggest that pain perceptions can be altered through music therapy.

Relaxation and imagery Imagery refers to the mental exercise of visualizing positive surroundings or circumstances. This may refer to pleasant vistas previously experienced or purely imaginary but very soothing locations. Participants also may create mental images of their cancer being battled successfully, with metaphoric representations or allegorical qualities. Relaxation techniques include deep breathing; breathing awareness; progressive muscular relaxation, moving from one section of the body to another; and active muscle contraction followed by relaxation. A review of nine randomized trials concluded with mixed results, with only three studies showing that relaxation techniques were effective in treating chronic pain.110 Syrjala et al.111 found that mucositis pain in bone marrow transplant recipients improved during a 5-week study in subjects treated with relaxation and imagery but not in those participating in a therapist support group or in a control group. Hypnosis may promote physiological and cognitive characteristics that are similar to progressive relaxation, imagery, and meditation.

rehabilitation medicine interventions Meditation and prayer Both meditation and prayer involve focused attention and may attempt to exclude negative or random thoughts. In addition to the spiritual outlook and beliefs that may benefit from prayer or meditation, both may be associated with a relaxation response, with attendant reductions in heart rate, respiratory rate, and blood pressure.112 Whereas meditation generally involves focusing inward, prayer often looks outward to a larger purpose or higher power. Prayer does not necessarily imply disdain for medical knowledge. Conventional medical views may consider religious beliefs in miraculous healing through prayer as incompatible with rational thought. However, those who pray may seek healing not only through cure but through hope in the next life and in a merciful God.113 In a survey of women with gynecological cancer, 49% felt they had become more religious after their diagnosis, and none felt less religious. More than 90% of these patients said their religious lives helped them sustain their hopes.114 Shapiro115 assessed a small group of long- and shortterm meditators and found a 62.9% incidence of at least one adverse event within the group, without significant differences between long- and short-term meditators. These adverse effects included disorientation, confusion, depression, increased awareness of one’s negative qualities and emotions, increased fears and anxiety, boredom, pain, and withdrawal from daily activities to pursue meditation. Most of the patients noted a greater sense of relaxation, lower levels of perceived stress, and more positive thinking, self-confidence, compassion, and tolerance of oneself and others.116

Conclusion Cancer pain is complex and may be related to the malignancy, its treatments, and prior comorbidities. The rehabilitationist’s knowledge of both musculoskeletal and neurologic causes of pain and disability, as well as treatment options, is key to caring for these patients. Rehabilitation specialists have many options available to treat cancer pain that often go unrecognized by medical professionals as well as patients. However, rehabilitation is becoming an increasingly important part of the pain-fighting armamentarium. Therapies, modalities, injections, orthotics, manipulation, and alternative medicine techniques often can provide adequate pain relief without the need for oral systemic medications. As cancer survivorship increases, greater emphasis will and should be placed on managing pain without

373 or with decreased use of chronic opiate medications. The rehabilitationist’s treatment of the two interrelated problems of pain and decreased function can lead to improvement in the physiatrist’s ultimate goal: improving the patient’s quality of life.

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j.b. fu, k.y. shin, and t.a. gillis 35. Greenman PE. Principles of manual medicine, 2nd ed. Philadelphia: Williams & Wilkins, 1996, p 52. 36. McPartland J, Miller B. Bodywork therapy systems. Phys Med Rehabil Clin North Am 10:583–602, 1999. 37. Pare A. Oeuvres completes. Paris: JB Balliere, 1948. 38. Goats GC, Keir KA. Connective tissue massage. Br J Sports Med 25:131–3, 1991. 39. Wakim K, Marin F, Terrier J, et al. The effects of massage on the circulation on normal and paralyzed extremities. Arch Phys Med Rehabil 30:135–44, 1949. 40. Kaada B, Torsteinbo O. Increase of plasma beta-endorphins in connective tissue massage. Gen Pharmacol 20:487–9, 1989. 41. Carrier EB. Studies on physiology of capillaries: reaction of human skin capillaries to drugs and other stimuli. Am J Physiol 61:528–47, 1922. 42. Barr JS, Taslitz N. The influence of back massage on autonomic functions. Phys Ther 50:1679–91, 1970. 43. Reed BV, Held JM. Effects of sequential connective tissue massage on autonomic nervous system of middle-aged and healthy adults. Phys Ther 68:1231–4, 1988. 44. Day JA, Mason RR, Chesrown SE. Effect of massage on serum level of beta-endorphin and beta-lipotropin in healthy adults. Phys Ther 67:926–30, 1987. 45. Ernst E. Massage therapy for low back pain: a systematic review. J Pain Symptom Manage 17:65–9, 1999. 46. Godrey CM, Morgan PP, Schatzker J. A randomized trial of manipulation for low-back pain in a medical setting. Spine 9:301–4, 1984. 47. Hoehler FK, Tobis JS, Buerger AA. Spinal manipulation for low back pain. JAMA 245:1835–8, 1981. 48. Konrad K, Tatrai T, Hunka A, et al. Controlled trial of balneotherapy in treatment of low back pain. Ann Rheum Dis 51:820–2, 1992. 49. Tan JC. Physical modalities. In: Practical manual of physical medicine and rehabilitation. St. Louis: Mosby, 1998, pp 133– 55. 50. Cassileth BR, Vickers AJ. Massage therapy for symptom control: outcome study at a major cancer center. J Pain Symptom Manage 28:244–9, 2004. 51. Smith MC, Kemp J, Hemphill L, Vojir CP. Outcomes of therapeutic massage for hospitalized cancer patients. J Nurs Scholarsh 34:257–62, 2002. 52. Wilkie DJ, Kampbell J, Cutshall S, et al. Effects of massage on pain intensity, analgesics and quality of life in patients with cancer pain: a pilot study of a randomized clinical trial conducted within hospice care delivery. Hosp J 15:31–53, 2000. 53. Ferrell-Torry AT, Glick OJ. The use of therapeutic massage as a nursing intervention to modify anxiety and the perception of cancer pain. Cancer Nurs 16:93–101, 1993. 54. Weinrich SP, Weinrich MC. The effect of massage on pain in cancer patients. Appl Nurs Res 3:140–5, 1990. 55. Watkins T, Mexeiner A: Musculoskeletal effects of ovarian cancer and treatment: a physical therapy perspective. Rehabil Oncol 21:12–17, 2003.

rehabilitation medicine interventions 56. Kundu A, Berman B. Acupuncture for pediatric pain and symptom management. Pediatr Clin North Am 54:885–99, 2007. 57. Pomeranz B. The scientific basis for acupuncture. In: Stux G, Pomeranz B, eds. Acupuncture textbook and atlas. Berlin: Springer-Verlag, 1987, pp 1–34. 58. Pomeranz B. Electroacupuncture and transcutaneous electrical nerve stimulation. In: Stux GG, Pomeranz B, eds. Basics of acupuncture, 2nd ed. Berlin: Springer-Verlag, 1991, pp 250– 60. 59. Helms JM. Acupuncture energetics: a clinical approach for physicians. Berkeley: Medical Acupuncture Publishers, 1995, pp 26–9. 60. Lee H, Schmidt K, Ernst E. Acupuncture for the relief of cancer-related pain – a systematic review. Eur J Pain 9:437– 44, 2005. 61. Felhendler D, Lisander B. Pressure on acupoints decreases postoperative pain. Clin J Pain 12:326–9, 1996. 62. Stevensen C. The role of shiatsu in palliative care. Complement Ther Nurs Midwifery 1:51–8, 1995. 63. Olson K, Hanson J. Using Reiki to manage pain: a preliminary report. Cancer Prev Control 1:108–13, 1997. 64. Diller KR. Analysis of burns caused by long-term exposure to a heating pad. J Burn Care Rehabil 12:214–17, 1991. 65. Curkovic B, Vitulic V, Babic-Naglic D, Durrigl T. The influence of heat and cold on the pain threshold in rheumatoid arthritis. Z Rheumatol 52:289–91, 1993. 66. Hartviksen K. Ice therapy in spasticity. Acta Neurol Scand 38:79–84, 1962. 67. Miglietta O. Action of cold on spasticity. Am J Phys Med 52:198–205, 1973. 68. Harris ED, McCroskery PA. The influence of temperature and fibril stability on degradation of cartilage collagen by rheumatoid synovial collagenase. N Engl J Med 290:1–6, 1974. 69. Schmidt KL, Ott VR, Rocher G, Schaller H. Heat, cold and inflammation (a review). Z Rheumatol 38:391–404, 1979. 70. Ho SS, Illgen RL, Meyer RW, et al. Comparison of various icing times in decreasing bone metabolism and blood flow in the knee. Am J Sports Med 23:74–6, 1995. 71. Taber C, Contryman K, Fahernbruch J, et al. Measurement of reactive vasodilation during cold gel pack application to non-traumatized ankles. Phys Ther 72:294–9, 1992. 72. Lehmann JF, de Lateur BJ. Diathermy and superficial heat and cold therapy. In: Kottke FJ, Stillwell GK, Lehmann JF, eds. Krusen’s handbook of physical medicine and rehabilitation, 3rd ed. Philadelphia: W. B. Saunders, 1982, pp 275–350. 73. Lowdon BJ, Moore RJ. Determinants and nature of intramuscular temperature changes during cold therapy. Am J Phys Med 54:223–33, 1975. 74. Travell J. Ethyl chloride spray for painful muscle spasm. Arch Phys Med Rehabil 33:291–8, 1952. 75. Oosterveld FG, Rasker JJ. Effects of local heat and cold treatment of surface and articular temperature of arthritic knees. Arthritis Rheum 37:1578–82, 1994. 76. Haker E, Lundeberg T. Pulsed ultrasound treatment in lateral epicondylagia. Scand J Rehabil Med 23:115–18, 1991.

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77. Nykanen M. Pulsed ultrasound treatment of the painful shoulder. A randomized, double-blind, placebo controlled study. Scand J Rehabil Med 27:105–8, 1995. 78. Lehman JF, Erickson DJ, Martin GM, Krusen FH. Comparison of ultrasonic and microwave diathermy in the physical treatment of periarthritis of the shoulder. Arch Phys Med Rehabil 35:627–34, 1954. 79. Lehmann JF, Fordyce WE, Rathbun LA, et al. Clinical evaluation of a new approach in the treatment of contracture associated with hip fracture after internal fixation. Arch Phys Med Rehabil 42:95, 1961. 80. Lehmann JF, McMillan JA, Brunner GD, Blumberg JB. Comparative study of the efficiency of short-wave, microwave and ultrasonic diathermy in heating the hip joint. Arch Phys Med Rehabil 40:510–12, 1959. 81. Lehmann JF, Masock AJ, Warren CG, et al. Effect of therapeutic temperatures on tendon extensibility. Arch Phys Med Rehabil 51:481–7, 1970. 82. Evcik D, Yigit I, Pusak H, Kavuncu V. Effectiveness of aquatic therapy in the treatment of fibromyalgia syndrome: a randomized controlled open study. Rheumatol Int 28:885–90, 2008. 83. Bartels EM, Lund H, Hagen KB, et al. Aquatic exercise for the treatment of knee and hip osteoarthritis. Cochrane Database Syst Rev CD005523, 2007. 84. Ventafridda V. Transcutaneous nerve stimulation in cancer pain. In: Bonica JJ, Ventafridda V, eds. Advances in pain research and therapy, vol. 2. New York: Raven Press, 1979, pp 509–15. 85. Sj¨olund BH, Eriksson MB. The influence of naloxone on analgesia produced by peripheral conditioning stimulation. Brain Res 173:295–301, 1979. 86. Melzack R, Vetere P, Finch L. Transcutaneous electrical nerve stimulation for low back pain. A comparison of TENS and massage for pain and range of motion. Phys Ther 63:489–93, 1983. 87. Melzack R, Jeans ME, Stratford JG, Monks RC. Ice massage and transcutaneous electrical stimulation: comparison of treatment for low-back pain. Pain 9:209–17, 1980. 88. Ericksson MB, Sj¨olund BH, Nielzen S. Long-term results of peripheral conditioning stimulation as an analgesic measure in chronic pain. Pain 6:335–47, 1979. 89. Wynn Parry CB. Pain in avulsion lesions of the brachial plexus. Pain 9:41–53, 1980. 90. Sindou M, Keravel Y. Pain relief through transcutaneous electrical nerve stimulation (TENS). Results on painful neurological disorders in 180 cases. Neurochirurgie 26:153–7, 1980. 91. Cotter DJ. Overview of transcutaneous electrical nerve stimulation for treatment of acute postoperative pain. Med Instrum 17:289–92, 1983. 92. Sinaki M. Osteoporosis. In: DeLisa JA, Gans BM, eds. Rehabilitation medicine: principles and practice. Philadelphia: JB Lippincott, 1993, p 1018. 93. Holdsworth F. Fractures, dislocations and fracture-dislocations of the spine. J Bone Joint Surg Am 52:1534–51, 1970.

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j.b. fu, k.y. shin, and t.a. gillis 104. Cepeda MS, Carr DB, Lau J, Lavarez H. Music for pain relief. Cochrane Database Syst Rev CD004843, 2006. 105. Igawa-Silva W, Wu S, Harrigan R. Music and cancer pain management. Hawaii Med J 66:292–5, 2007. 106. Siedliecki SL, Good M. Effect of music on power, pain, depression, and disability. J Adv Nurs 54:553–62, 2006. 107. Standley J. Clinical applications of music therapy and chemotherapy: the effects on nausea and emesis. Music Ther Perspect 9:91–6, 1992. 108. Thompson HJ. The management of post-operative nausea and vomiting. J Adv Nurs 29:1130–6, 1999. 109. Magill-Levreault L. Music therapy in pain and symptom management. J Palliat Care 9:42–8, 1993. 110. Redd WH, Montgomery GH, DuHamel KN. Behavioral intervention for cancer treatment side effects. J Natl Cancer Inst 93:810–23, 2001. 111. Syrjala KL, Donaldson GW, Davis MW, et al. Relaxation and imagery and cognitive-behavioral training reduce pain during cancer treatment: a controlled clinical trial. Pain 63:189–98, 1995. 112. Benson H. The relaxation response: history, physiological basis and clinical utility. Acta Med Scand 660:231–7, 1982. 113. Hufford DJ. Epistemologies in religious healing. J Med Philos 18:175–94, 1993. 114. Roberts JA, Brown D, Elkins T, et al. Factors influencing views of patients with gynecological cancer about end-of-life decisions. Am J Obstet Gynecol 176:166–72, 1997. 115. Shapiro DH Jr. Adverse effects of meditation: a preliminary investigation of long-term meditators. Int J Psychosom 39:62– 7, 1992. 116. Shapiro DH Jr. Overview: clinical and physiological comparison of meditation with other self-control strategies. Am J Psychiatry 139:267–74, 1982.

SECTION VII

THE ROLE OF ANTINEOPLASTIC THERAPIES IN PAIN CONTROL

20

Palliative radiotherapy alysa fairchild ab and edward chow b a University of Alberta and University of Toronto

Introduction External beam radiotherapy (EBRT) meets the criteria for a good palliative intervention for control of cancer pain, and in this chapter, some guiding principles for decision making in treatment planning are described. New developments in the prevention of adverse effects secondary to radiotherapy (RT) are discussed. The effectiveness of RT for nociceptive, neuropathic, and visceral pain are demonstrated using the settings of bone and brain metastases as the main clinical examples, and RT’s role in the treatment of complications of bone metastases are outlined. The integration of palliative RT with other modalities, issues surrounding reirradiation, and current controversies also are highlighted.

Radiotherapy When ionizing radiation travels through a living cell, it can damage the reproductive material in the cell either directly or indirectly. Direct DNA damage includes base deletions and single- and double-strand breaks. Indirect damage occurs when radiation ionizes water molecules, resulting in free radicals, which in turn damage DNA. Repair of DNA damage is possible in both normal cells and cancer cells, but cancer cells have less capacity to do so, creating a therapeutic ratio that can be exploited. This is part of the rationale behind fractionation, or dividing the total dose of radiation into a number of smaller doses (fractions) delivered over time: This allows normal tissues to repair damage that cancer cells cannot.1,2 Typically, patients are treated once per day, Monday through Friday, a schedule that has evolved empirically to balance normal tissue repair with tumor cell kill, although there are clinical scenarios in which more than one treatment is given per day or treatment is administered on weekends. Radiation dose is measured in Gray (Gy); 1 Gy is 1 joule of absorbed energy per

kilogram. One centigray (cGy) is equivalent to 0.01 Gy (or 1 rad in the old system of measurement). RT delivery can be broadly classified as via an external beam (teletherapy) or via radioactive sources implanted or inserted into a body surface, tissue, or cavity near the tumor, or into the tumor itself (brachytherapy). Additionally, radiopharmaceuticals are considered subtypes of brachytherapy; these are ingested or intravenously administered as inorganic soluble compounds. EBRT utilizes high-energy gamma rays produced by a linear accelerator, or x-rays given off by a radioactive cobalt source housed within the head of a treatment machine. This chapter focuses primarily on external beam radiation. Planning of EBRT involves a series of sequential steps. After determining a patient is a candidate for radiation, “simulation” is required to localize the proposed volume to be treated. This can be done either clinically or under radiologic (e.g., fluoroscopy, CT) guidance. Construction of immobilization devices is sometimes required. Only after dose calculation and patient education can treatment commence. Although there are few absolute contraindications to RT, especially when delivered with palliative intent, the patient must be able to lie still unattended on the simulator and treatment tables, which may be difficult in the presence of delirium, orthopnea, or uncontrolled pain.

Principles of palliative radiation therapy A general approach to palliation in advanced cancer is to identify the cause of the symptom (while keeping in mind nonmalignant etiologies); treat the reversible, such as fracture; institute pharmacological therapies; rule out iatrogenic causes and chronic pain syndromes; address nonphysical factors; and employ supportive care liberally.3,4 The general goals of palliative RT are relief of pain, preservation of mobility and function, prevention of future complications, 379

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380 preservation of quality of life (QOL), maintenance of skeletal integrity, and minimization of both hospitalization and rehabilitation.3,4 A good palliative intervention should accomplish one or more of these aims and be safe, with minimal acute toxicity; have a high possibility of benefit; require the shortest possible time investment; be minimally invasive, with little recovery time; and be cost-effective. The optimal palliative RT regimen is one that provides prompt and effective symptom relief with minimal toxicity and patient inconvenience. About half of all patients with cancer will receive RT with palliative intent during the course of their illness.5 Palliative RT is a noninvasive, effective, relatively nontoxic, cost-effective intervention for symptom control.6 However, by and large it does not confer a survival benefit compared with supportive care only. Exceptions are outlined in this chapter. Tumors usually do not have to be completely eradicated to relieve symptoms;1 therefore, doses lower than those required for total lesion ablation are used in palliative situations. The use of a lower total dose than that required for cure, but which still achieves symptom control, has several advantages: the risk of acute side effects is minimized, which increases patient QOL and acceptance of treatment; RT can be delivered over fewer fractions, which decreases transportation and hospital admission requirements; it is more convenient for the patient, decreases discomfort with positioning, frees resources for others, and decreases the “opportunity cost.” Kirkbride and Barton1 described the latter as the cost associated with lost opportunities for patients to spend their remaining days as they choose. Although the possibility of long-term side effects should be considered, this is usually less of an issue in patients with a limited life span, who are not expected to survive long enough to be at risk.1,2 In a patient with incurable cancer, treatment may be deferred until symptoms arise, unless the patient is at risk of a serious adverse outcome with disease progression, such as spinal cord compression, airway obstruction, or fracture of a weightbearing bone. Otherwise, it is not standard practice to prophylactically irradiate an asymptomatic metastatic site that may or may not cause future problems. Improvement in symptoms after RT commonly commences from 1 week to 10 days, reaches a maximum within 4–6 weeks, and may last for the rest of the patient’s life.7 Because of this lag in symptom palliation, it is imperative that analgesics be optimized and consultation for additional supportive modalities, such as slings or crutches, takes place.

Table 20.1. Examples of factors to be taken into account when planning palliative radiotherapy Assess the status of the cancer r Confirm the diagnosis r Assess the extent of the disease as far as is necessary to direct management Assess the patient’s symptoms and functional status r Identify specific symptoms, and establish their relative importance r Establish the cause(s) of the most important symptom(s) r Establish the patient’s overall level of function Assess the prognosis r Assess the rate and pattern of progression of the disease r Review previous treatment and assess response to previous treatment Assess current management r Review current cancer therapy r Review current symptomatic management r Review supportive care Assess the feasibility of radiotherapy r Assess the volume required to encompass the symptomatic lesion(s) r Review previous RT to that volume r Assess the technical feasibility of RT r Assess the potential toxicity of RT Assess the patient’s preferences r Elicit the patient’s values r Elicit the patient’s priorities From Mackillop8

With a few exceptions (see “Visceral Pain”), EBRT does not work well for diffuse or extensive organ involvement, such as lung metastases; acute radiation toxicity may be severe, outweighing any potential benefit.2 Doses of palliative RT are not identical for all patients with the same treatment indication. At the time of consultation, the radiation oncologist (RO) must take into account many factors to determine whether the patient is likely to benefit. Tumor factors such as histology and location are considered, as well as patient factors such as symptom burden, functional status, and life expectancy, and treatment factors such as the length of treatment course likely to be effective. Many of these factors were reviewed by Mackillop8 (Table 20.1). Understanding the patient’s condition and correlating clinical findings with appropriate imaging are essential for treatment planning. Fields should cover disease most responsible for symptoms, but not necessarily all visible disease. The treatment schedule should respect the patient’s performance status and degree of systemic disease, aiming to provide relief with minimal morbidity. In view of the fact that the intricacies of treatment planning often are outweighed by the complexities of decision making,

palliative radiotherapy Table 20.2. Ten rules for the practice of palliative radiotherapy 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 8.1 8.2 9.0 10.0

Palliative RT should be part of a comprehensive program of care The decision to recommend palliative RT should he based on a thorough assessment of the patient The decision to recommend palliative RT should be based on objective information The risk–benefit analysis should include consideration of all aspects of the patient’s well-being The short-term risks and benefits of palliative RT are more important than those that may or may not occur in the future The decision to use palliative RT should be consistent with the values and preferences of the patient The patient should be involved in the treatment decision to the extent that she or he wishes Time is precious when life is short Delays in starting palliative RT should be as short as reasonably achievable Courses of palliative RT should be no longer than necessary to achieve their therapeutic goal Palliative and curative goals should not be considered mutually exclusive Palliative RT should consume no more resources than necessary

From Mackillop8

Mackillop8 outlined 10 rules to guide the prescription of palliative RT based on well-known ethical principles (Table 20.2). Among them are common-sense guidelines that serve as a reminder that “time is precious when life is short,” and that treatment should consume no more resources than necessary. As he additionally articulates, treatment recommendations should be evidence based, and if the available evidence is deficient, then practitioners have an obligation to participate in the clinical research that will provide it.8 More than 10 years after the publication of Mackillop’s article, however, controversy still exists regarding the optimal dose fractionation schedule for many palliative RT indications. This may be a result of multiple, conflicting clinical trials; the absence of strong level 1 evidence; or difficulties in the translation of literature results to general practice. It is also important to note that patients with metastatic disease who are enrolled in clinical trials tend to have a better prognosis, or at least better functional status, than the majority who are not.9 This latter group, often with active, progressive disease, may be best managed with supportive care alone.

Radiotherapy side effects The main objective in RT is to treat the tumor while minimizing dose to surrounding normal tissue, thereby minimizing the risk of side effects. A corollary is that the

381 larger the volume of tissue treated, the higher the risk of toxicity.1 As it is a localized treatment modality, benefits and potential side effects are site specific; the only exception to this is fatigue, the etiology of which is unknown.2 Acute side effects are self-limited, lasting days to weeks, and their severity cannot generally be predicted a priori. Most acute side effects do not peak until after treatment completion.1 Tips on side effect management can be found in the excellent reviews by Kirkbride and Barton1 and Samant and Gooi.2 Late local effects may occur months to years after therapy and usually are permanent, and should be managed by an RO if they occur.2 Careful treatment planning is the most critical aspect of reducing side effects. Skin reactions are usually minimal, limited to the radiation portal, and often treated similarly to sunburns.2 Up to one third of patients will experience some degree of nausea and/or anorexia, particularly when large volumes encompassing the pelvis, epigastrium, or thoracolumbar spine are treated.10 Patients should be offered prophylactic antiemetics, prescribed orally 30–60 minutes before RT and continued on an as-needed basis between fractions. After RT to the brain, complete alopecia will occur over the next few weeks. Less commonly, headache, nausea, emesis, weakness, and otitis media occur.5 Subacute somnolence syndrome several months after RT is well recognized but infrequent. Late complications after brain treatment can manifest as neurologic deterioration, dementia, or both.5 Mucositis and esophagitis occur after RT to the head and neck or thorax and are treated with dietary modifications, oral rinses, antifungals, analgesics, and cytoprotective agents.2,11 Local irritation from mucositis in the oropharyngeal region may be relieved by analgesics, the “Pink Lady” formulation, or benzydamine mouthwashes. Secondary infections, such as Candida, should be treated. If large amounts of small intestine are included in the fields, radiation enteritis may occur.11 This is manifested by cramping; frequent, loose stools; and occasionally bleeding. Treating the pelvis also may result in short-lived diarrhea, the risk of which is diminished in view of the large doses of opioids patients are commonly taking.10 If Clostridium difficile is not a consideration, antidiarrheal medications such as loperamide may be used. Oral fluids and dietary modifications should also be instituted. Proctitis can be treated with sitz baths and local anorectal therapy. Radiation cystitis often responds to increased fluid intake, but coexistent infection should be ruled out. Hematologic side effects are usually mild and transient, but bone marrow suppression may occur if the treatment

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382 Table 20.3. Incidence of pathologic fracture, from selected RCTs and meta-analyses Trial

Dose

Fracture rate (%)

Dose

Fracture rate (%)

P value

RTOG 7402,a 1982 RTOG 7402,b 1982 BPTWP, 1999 Dutch, 1999 RTOG, 2005 TROG 9605, 2005 Scandinavian,c 2006 Sze, 2003d Wu, 2003d,e Chow, 2007d

Low 20 Gy/5 8 Gy/1 8 Gy/1 8 Gy/1 8 Gy/1 8 Gy/1 Single fraction Single fraction Single fraction

5 4 2 4 5 4 4 3 Not pooled 3

High 40.5 Gy/15 20 Gy/5 or 30 Gy/10 24 Gy/6 30 Gy/10 20 Gy/5 30 Gy/10 Multiple fraction Multiple fraction Multiple fraction

8 18 0.5 2 4 4 11 2 Not pooled 3

No P value 0.02 NS ⬍0.05 No P value NS No P value 0.03 N/A NS

a

Multiple metastases cohort. Solitary metastasis cohort. c Not referable to treatment site only and proportions calculated based on absolute number reported. d Meta-analysis. e Not pooled because of trial heterogeneity. Abbreviations: BPTWP, Bone Pain Trial Working Party; N/A, not assessable; NS, not significant. b

portals are large, the total dose is moderate to high, and a significant proportion of marrow is included, especially in heavily pretreated patients.11 Bone weakened by disease will not be strengthened immediately by EBRT. Fractures after RT have been reported in up to 18% of patients.11 (See under “Nociceptive pain: bone metastases” and Table 20.3.) Pelvic stress fractures may occur but are more likely after radical RT doses. Pain flare After a course of RT to a volume that includes bony metastases, pain flare, a self-limited worsening of symptoms at the index site within a week of commencing treatment, may be problematic.12 Definitions of pain flare in the literature vary, for example, in terms of whether they take into account concomitant changes in analgesic usage. To distinguish pain flare from disease progression, pain scores and analgesic intake usually must return back to baseline after the transient increase.13 Estimates of incidence of pain flare vary from 10% to 44% following EBRT, and in one trial, pain flare lasted for a median of 3 days.12,14–16 The proportion of patients experiencing pain flare is reported to be higher after large, single fractions than after completing multiple, smaller fractions.12,16 In the first few days following RT, patients can be instructed to take extra breakthrough analgesic doses if they experience increased pain. However, preventive measures are always preferred. Dexamethasone, a well-known adjuvant analgesic, is a good choice as a potential prophylactic agent because of its long half-life (36–54 hours). The

first study reporting a potential role for dexamethasone in the prophylaxis of pain flare after single-fraction RT was published recently.17 One dose of dexamethasone (8 mg by mouth) was administered 1 hour before 8 Gy in one fraction, delivered for painful bone metastases.17 Patients completed the Brief Pain Inventory at baseline and daily for 10 days. Pain flare was defined as a two-point increase in worst pain on an 11-point numerical rating scale with no decrease in analgesic, or a 25% increase in analgesic intake without a decrease in worst pain score. Pain score and analgesic intake were required to return to baseline for the definition of flare to be satisfied. In the 33 patients enrolled in the study, median total oral morphine equivalent at baseline was 18 mg/day, and baseline mean worst pain was 7.8/10. No significant toxicity was observed secondary to the dexamethasone. Twenty-four percent of the patients (8/33) experienced pain flare, starting anywhere from day 3 to day 7 after RT and lasting from 1 to 6 days. The incidence of flare in the first 2 days after dexamethasone was 3%.17 A multicenter phase II Canadian trial investigating the effectiveness of dexamethasone in prevention of pain flare is ongoing, with a randomized phase III trial planned.

Nociceptive pain: bone metastases Bone metastases remain the most common cause of cancerrelated pain and the quintessential example of nociceptive (somatic) pain. Bone lesions are the sites of metastases most likely to require palliative RT, which is the most costeffective treatment modality available.6,7,10 Painful bony metastases are so prone to causing difficulty with pain that a significant body of literature has emerged concerning repeat

palliative radiotherapy irradiation to the same site over time, which is dealt with separately (see “Reirradiation”). Radiation therapy for bone metastases There have been approximately 25 randomized controlled trials (RCTs) published since the 1980s investigating different dose fractionation schedules for uncomplicated bone metastases.18 Although there is no specific, accepted definition of uncomplicated, it is generally taken to mean the absence of associated complications, such as neuropathic signs and symptoms, or impending or established fracture. A growing body of empirical evidence, including multiple RCTs, two systematic reviews, and two meta-analyses, has shown that single-fraction palliative RT provides pain relief for uncomplicated bone metastases equivalent to that of multiple fractions. Nevertheless, considerable controversy over the optimal treatment schedule still exists.19 Recently, three large methodologically sound RCTs, as well as an updated meta-analysis, were reported, each confirming equivalence between long-course and short-course treatment schedules for analgesia.18,20–22 In one of the first randomized studies (Radiation Therapy Oncology Group [RTOG] 74–02), patients were stratified by whether they had single or multiple metastases.23 The former group was randomly assigned to receive 40.5 Gy divided into 15 daily fractions (40.5 Gy/15) or 20 Gy/5. The latter cohort was randomly assigned to receive 15 Gy/5, 20 Gy/5, 25 Gy/5, or 30 Gy/10. Ninety percent of patients experienced some relief of pain, and 54% achieved eventual complete pain relief. The median duration of pain relief was 12–15 weeks. The authors concluded that low-dose, short-course schedules were as effective as higher-dose, protracted regimens. There were some differences found, however, in terms of pathologic fracture incidence after RT. In the solitary metastasis group, an 18% incidence of fracture was seen in the high-dose group after RT versus 4% in the lower-dose group (Table 20.3). Neither toxicity nor reirradiation was assessed. A reanalysis of the same set of data grouped all patients together and assessed pain relief in addition to analgesic use.24 The number of fractions was found to be statistically significantly related to complete combined relief (i.e., the absence of pain and no use of narcotics), and the author implied that protracted dose fractionation schedules were more effective than short-course schedules. This was contrary to the original report, highlighting the choice of end points as important in defining the outcomes of clinical trials.25 Perhaps the only conclusion that can be drawn is

383 that the design of the trial was inadequate to answer the questions it posed.1 Subsequent to the RTOG trial, there were multiple prospective randomized trials evaluating different dose fractionation schedules, most with one or more serious design flaws.25 It was not until the late 1990s that more consistent and conclusive data began to emerge from several large multicenter phase III RCTs. The U.K. Bone Pain Trial Working Party26 randomly assigned 765 patients with bone metastases to either an 8-Gy single fraction or a multifraction regimen (20 Gy/5 fractions or 30 Gy/10 fractions). There were no differences in time to first improvement in pain, time to complete pain relief, or time to pain progression up to 12 months from randomization. There were no significant differences in the incidence of nausea, vomiting, spinal cord compression, or pathological fracture between the two groups (Table 20.4). The Dutch Bone Metastases Study included 1171 patients and found no difference in pain relief or QOL following a single 8-Gy fraction or 24 Gy/6.27 More pathological fractures were observed in the single-fraction group, but the absolute percentage was low (Table 20.3). There was no difference in quality-adjusted life expectancy or toxicity, although specific proportions of the latter were not reported. The RTOG repeated its multicenter phase III study, randomly assigning patients with prostate or breast cancer and one to three sites of painful bone metastases to either 8 Gy/1 or 30 Gy/10 over 2 weeks.20 The overall response rate was 66% in 897 eligible patients. Complete and partial responses were 15% and 50% in the single-fraction arm, compared with 18% and 48% in the multiple-fraction arm, respectively (P = 0.60). Patients in both treatment arms had equivalent narcotic use at 3 months, and proportions of patients experiencing pathologic fracture were almost identical. Grade 2–4 acute toxicity was more frequent in the multiple-fraction arm (17% vs. 10%, P = 0.002), and late toxicity was rare (4%) in both arms (Table 20.4). Ten Scandinavian centers planned to recruit 1000 patients to a trial randomly assigning patients to the same treatment schedules mentioned earlier.21 The data monitoring committee recommended study closure after 376 patients were accrued because interim analyses indicated that the treatment groups had equivalent outcomes. Similar pain relief within the first 4 months was reported, and this was maintained throughout the 28-week follow-up. No differences in fatigue, global QOL, or survival were found, although fewer patients in the single-fraction arm experienced toxicity (no absolute numbers were reported). More patients

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384 Table 20.4. Incidence of toxicity, from selected RCTs and meta-analyses Trial

Dose

Toxicity

Dose

Toxicity

P value

RTOG 7402, 1982 BPTWP, 1999 Dutch, 1999 RTOG, 2005 TROG 9605, 2005 Scandinavian, 2006 Sze, 2003b Wu, 2003b,c Chow, 2007b

Lower 8 Gy/1 8 Gy/1 8 Gy/1 8 Gy/1 8 Gy/1 Single fraction Single fraction Single fraction

Not reported 30% (emesis) Not reported Grade 2–4, 10% Grade 3, 2% “Fewer”a patients “Similar in severity” Not pooled “Generally similar”

Higher 20 Gy/5 or 30 Gy/10 24 Gy/6 30 Gy/10 20 Gy/5 30 Gy/10 Multiple fraction Multiple fraction Multiple fraction

Not reported 32% (emesis) Not reported Grade 2–4, 17% Grade 3, 2% “More patients” “Similar in severity” Not pooled “Generally similar”

N/A NS NS 0.002 No P value No P value No P value N/A N/A

a

Absolute numbers not stated. Meta-analysis. c Not pooled because of trial heterogeneity. Abbreviations: BPTWP, Bone Pain Trial Working Party; N/A, not assessable; NS, not significant. b

sustained a pathologic fracture in the multiple-fraction arm (no P value) (Table 20.3). A third RCT investigating this same randomization (8 Gy/1 vs. 30 Gy/10) was recently published in abstract form, reporting on 70 patients. The mean reduction in pain and the number of responses in the two groups were not statistically different.22 Two earlier meta-analyses showed no significant difference in complete and overall pain relief between singleand multiple-fraction palliative EBRT.28,29 Results were remarkably similar, with the Wu et al.29 meta-analysis reporting a complete response rate (absence of pain) of 33% and 32% after single- and multiple-fraction RT, respectively, compared with 34% and 32% for Sze et al.28 The Wu group’s overall response rates were 62% and 59%, compared with 60% and 59% for the Sze group, for single- and multiple-fraction RT, respectively. When restricted to evaluable patients, overall response rates became 73% for each arm.29 Most patients experienced pain relief in the first 2–4 weeks after RT of any duration.29 The Wu group’s report, however, did not pool end points such as toxicity or pathologic fracture because of trial heterogeneity. Sze et al.28 did pool the latter, finding a significantly higher pathologic fracture rate (3% vs. 2%, P = 0.03) after single-fraction RT. (For retreatment results, see “Reirradiation.”) Side effects, consisting generally of nausea and vomiting, were similar in severity for both treatment arms (Table 20.4). An updated meta-analysis reported results from 16 RCTs, totaling 2513 and 2487 randomizations to single-fraction and multiple-fraction arms, respectively.18 Overall and complete response rates of 58% and 23% for patients receiving single-fraction RT, versus 59% and 24% for patients randomly assigned to multiple-fraction arms (P = not significant [NS]), were demonstrated, confirming the

conclusions of the 2003 systematic reviews. After singlefraction RT, 3.2% of patients had fractures, compared with 2.8% after multiple fractions (P = 0.75). No differences in acute toxicities were found, but these were not pooled because of heterogeneity. Controversy over the optimal dose fractionation has almost entirely ignored patient choice, with three studies to date having investigated patients’ preferences of RT schedules.30–32 In one study, 21 Australian patients with bone metastases who had received RT between 6 weeks and 2 years previously participated in structured interviews in which they were asked to indicate the relative priority attributed to different aspects of treatment.30 Participants generally considered medical appointments to be physically demanding and rated sustained pain relief and reduced risk of future complications their highest priorities. Convenience was acknowledged, but factors such as traveling distance and brevity of treatment were considered of secondary importance to overall QOL and treatment efficacy. Most patients favored single-fraction RT, assuming equivalent outcomes.30 Patients in Singapore and Canada were studied using the same patient preference instrument, which presented differences and similarities between single- and multiplefraction RT.31,32 In the Singapore study, 85% of patients (53/62) chose extended courses of RT (24 Gy/6) compared with a single treatment, because of lower retreatment rates and decreased fracture risk; choice did not seem to depend on age, performance status, primary cancer site, cost, or pain score.31 In the Canadian study, 76% of patients (55/72) chose a single 8-Gy treatment as opposed to 1 week of RT, because of greater convenience.32 Patients who chose the 1-week schedule did so largely because of the decreased likelihood

palliative radiotherapy of pathologic fracture. Older and retired patients were more likely to select single-fraction RT. Differences in the aforementioned three studies may be explained in part by cultural differences and potentially by differences in the decision aid instrument.19 Despite the overwhelming amount of randomized evidence and obvious advantages for patients, there has been reluctance to adopt single-fraction schedules as global standard practice to date. A recent article reviewed surveys published between 1988 and 2006 on prescription patterns for RT for bone metastases.19 American respondents indicated an overwhelming preference for the 30 Gy/10 schedule, and 90%–100% of ROs preferred multiple over single fractions. Approximately 85% of Canadian ROs preferred multiple fractions, most often as 20 Gy/5 over 1 week. Multiple fractions again were commonly used in the United Kingdom, Western Europe, Australia and New Zealand, and India; however, oncologists in these countries would consider single-fraction schedules in up to 42% of courses.19 However, the first indications of a shift in prescription patterns have started to appear. In the United Kingdom, a practice audit performed in 2003 revealed the most common palliative RT schedule to be delivery of a single fraction.33 In Sweden, a 2001 national audit reported that “the principle of irradiation of skeletal metastases with a single or few fractions has been widely adopted in clinical practice” since 1992.34 After the Dutch trial was published in 1999, “almost all Dutch institutions either changed or [were] planning to change their protocols to [single fraction] for palliation of bone metastases.”35 The recently published Scandinavian trial was terminated early because of slow recruitment, which was blamed on physician reluctance to randomize between single and multiple fractions.21 An international study updating patterns of practice in palliative RT is underway, with results expected to illustrate regional changes in response to recent clinical trials and meta analyses. This study also will reexamine issues taken into account in decision making to more closely pinpoint reasons behind the reluctance to employ single-fraction RT. To date, these issues have been hypothesized as oncologist related, such as training; setting related, such as waiting list length; and disease related, such as site of lesion or presence of fracture.19

Complications of bone metastases: impending or established pathologic fracture A review of 1800 patients reported an 8% incidence of pathologic fractures, ⬎50% of which were a result of breast

385 cancer.36 Annual fracture rates of 20% may be seen in hormone-resistant prostate cancer.37 Other malignancies, such as kidney, lung, and thyroid carcinoma, each account for 5%–10%.36 Approximately 10% of all bone metastases, usually located in the femur, require some form surgical intervention. The femoral neck is responsible for 50% of proximal femoral fractures, the subtrochanteric region for 30%, and the intertrochanteric region 15%.38 Impending fracture and risk prediction An impending fracture is defined as a bony metastasis that, if not addressed, has a significant likelihood of fracture under normal physiological loads. Although some physicians believe that all patients with proximally located femoral metastases should undergo preventive surgery, this would result in a large number of unnecessary surgical procedures.39 Therefore, many studies, mostly in the context of femoral fractures, have attempted to predict fracture risk based on clinical and/or radiologic findings.3,38–54 Incidence of long bone fractures has been found to be related to many patient and tumor factors (Table 20.5). For example, functional pain is caused by a bone that is mechanically weak and can no longer support the normal stresses of daily activities; this is the most strongly positive predictor of fracture in some series.38 However, many of these retrospective studies were based on two-dimensional imaging and surgical data only. Additionally, most investigators did not specifically state how they measured such parameters as circumferential cortical involvement. In the reporting of fracture post RT in the dosefinding randomized trials, risk was almost never assessed before treatment, making definitive conclusions from these data difficult. Fidler43,46 found that the incidence of long bone fractures was related to the degree of cortical involvement. When 25%–50% of the cortex was involved, fracture incidence was 3.7%, rising to 61% and 79%, respectively, when 50%– 75% and ≥75% was involved. Mirels50 devised a clinical scoring system grading the site, pain pattern, lesion size, and radiographic appearance, based on assessment of 78 cases (Table 20.6). Each factor was given a score of 0–3. For scores ≤7, the risk of fracture is ⬍5%; for these cases noninvasive management is appropriate. For scores ≥9, fracture can be said to be almost inevitable, and fixation should be performed. Lesions scoring 8 are intermediate, with a risk of fracture of 15%, and should be assessed on a case-by-case basis. This system is a useful guide for nonorthopedists for directing referrals. However, Damron55 has suggested that this classification

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386

Table 20.5. Indications for surgery in impending fractures of the femur References

Indication for surgical intervention

38, 40–42, 44, 50–51, 53–54 38, 40–42, 54 47 38, 40–42, 44, 47, 50–52 40, 42, 44 40, 44, 48 39, 49 53 39–40, 44, 47 38, 41, 43, 46, 49, 51, 54 50 44 3 45, 47, 50 45 47 49 53 38 38 38 a

r Increasing pain during or after RT, especially with weightbearing r Lesion size ⬎25 mm r Lesion size ⬎20 mm r Osteolytic appearance on radiographs r Transverse cortical destruction r Axial cortical destruction (present) r Axial cortical destruction ⬎30 mma r Axial cortical destruction ⬎38 mm r Circumferential cortical destruction (present) r Circumferential cortical destruction (⬎50%) r Circumferential cortical destruction (⬎66%) r Cortical lesion of any size secondary to lung carcinoma r Lesser trochanter avulsion fracture r Any proximal lesion r Diffusely mottled lesion r Increased body weight and activity r Ratio of width of metastasis to width of bone ⬎0.6 r Ratio of width of metastasis to width of bone ⬎0.9 r General health adequate to tolerate surgery and remaining bone adequate to support the surgical construct r Life expectancy ≥1 month (weightbearing bone) r Life expectancy ≥3 months (non-weightbearing bone)

Except lesions in femoral neck, where axial cortical destruction ⬎13 mm is considered significant.

has a high false-negative rate, with a specificity of only 35%. The need for prophylactic stabilization had been called into question after Cheng et al.45 reported a series of highrisk patients successfully managed with RT alone. In this retrospective series of 59 patients with metastatic breast cancer, none of the high-risk osteolytic lesions fractured after treatment with 30 Gy/10. An RCT by Koswig and Budach56 reported that remineralization of lytic bone lesions was greater following 30 Gy/10 than after a single 8 Gy, as determined by CT scanning. At 6 months post RT, bone density was increased by an average of 173% following 30 Gy/10, compared with 120% following 8 Gy/1 (P ⬍ 0.001). However, interpretation Table 20.6. Mirel’s criteria for risk prediction of fracture Score Variable

1

2

3

Site Pain Lesion Size

Upper limb Mild Blastic ⬍1/3

Lower limb Moderate Mixed 1/3–2/3

Peri-trochanter Functional Lytic ⬎2/3

From Mirels.50

of these data is problematic until CT data are further correlated with fracture risk. In the randomized Dutch Bone Metastasis Study on the palliative effect of a single fraction of 8 Gy versus 24 Gy/6, database analysis revealed 14 fractures in 102 patients with femoral metastases.39 Twenty-three percent of the patients (10/44) had received a single fraction, and 7% (4/58) had received multiple fractions. Patients with lesions suspected to be at high risk of fracturing at baseline were excluded from study entry. In general, patients in the single-fraction group had a higher chance of experiencing a pathological fracture than those in the multiplefraction group, with a median time to fracture of 7 weeks (single fraction) versus 20 weeks (multiple fractions). Results suggest that multiple fractions postponed fracturing longer than a single fraction. Patients who remained free from fracturing were not re-treated more often; therefore, higher total dose of RT was not a valid explanation for the absence of expected fractures. On pretreatment radiographs, the amount of axial cortical involvement was the only predictive parameter for fracturing. The investigators recommended treating femoral metastases with an axial cortical involvement length ⬎30 mm with prophylactic surgery because of a 25% fracture incidence. Although more fractures occurred after a single dose of 8 Gy, the

palliative radiotherapy investigators could not prove the treatment schedule to be predictive.39 Impending or established pathologic fractures treated with radiotherapy alone Although there are multiple benefits to prophylactic fixation followed by postoperative radiotherapy (PORT; see later), a proportion of patients will not be candidates for an operative procedure, or will refuse surgical intervention. Often a minimum life expectancy (6–12 weeks) is required so that the patient survives a sufficient time to justify the morbidity and mortality risk. Patients also must have a reasonable performance status, with manageable comorbidities, and remaining bone adequate to support any implanted hardware.38 Otherwise, patients may receive RT alone. Although it can provide pain relief and tumor control, it does not restore bone stability, and remineralization will take weeks to months.10 Patients should be warned of the increased risk of fracture in the peri-radiation period as a result of an induced hyperemic response at the periphery of the tumor that weakens the adjacent bone in the short term. Therefore, measures such as crutches, a sling, or a walker should be taken to reduce anatomic forces across the lesion. Published data on the results of local irradiation alone for pathologic fracture are sparse. One retrospective series analyzed 27 pathologic fractures in various sites treated with doses of 40–50 Gy over 4–5 weeks. Healing with remineralization was seen in 33% of these patients, with pain relief in 67%.57 There is no consensus on appropriate dose fractionation, but most authors recommend a multifraction course of EBRT in this situation.39 In practice, 20–40 Gy for established pathologic fracture is generally given over 1–3 weeks. In the specific case of an apparently solitary, histologically confirmed metastasis, especially after a long disease-free interval, some clinicians may wish to give a higher dose (e.g., 40–50 Gy) under the assumption that this will provide long-term control. Adjacent joints should be spared unless there is tumor involvement or their inclusion is necessitated by an appropriate margin.58 Postoperative radiotherapy An implant will fail from repetitive loading unless the bone heals, but fractures in cancerous bone heal slower than those through normal bone. Adjunctive modalities, such as RT, often are required to tip the balance in favor of healing, presuming that site has not yet been treated. Additional

387 supportive care, such as physiotherapy, and comfort measures to assist with analgesia and prevent contractures should always be considered. Traditionally, PORT is used to promote bone healing by suppressing tumor growth, thereby preventing destabilization of the prosthesis by maintaining the structural integrity of the bone in which the implant is fixed.59 It is thought to decrease pain, minimize the risk of disease progression, minimize implant failure, and reduce the risk of refracture.60 Townsend et al.60 reported normal use of extremity (with or without pain) in 53% of patients receiving PORT versus 11.5% after surgery alone in a review of 64 orthopedic procedures performed in 60 patients. Second orthopedic procedures to the same site were more frequent in the group that received surgery alone. Interestingly, the actuarial median survival for the surgery-alone group was 3.3 months, compared with 12.4 months for the PORT group. However, this study needs to be interpreted with caution because of its retrospective nature and possible selection biases. No good evidence exists on the optimal dose, but most ROs use a multifraction schedule similar to that of patients receiving radiation alone for impending fracture, such as 20–40 Gy over 1–4 weeks.5,11,60 The portal usually encompasses the entire implant with a margin, and in many cases this will involve treating the entire bone. Following intramedullary nailing, the entire length of bone is thought to be at risk of seeding, so the whole surgical field and all implanted hardware should be included in the radiation field. Treatment is generally started within 2–4 weeks of surgery, after the wound has healed. Patients should be assessed 4 weeks after RT, and if there has been no improvement in pain control, they should be referred to an appropriate orthopedic specialist, especially if mechanical or functional pain still exists.3 Some authors have suggested that for patients whose life expectancy may be only a few weeks or months, pain relief may be a more reasonable goal than rehabilitation and mobilization.59 In this situation, consideration may be given to single-dose RT, with the understanding that supporting evidence is nonexistent.5 In extremely debilitated patients, EBRT may not be indicated at all. A few arguments against the utility of PORT have been put forth, including a) lack of efficacy in the presence of radioresistant histology, b) the short-term radiation-induced weakening of the bone alluded to earlier, c) radiationinduced impairment in wound healing, and d) the fact that it may be unnecessary in view of newer surgical techniques and implements, such as bone cement.38,61 Patients without visceral metastases and those who have a relatively long

388 predicted survival (⬎3 months) are more likely to benefit from PORT. Prospective trials are urgently needed to clarify this issue and to give some guidance on the issues of technique and dose fractionation schedule.

Integration of palliative radiotherapy with other modalities With advances in minimally invasive surgery, innovative radiopharmaceuticals, newer-generation bisphosphonates, and concurrent systemic chemotherapy, new combinations of modalities are being explored for additive or synergistic effects to improve clinical outcomes in the treatment of advanced cancer, especially in the treatment of bone metastases. Radiotherapy and minimally invasive surgical techniques Nowhere is the need for multidisciplinary, cooperative assessment more imperative from a patient QOL perspective than in the area of balancing the need for surgical intervention for advanced cancer with its potential side effects. Literature surrounding pathologic fracture, one example, has been outlined above. Percutaneous vertebroplasty (PVP) and kyphoplasty are minimally invasive surgical techniques that are alternatives to open surgery for restoring stability to bone metastases in the spine, pelvis, and elsewhere. Patients who are not candidates or who decline an invasive surgical procedure may in fact benefit from these procedures. Both involve the injection, under local and/or general anesthesia, of bone cement (polymethyl methacrylate [PMMA]) into a lytic metastasis for stabilization, with the difference being whether or not a balloon is used prior to create or enlarge a cavity for the PMMA. This is the case in kyphoplasty, but not in PVP. PVP in particular has been used to salvage patients experiencing progression of pain after EBRT.62 Radiotherapy and radiopharmaceuticals Improved outcomes have been demonstrated by some studies when radiopharmaceuticals have been combined with RT. For example, the multicenter Trans-Canada study compared RT with 10.8 mCi of strontium chloride 89 (89Sr) or placebo in 126 patients with bone metastases secondary to hormone-refractory prostate cancer.63 Forty percent of the 89Sr patients were classified as pain-free at 3 months, compared with 23% of placebo patients. Seventeen percent of patients receiving 89Sr discontinued analgesics as

a. fairchild and e. chow compared with 2% in the placebo group. At 3 months, 59% of 89Sr patients were free of new painful metastases versus 34% in the placebo arm (P ⬍ 0.05), with an increased median time to further local RT of 35 weeks versus 20 weeks. QOL, pain relief, and improvement in physical activity were also statistically significantly superior in the 89Sr arm, with acceptable hematologic toxicity and an overall management cost savings. A Norwegian randomized trial, however, reported no advantage in pain relief with the addition of 89Sr to local RT.64 All patients received 30 Gy/10 fractions and either 89Sr or placebo on the first day of RT. Unfortunately, this trial was closed early because of slow accrual, with 89 patients treated according to protocol. Response rates at 3 months were 30% in the 89Sr group and 20% in the control group (P = NS), but addition of 89Sr did decrease alkaline phosphatase at 3 months (P = 0.001). There was no difference in number of patients with progression (41% vs. 51%), progression-free survival, or reported QOL or prostate-specific antigen level. Canadian practice guidelines currently do not recommend 89Sr as a routine adjuvant to local RT because of such conflicting results.65 Radiotherapy and bisphosphonates Bisphosphonates are analogues of pyrophosphate that bind avidly to exposed bone mineral. During bone resorption, they are internalized by the osteoclast and subsequently cause cell death, resulting in prevention of further osteolysis. Over the past 10 years, bisphosphonates have become established as a valuable adjunctive approach to other systemic treatments in multiple primary tumor types. More recently, a role in combination with EBRT has been investigated. The first report to explore differences in clinical and radiologic responses to concurrent RT and ibandronate by different types of metastases (lytic, sclerotic, mixed) was published recently.66 Patients received 30–40 Gy concurrent with the first dose of intravenous ibandronate, which was repeated monthly to a maximum of 10 injections. Of the 70 patients enrolled, 52 were evaluable at 3 months; bone lesions were classified as lytic in 22, mixed in 16, and sclerotic in 14 of these 52 patients. All groups experienced significant reduction in pain and opioid requirements and significant improvement in performance status and QOL at each follow-up visit (3, 6, and 10 months) compared with baseline. At 3 months, pain responses were 41% complete response and 59% partial response in patients with lytic lesions, 75% complete and 25% partial in those with mixed lesions, and 79% complete and 21% partial in the sclerotic

palliative radiotherapy

389

Table 20.7. Incidence of reirradiation, from selected RCTs and meta-analyses Trial

Dose

Reirradiation rate (%)

Dose

Reirradiation rate (%)

P value

RTOG 7402, 1982 BPTWP, 1999 Dutch, 1999 RTOG, 2005 TROG 9605, 2005 Scandinavian, 2006a Sze, 2003b Wu, 2003b,c Chow, 2007b

Lower 8 Gy/1 8 Gy/1 8 Gy/1 8 Gy/1 8 Gy/1 Single fraction Single fraction Single fraction

Not reported 23 25 18 29 16 22 Not pooled 20

Higher 20 Gy/5 or 30 Gy/10 24 Gy/6 30 Gy/10 20 Gy/5 30 Gy/10 Multiple fraction Multiple fraction Multiple fraction

Not reported 10 7 9 24 4 7 Not pooled 8

N/A ⬍0.001 Sig (no value) ⬍0.001 0.41 No P value ⬍0.0001 N/A ⬍0.0001

a

Proportions calculated based on absolute number reported in paper. Meta-analysis. c Not pooled because of trial heterogeneity. Abbreviations: BPTWP, Bone Pain Trial Working Party; N/A, not assessable; Sig, significant. b

metastases group. Bone density was significantly increased in all groups at all time points compared with baseline, except for the sclerotic group at 3 months. This approach clearly shows promise, but further studies are needed in this area to define the optimal duration of use.66 Radiotherapy and chemotherapy Whether combining RT and chemotherapy conclusively improves symptom relief or QOL for patients with advanced cancer is unknown, but trials investigating these two modalities have been undertaken in non–small cell lung cancer (NSCLC),67 for example, with promising results.

Neuropathic pain: bone metastases Neuropathic pain is defined as pain initiated or caused by a primary lesion or other dysfunction in the nervous system,68 often with a radiating component. It is one of the most difficult cancer pain syndromes to treat, in part because of relatively unpredictable responses to typical analgesics.69 Characteristic symptoms include spontaneous pain, altered sensation (hypoesthesia or hyperesthesia), and allodynia (pain evoked by a non-noxious stimulus).70,71 It is typically associated with a dermatomal distribution of pain or dysesthesia, and often described by patients as burning or electric shock–like.10 The primary approaches to treating tumor-related neurologic injury are control of the underlying tumor and use of concomitant symptomatic measures. Neuroablative procedures are usually a measure of last resort.70 Neuropathic bone pain does respond to radiation.72 There is some evidence to suggest that ROs are more reluctant to use single fractions of RT when neuropathic pain is present.73,74 Possible reasons include the belief that

tumor shrinkage is required to relieve mechanical pressure on nerves, concern about occult spinal cord or cauda equina compression, or the general exclusion of patients with neuropathic pain in trials examining efficacy of single-fraction EBRT.74 One of these trials did retrospectively identify a small number of patients with “referred” pain.26 The authors stated that “the likelihood and durability of pain relief in [84/761] patients thought to have referred pain at presentation was not significantly different from that of patients without referred pain.” No firm conclusions were drawn concerning this subgroup, however. Roos et al.74 compared a single 8-Gy RT dose versus 20 Gy/5 for 245 per protocol patients with cancer at any primary site and bone metastases causing neuropathic pain. Both schedules were highly effective: pain relief was seen in 53%–61% of patients, with 26%–27% experiencing complete response. Time to treatment failure was higher in the fractionated arm (3.7 months vs. 2.4 months), but, like the response rates, the difference did not reach statistical significance within the confidence limits set by the noninferiority trial. Rates of spinal cord compression, pathological fracture, and retreatment with RT in relation to the index site were not significantly different (Tables 20.3, 20.4, and 20.7). The authors concluded that a single fraction of RT was not as effective as multiple fractions for the treatment of neuropathic pain – but was not significantly worse. They recommended that 20 Gy/5 fractions be used as the standard schedule, but in patients with a short expected life span or poor performance status, in whom the cost and/or inconvenience of multiple treatments is a factor, a single fraction also may be considered. In a subsequent cost-effectiveness analysis of the trial data, although larger retreatment costs were associated with the single-fraction arm, these were

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390 offset by savings in medication and hospital admission costs, as well as by the lower cost of initial RT.75

Visceral pain General Visceral pain is associated with distention and is usually dull, poorly localized, and crampy.76 The cause, such as hepatomegaly or abdominal mass, often can be pinpointed on examination, but imaging may be needed to rule out obstruction of tubular organs.76 The role of RT for visceral metastases is palliative, with the intent of providing pain relief and/or improvement in other symptoms. Visceral pain originating from disease in the brain, lung, liver, pelvis, and skin are discussed. For less common manifestations of visceral pain treated with palliative RT not described here, excellent reviews exist, such as Lutz et al.7 Brain Brain metastases are common, with 20%–40% of all patients with cancer experiencing metastatic spread to the central nervous system (CNS) during the course of their disease, with lung cancer responsible for the largest proportion (⬎50%).77 Brain metastases can significantly alter a patient’s QOL, along with contributing to a visceral pain syndrome in the form of headache, the most common presenting symptom.5 Other indications to treat brain metastases include improvement in neurological symptoms such as impaired mentation. There presently is no consensus on the management of asymptomatic brain metastases. Patients with brain metastases represent a heterogeneous group. A proportion may benefit from combinations of aggressive treatment modalities, such as surgery, stereotactic radiosurgery (SRS), systemic therapy, and whole-brain radiation therapy (WBRT). An improvement in median survival can be achieved from 1 month (no treatment), to 2 months (steroids alone), to 3–6 months (steroids plus WBRT).78,79 For patients with multiple metastases, one trial performed in the pre-CT era compared oral prednisone to WBRT alone, with a resulting median survival of 10 weeks compared with 14 weeks in the combined arm (no P value reported), and a similar proportion of patients with improved functional status.80 However, 25%–50% of patients with brain metastases will die of progression of disease in the brain.81 Several different dose fractionation schemas of WBRT have been investigated, including 20 Gy/5, 30 Gy/10, 30 Gy/15, 40 Gy/15, 40 Gy/20, and 50 Gy/20. There

were no differences in symptomatic improvement (approximately one half to three fourths of patients), median time to progression (8–12 weeks), or median survival (15–21 weeks).82,83 A recent practice guidelines report found no significant difference in mortality, symptom control, or neurological function improvement for different doses of WBRT.9 Altered fractionation, concurrent radiosensitizers, and EBRT partial brain dose escalation have not proved to be clinically useful to date.9,84 Although studies investigating chemotherapy and WBRT suggested an improved brain response, they also generally reported increased toxicity and no survival benefit.9 The 30%–40% of patients presenting with a solitary metastasis to the brain may be candidates for surgical resection or SRS followed by adjuvant WBRT.85 For patients with good performance status and minimal or no evidence of extracranial disease, surgical excision followed by WBRT has been shown to improve survival over WBRT alone.9,86,87 Postoperative WBRT can improve local control.9,86 For single brain metastases, three RCTs examined the use of WBRT with or without surgical resection, with no difference in overall mortality at 6 months when the three studies were pooled.9 However, two of these trials reported a statistically significant improvement in overall median survival and duration of functional independence.86,87 One found a significantly higher proportion of patients with in-brain failure after surgery alone (70% vs. 18%, P ⬍ 0.001).88 The one trial reporting on QOL did not detect a difference.89 Addition of an SRS boost to WBRT for patients with good performance status recently was shown to improve survival for patients with a single brain metastasis and to improve functional autonomy for patients with two to three brain metastases.90 Three trials have examined the use of WBRT with or without SRS boost, and none could detect improvement in overall survival for patients with one to four lesions. However, in specific subsets of patients on post hoc multivariate analysis, SRS boost did improve survival (patients ⬍65 years old, Karnofsky performance status ≥70, controlled extracranial disease, squamous cell cancer or NSCLC). All three trials reported improved control of the treated brain lesions at 1 year after radiosurgery boost. QOL data have not been reported, and moderate to severe toxicity is uncommon. Lung The majority of patients with newly diagnosed lung cancer have incurable disease and symptoms related to the primary intrathoracic tumor.5 Ninety percent of patients with

palliative radiotherapy advanced lung cancer suffer from pain at some point in their illness trajectory,5 most commonly in the chest and bone and usually worsening over time. Palliative RT is effective for improvement of symptoms such as chest pain and dyspnea91–93 and results in increased global QOL in approximately one third of patients.94 For locally advanced, unresectable NSCLC, survey results and practice audits suggest wide variation in aim of treatment, total dose, and number of fractions prescribed, reflecting a lack of consensus on optimal treatment. It seems that the optimal dose of RT needed to palliate advanced lung cancer has not yet been well defined, analogous to the current situation with bone metastases. Eleven RCTs comparing various RT dose schedules for locally advanced lung cancer published since 1991 have concluded that there is no difference in the rate of palliation of intrathoracic symptoms,95–105 although higher doses tend to result in more severe toxicity. This conclusion has been echoed by one systematic review, which was updated recently.106,107 However, survival results were not quite as straightforward. Three trials found better survival with higher doses of radiation,98,101,104 one trial found that higher doses were associated with worse survival,105 and the remainder reported equivalent survival.95–97,99,100,102,103 The systematic review concluded that any survival benefit would likely be minimal and confined to patients with good performance status.106,107 We have updated the systematic reviews to include quantitative pooling of the 13 RCTs investigating different RT dose fractionation schedules. This includes 3473 patients with locally advanced and/or metastatic lung cancer not suitable for curative-intent treatment. For palliation of chest pain in evaluable patients, five trials reported a total of 275 patients in the higher-dose arms and 264 patients in the lower-dose arms assessable for complete resolution. A complete response was achieved by 51.9% of patients in the lower-dose arms and 57.5% in the higher-dose arms (P = 0.43). A total of 484 patients in the higher-dose and 474 in the lower-dose arms of eight trials were evaluable for any degree of improvement (complete and partial responses); 63.8% and 64.8% of patients, respectively, reported that their chest pain improved after RT (odds ratio, 1.0; 95% CI, 0.89–1.12; P = 0.94). Interestingly, an improvement in survival was associated with higher RT doses. Liver Although surgical resection, percutaneous ethanol injection, chemoembolization, cryotherapy, and thermal ablation

391 all have been used to treat liver metastases, most require potential patients to have metastases ⬍4 cm and located away from major blood vessels, the biliary tract, and the diaphragm.108 Even brachytherapy with yttrium 90 microspheres, although allowing localized delivery of radiation to tumors via hepatic arterial delivery, is limited to tumors ⬍5 cm because of rapid dose fall-off.108 Many patients do not fit these specific criteria, and it is this population in which RT has been studied. Initially, EBRT to the whole liver was offered to patients experiencing pain secondary to widespread metastases causing capsular stretch. However, radiation tolerance limits the dose available when treating the whole liver to that well below what would be needed for long-term control of disease, and even that carries risks of significant acute and late toxicity.5 Successive RTOG studies have shown that RT alone can result in short-lived palliation of symptoms.109–111 In 75%–90% of patients, doses of 20–30 Gy in fractions of 2–3 Gy delivered to the entire liver result in reduction of abdominal pain secondary to hepatic distention. Hepatomegaly may shrink, and results of liver function tests may improve. Pain relief takes approximately 10–12 days and lasts a median of about 3 months. However, most patients will experience side effects due to RT and succumb to their disease within 4–6 months. More recently, conformal RT delivery approaches have allowed dose escalation to metastases to increase the chances of long-term control while sparing normal tissue to decrease the risk of radiation-induced liver disease (RILD).108 Another advantage is that the risk of RILD can be estimated based on dose received by the surrounding normal liver, and patients can be counseled and managed appropriately.112 In one study of patients with unresectable liver metastases secondary to colorectal cancer, the median diameter of the treated metastases was 10 cm. Patients were treated with conformal RT and concurrent intra-arterial chemotherapy; the response rate in evaluable patients was 86%. At a median follow-up of 27 months, 1-year survival was 81% and 2-year survival was 30%, far in excess of what would be expected with conservative treatment.113 Use of this approach with liver metastases secondary to cancers other than colorectal is more limited, but appears promising.114 Recurrent or metastatic pelvic masses In addition to pain, recurrent or metastatic pelvic masses may cause troublesome bleeding, obstructive symptoms, edema, fistula formation, and discharge, with attendant deleterious effects on QOL. Because many patients

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392 with advanced pelvic malignancies have a limited life expectancy, abbreviated treatment approaches have been explored.7 In a prospective cohort study, effective symptom palliation was seen following one to three fractions of 10 Gy to the pelvis given 4 weeks apart. Although the overall response rate to treatment was 41%, the severe late toxicity rate was 49% in patients who received all three fractions.115–118 Given the high complication rate, RTOG 8502 investigated 370 cGy twice a day for 2 days, randomly assigning patients to a rest interval of either 2 or 4 weeks, and repeated this three times, to a total dose of 44.4 Gy/12.119 This regimen was associated with a much lower risk of late toxicity that did not differ between arms (7%). Approximately 50% of patients experienced complete pain relief, and 90% had complete resolution of bleeding or obstruction.120 Patients who received treatment with shorter break intervals were more likely to suffer acute side effects, but also more commonly completed all three courses than patients who had the longer breaks.7 A dose–response relationship has been reported, with repeat fractions giving more effective palliation.117,118 A review addressing the question of the most effective dose fractionation for symptom relief in patients with pelvic recurrence from colon or rectal cancer included studies of doses ranging from 15 to 70 Gy but could not provide a definitive answer.121 Metastatic para-aortic lymphadenopathy from pelvic primary cancers may result in lower back pain, which is also effectively palliated with local RT. Skin Neglect of skin lesions may lead to patients presenting with large destructive lesions invading surrounding soft tissue and bone, resulting in pain along with bleeding, ulceration, and secondary infection. A short course of palliative RT can reduce bleeding and allow ulcerative lesions to dry, making nursing care easier. Malignant melanoma is an aggressive primary skin cancer with high rates of distant metastases. Palliative RT does provide effective and durable palliation for this disease entity as well, despite the disease having the reputation of being relatively radioresistant. Fractional doses of ≥400 cGy are thought to be more effective than those ⬍400 cGy, with response rates of 82% versus 36%, respectively.122 Painful nodal masses and enlarging cutaneous or subcutaneous metastases also are usually responsive to RT.2

Reirradiation General Certain subsets of patients with metastatic disease have longer life expectancies than in the past, in large part because of advances in systemic therapy. Therefore, more and more patients are outliving the duration of benefit provided by their initial palliative RT, requiring consideration of reirradiation of previously treated sites at a later date.7 Reirradiation is offered in clinical situations in which other modalities, such as surgery or chemotherapy, are either ineffective or not indicated.123 The risks of no treatment and the rationale for why other types of antineoplastic therapy are unsuitable should be stated and the risks and benefits thoroughly discussed.124 There are three scenarios in which reirradiation may be considered, and it is unclear whether response to retreatment is similar for each: 1. The patient experiences no pain relief or pain progression after initial RT 2. The patient experiences partial response after initial RT but hopes to achieve a greater response with further treatment 3. The patient experiences partial or complete response after initial RT but subsequently has a recurrence of pain When assessing retreatment rates after RT, it is important to be aware that one reason why more patients receive repeat treatment after a single dose of RT is because they can.7 Many ROs are reluctant to prescribe a second course of treatment after a patient has had more than 30 Gy, particularly if the spinal cord or another sensitive normal tissue is in the treatment volume.7,11 Additionally, patients who could potentially benefit from further treatment may be lost to follow-up or may not be referred back. When considering reirradiation, many factors need to be taken into account. What dose and fractionation has the area already received? What is the patient’s performance status? Would additional RT be effective, or is the patient a candidate for supportive care only? What is the time interval since previous treatment? Are there observable radiation sequelae from previous treatment? What are the critical normal structures in the proposed field, and will the patient survive long enough to be at risk of severe toxicity to them?123,125 Use of radiation delivery methods other than EBRT may be in order; for example, brachytherapy and radiopharmaceuticals may be just as effective but avoid

palliative radiotherapy the risk of additional toxicity to surrounding normal tissue. Electron therapy may address a symptomatic superficial tumor sufficiently but avoid delivering unnecessary dose to deeper structures. Careful treatment planning is essential to minimize the risk of serious side effects, even in a population with limited life expectancy. The clinical indications, optimal dose and fractionation, and techniques for retreatment are controversial and vary among physicians. The response to reirradiation is variable, and no consistent policy is recommended or followed. Individual oncologists may find decision making difficult because of the multiple “one-off” situations, make general guidelines impossible.124 Many ROs are reluctant to reirradiate because of a lack of precise quantitative data on the time course, magnitude, and tissue specificity of long-term occult radiation injury recovery.125 We await with interest the results of a Canadian survey of ROs concerning management of common in-field recurrence scenarios. Bone In RCTs, reirradiation for bone metastases was delivered at the discretion of the treating ROs, who were not blinded to initial treatment received. Additionally, there were no guidelines explaining when, why, and what dose of radiation should be prescribed for the second course. In the studies that compared a single dose of 8 Gy with a longer course of treatment, the rates of retreatment were significantly higher after the single-dose RT (Table 20.7).7 For example, in the Bone Pain Trial Working Party26 trial, retreatment was twice as common after 8 Gy than after multifraction RT. In the initial report of the Dutch Bone Metastasis Study, retreatment rates were 25% in the singlefraction arm versus 7%.27 These data subsequently were reanalyzed by initial treatment response and number of fractions in subsequent courses (see later). Patients in the single-fraction arm of the 2005 RTOG study also had a higher rate of retreatment (18% vs. 9%, P ⬍ 0.001).20 In the Scandinavian trial, retreatment rates again were higher in the single-fraction arm, but no P values were reported.21 Only two of the three published meta-analyses have pooled this outcome, with Sze et al.28 finding a significantly higher retreatment rate across studies (22% vs. 7%, P ⬍ 0.0001). This was echoed by Chow et al.,18 who reported 20% (single fraction) versus 8% (multifraction) retreatment rates (P ⬍ 0.0001). Many studies have suggested that 4–6 weeks is the minimum time interval to maximum response after EBRT for bone metastases. Therefore, consideration of retreatment

393 should be delayed until this time, which allows response to the first course to be adequately assessed and any pain flare to have resolved.10 Price et al.126 reported on seven patients who, after failure to respond to the initial 4-Gy fraction, were given repeat RT within 8 weeks. Four of them received a single 8 Gy dose, and the other three a fractionated course. No significant pain relief was achieved by the second RT treatment in these seven patients. Uppelschoten et al.127 reported that after long intervals from a previous 6-Gy single dose, reirradiation with another 6 Gy was able to reduce pain in 13 of 18 patients. In a retrospective analysis of 105 consecutive patients treated with palliative RT for painful bone metastases, 280 individual treatment sites were identified, 57 of which were re-treated once and eight of which were re-treated twice.128 The overall response rate to initial treatment was 84% for pain relief; at first retreatment, this was 87%. Seven of 8 patients (88%) re-treated a second time also achieved pain relief. Seventeen of 23 patients (74%) responded to a second course consisting of a single fraction, which was not significantly inferior to the response in 31 of 34 (91%) obtained with more protracted regimens. No relation to radiation dose, primary tumor type, or site was seen. Hoskin et al.129 randomly assigned patients to either 4 Gy/1 or 8 Gy/1 in the treatment of metastatic bone pain. During the 12-week study period, 28 patients assigned to 4 Gy were re-treated with RT to the same site compared with 12 patients assigned to 8 Gy. Twelve of 17 evaluable patients (71%) responded to retreatment in the 4-Gy arm and four of nine (44%) responded in the 8-Gy arm. Jeremic et al.130 investigated the effectiveness of 4 Gy/1 given for retreatment of bone metastases after previous single-fraction RT. Of 135 patients re-treated, 109 were re-treated because of pain relapsing, whereas 26 patients were re-treated because of initial nonresponse. Of the 109 patients reirradiated for pain relapse, 80 (74%) responded (complete response, 31%; partial response, 42%). Among the 26 patients who initially did not respond, there were 12 responses(46%). The authors concluded that the lack of response to initial single-fraction RT should not deter repeat irradiation. Toxicity in their series was mild and mainly gastrointestinal. Pathological fractures were reported in three of 135 patients (2%) and spinal cord compression in three of 135 patients (2%). The same group recently reported the efficacy of a second single 4-Gy reirradiation dose (i.e., a third course to the same site) for painful bone metastases.131 The overall response rate of the 25 patients (19 responders and six

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394 nonresponders to the two prior single fractions) was 80%, with complete response and partial response both 40%. No acute or late severe toxicity was observed. The Dutch Bone Metastases Study Group recently reanalyzed their data to specifically report the efficacy of reirradiation.132 Of patients not responding to initial radiation, 66% who initially received 8 Gy/1 responded to retreatment, compared with 33% of patients who initially received a multifraction course. Retreatment in patients after pain progression was successful in 70% of those who received a single fraction initially, as compared with 57% of those who received more than one fraction. Overall, reirradiation was effective in 63% of all such treated patients. It is therefore worth considering reirradiation of sites of metastatic bone pain after initial RT, particularly when this follows an initial period of response. There is also evidence that a proportion of initial nonresponders will respond. The preferred dose schedule, however, is unknown. To date, no prospective randomized study has been completed. However, a large prospective randomized intergroup study employing common reirradiation schedules has been launched.133 Patients with painful bone metastases who have received prior palliative RT will be included. The initial dose to extremities or ribs may be 6 Gy/1, 8 Gy/1, 18 Gy/4, 20 Gy/5, 24 Gy/6, or 30 Gy/10. The initial dose to metastases in the spine and pelvis may be 6 Gy/1, 8 Gy/1, 18 Gy/4, or 20 Gy/5. Patients given an initial dose of 24 Gy/6, 27 Gy/8, or 30 Gy/10 to the spine or any part of the pelvis are not eligible. Patients who received initial doses of 24 Gy/6, 27 Gy/8, or 30 Gy/10 to the acetabulum, hip, or proximal femur are eligible as long as the initial medial field border did not cross midline. Patients are randomly assigned to either 8 Gy/1 or 20 Gy in five or eight daily fractions; 20 Gy/8 is delivered if the initial RT course was multifraction and included the spine or whole pelvis. The primary end point is pain relief after reirradiation. Secondary objectives pertain to side effects and QOL. Brain Multiple modalities should be considered when embarking upon retreatment of metastatic disease to the brain; these are excellently reviewed by Morris.123 Importantly, the extent and rate of progression of disease outside the CNS must be considered.123 In general, patients showing signs of progression within 3–4 months of initial WBRT are unlikely to respond. However, patients with a prolonged survival of ⬎6–9 months, with new neurological symptoms and a reasonable functional status, may benefit from repeat

irradiation to the whole brain, especially if they are not candidates for SRS. Patients treated for radiologic progression without neurologic symptoms seem to have a higher complication rate.123 The recommended total dose of repeat WBRT of 20–30 Gy should be delivered in small (200–250 cGy) doses per fraction. The proportion of patients with symptom improvement or stabilization is variable, at 27%–70% and 13%– 52%, respectively.123,134–136 One study reported 100% in-field control and 89% CNS control,135 with another describing a median duration of response of 10 weeks.136 However, proportions of patients experiencing serious side effects also varied, from 0%–100%, with some treatmentinduced deaths, leukoencephalopathy, dementia, and radiation necrosis.

Conclusions With an increasing number of treatment modalities and pharmaceuticals effective for relief of pain, the multidisciplinary approach to patient assessment has never been more important to deriving a management plan best suited for the individual. There is an urgent need for large welldesigned prospective clinical trials in many areas of palliative radiation for pain control, especially in the settings of neuropathic and visceral pain. References 1. Kirkbride P, Barton R. Palliative radiation therapy. J Pall Med 2:87–97, 1999. 2. Samant R, Gooi AC. Radiotherapy basis for family physicians: potent tool for symptom relief. Can Fam Physician 51:1496– 501, 2005. 3. BASO: British Association of Surgical Oncology. The management of metastatic bone disease in the United Kingdom. Eur J Surg Onc 25:3–23, 1999. 4. Falkmer U, Jarhult J, Wersall P, et al. A systematic overview of radiation therapy effects in skeletal metastases. Acta Oncol 42:620–33, 2003. 5. Hoegler D. Radiotherapy for palliation of symptoms in incurable cancer. Curr Prob Cancer 21:134–83, 1997. 6. Chow E, Wong R, Hruby G, et al. Prospective patient-based assessment of effectiveness of palliative radiotherapy for bone metastases in an outpatient radiotherapy clinic. Radiother Oncol 61:77–82, 2001. 7. Lutz ST, Chow EL, Hartsell WF, et al. A review of hypofractionated palliative radiotherapy. Cancer 109:1462–70, 2007. 8. Mackillop WJ. The principles of palliative radiotherapy: a radiation oncologist’s perspective. Can J Oncol 6(Suppl 1):5– 11, 1996.

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of the long bones. A retrospective study of 233 surgically treated fractures. Eur J Surg 160:535–42, 1994. Chow E, Holden L, Danjoux C, et al. Successful salvage using percutaneous vertebroplasty in cancer patients with painful spinal metastases or osteoporotic compression fractures. Radiother Oncol 70:265–7, 2004. Porter A, McEwan A, Powe J. Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistance metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25:805–13, 1993. Smeland S, Erikstein B, Aas M, et al. Role of strontium-89 as adjuvant to palliative external beam radiotherapy is questionable: results of a double-blind randomized study. Int J Radiat Oncol Biol Phys 56:1397–404, 2003. Bauman G, Charette M, Reid R, et al. Radiopharmaceuticals for the palliation of painful bone metastases – a systematic review. Radiother Oncol 75:258e1–258.e13, 2005. Vassiliou V, Kalogeropoulou C, Giannopoulou E, et al. A novel study investigating the therapeutic outcome of patients with lytic, mixed and sclerotic bone metastases treated with combined radiotherapy and ibandronate. Clin Exp Metastasis 24:169–78, 2007. Michael M, Wirth A, Ball DL, et al. A phase I trial of high-dose palliative radiotherapy plus concurrent weekly Vinorelbine and Cisplatin in patients with locally advanced and metastatic NSCLC. Br J Cancer 93:652–61, 2005. Merskey H, Bogduk N. Classification of chronic pain. Seattle: IASP Press, 1994. Grond S, Radbruch L, Meuser T, et al. Assessment and treatment of neuropathic cancer pain following WHO guidelines. Pain 79:15–20, 1999. Kanner R. Diagnosis and management of neuropathic pain in patients with cancer. Cancer Invest 19:324–33, 2001. Roos DE. Continuing reluctance to use single fractions of radiotherapy for metastatic bone pain: an Australian and New Zealand practice survey and literature review. Radiother Oncol 56:315–22, 2000. Rutten EH, Crul BJ, Van Der Toorn PP, et al. Pain characteristics help to predict the analgesic efficacy of radiotherapy for the treatment of cancer pain. Pain 69:131–5, 1997. Crellin AM, Marks A, Maher EJ. Why don’t British radiotherapists give single fractions of radiotherapy for bone metastases? Clin Oncol 1:63–6, 1989. Roos DE, Turner SL, O’Brien PC, et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (TROG 96.05). Radiother Oncol 75:54–63, 2005. Pollicino CA, Turner SL, Roos DE, et al. Costing the components of pain management. Analysis of TROG 96.05: one versus five fractions for neuropathic bone pain. Radiother Oncol 76:264–9, 2005. Chang VT, Janjan N, Jain S, Chau C. Update in cancer pain syndromes. J Palliat Med 9:1414–34, 2006. Coia LR, Roda PI. Palliation and care of the terminal patient. In: Coia LR, Moyland DJ, eds. Introduction to clinical

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21

Palliative systemic antineoplastic therapy sunil m. patel and michael j. fisch The University of Texas M. D. Anderson Cancer Center

Introduction Palliative care for patients with advanced cancer centers on alleviating suffering and promoting quality of life. Understandably, the emphasis of palliative care is on mitigating the impact of the malignancy on the individual rather than persisting in the direct battle against the cancer. In this shift toward palliation, patients and providers sometimes lose sight of the potential value that anticancer therapy can provide in terms of relieving symptoms and preserving function. Conversely, as advances in medical oncology have led to improved outcomes in a number of tumor types, enthusiasm for new cancer therapies must be tempered by the very real drawbacks of such therapies. Systemic anticancer therapy such as chemotherapy, hormonal therapy, or other modalities (e.g., targeted therapy, immunotherapy) may expose the patient with advanced cancer to significant risks. In addition to toxicity-related risks, added expense and the loss of valuable time and energy, which could be utilized in other ways, are other important factors to consider. The uncertainty regarding outcomes and the complexity involved in making treatment decisions have made the issue of palliative systemic therapy controversial and, at times, a source of conflict between providers and family members. From the provider’s perspective, the intricacy and heterogeneity of cancer have become increasingly daunting, as recalling the varied natural histories and ever-changing treatment strategies for even the most common tumor types is difficult for all medical practitioners, including medical oncologists. As the practice of medical oncology shifts toward tumor-specific treatment strategies and with genetic signature-based “personalized” therapy already being utilized, overarching principles of therapeutic oncology are still in the forefront and are the focus of this chapter. This chapter outlines the therapeutic rationale for considering

palliative systemic therapy, including how to select patients who are most likely to benefit from therapy, how to ascertain patient preferences, and how to choose the appropriate time to initiate therapy as well as discontinue it. Basic information related to chemotherapy, hormonal therapy, and targeted therapies also is reviewed.

Determining whether palliation is the appropriate goal The first step in selecting patients for palliative systemic therapy is to make sure that the patient is not being prematurely offered palliative therapy when a realistic chance of cure is still available. Although this generally is not a problem for medical oncologists, it may be difficult for other specialists involved in palliative care to recall which disseminated malignancies are currently considered curable under some circumstances. Table 21.1 summarizes the response categories for first-line systemic therapy for metastatic cancer. With the exception of hairy cell leukemia and germ cell cancer, which usually are cured with conventionaldose chemotherapy, each of those diseases has been shown to be amenable to dose-intense chemotherapy or targeted therapy.1 As a testament to the ever-evolving nature of clinical oncology, cancers such as chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (GISTs), which just a few years ago were thought to essentially be incurable, are now brought into long-term remission with imatinib, an orally administered small molecule inhibitor of the dysregulated protein responsible for unchecked cellular growth in these malignancies.2,3 There are other malignancies for which cure with systemic therapy is more than an anecdotal event, but it happens in fewer than 10% of patients. These diseases (e.g., renal cell carcinoma [RCC], malignant melanoma, and bladder cancer) can create significant confusion. Patients 399

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400 Table 21.1. Response categories for first-line systemic therapy for metastatic cancer

Performance status is a powerful predictor of prognosis and treatment outcome

Potentially curable Acute myeloid leukemia Acute lymphocytic leukemia (childhood) Chronic myelogenous leukemia Myelodysplastic syndrome Hodgkin’s disease Non-Hodgkin’s lymphoma (some subsets) Hairy cell leukemia Germ cell tumors Gastrointestinal stomal tumors Highly responsive (response rates ≥50%) Breast carcinoma Ovarian carcinoma Androgen-dependent prostate cancer (hormonal therapy) Small cell lung carcinoma Lymphoma (some subsets) Multiple myeloma Moderately responsive (response rates ≥30%) Non–small cell lung cancer Colorectal cancer Transitional cell carcinoma of the urothelial tract (e.g., bladder cancer) Sarcoma (some subsets) Endometrial carcinoma (hormonal therapy) Less responsive (response rates ≤30%) Gastric carcinoma Esophageal carcinoma Head and neck carcinoma Pancreatic carcinoma Androgen-independent prostate cancer Osteogenic sarcoma Hepatocellular carcinoma Renal cell carcinoma Malignant melanoma Mesothelioma Anaplastic thyroid cancer Islet cell and carcinoid tumors

Performance status refers to a judgment about the level of activity that a patient exhibits. It is also referred to as functional status. In clinical trials of chemotherapy, the first and most widely used measure was the Karnofsky Performance Status (KPS) described in 1948 as part of an outcome evaluation of nitrogen mustard use in the treatment of unresectable bronchogenic carcinoma.4 Another activity scale was developed in 1960 by Zubrod et al.5 and later adapted by the Eastern Cooperative Oncology Group (ECOG) for use in various chemotherapy trials.6 These performance status measures are summarized in Table 21.2. For the purpose of most clinical trials, “good” performance status is considered ECOG level 0 or 1 (KPS ≥70%), ECOG level 2 is considered borderline, and ECOG levels 3 and 4 are considered “poor” performance status. Measurement of performance status is limited by the fact that it involves only a crude, unidimensional quantification of activity levels and that it is observer rated rather than self-reported. Physicians tend to underestimate symptoms and overestimate function relative to patients.7 However, it has the advantage of being easy to administer and its interpretation is straightforward. Performance status has been shown to be a powerful prognostic factor for outcome in a variety of diseases8–16 as well as a predictive factor for response to therapy.17 For these reasons, performance status is commonly used as a stratification factor in clinical trials or as an eligibility criterion. For example, one might limit the generalizability of a trial of combination chemotherapy because the trial included (or benefited) only patients with good performance status. There also are numerous examples in which

may receive inconsistent messages about the intent of therapy, sometimes hearing the word cure and on other occasions hearing the intent of therapy framed in palliative terms only. Generally speaking, these diseases are sometimes curable for patients in good general health with low-bulk disease in favorable sites. Finally, there are some diseases for which complete resection of isolated metastatic sites can produce long-term survival. These cancers may include metastatic colorectal cancer with resectable liver metastases, metastatic sarcoma, melanoma, RCC with resectable lung metastases, and relapsed, refractory germ cell cancer with resectable pulmonary or retroperitoneal metastases. In each instance, the goal is to render the patient disease-free through surgery. When this approach is feasible, as many as 20% of patients obtain long-term survival.

Table 21.2. Performance status by ECOG and Karnofsky criteria Grade

Description

0

Fully active, able to carry on all pre-disease performance without restriction (Karnofsky 90–100) Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work (Karnofsky 70–80) Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours (Karnofsky 50–60) Capable of only limited self-care, confined to bed or chair more than 50% of waking hours (Karnofsky 30–40) Completely disabled; cannot carry on any self-care; totally confined to a bed or chair (Karnofsky 10–20)

1

2 3 4

palliative systemic antineoplastic therapy performance status is used as an outcome measure, including in Karnofsky’s original paper. Patients with better performance status tend to have fewer symptoms and to live longer, and are also more likely to respond to therapy. Patients most likely to benefit from palliative chemotherapy for lung cancer are those with ECOG performance status of 0 or 1.18 This rule of thumb is potentially applicable to other patients with advanced solid tumors that exhibit only modest response rates (30%– 50%) with chemotherapy. Patients with ECOG performance status level 2 or worse generally are less likely to experience the same absolute benefit attributable to chemotherapy, and those with poor performance status often have an unfavorable risk/benefit ratio when offered conventional chemotherapy for advanced cancer compared with supportive care alone. There are exceptions to this rule, as one might expect with any rule of thumb. For example, patients with diseases that have rapid doubling times and are also known to be very sensitive to chemotherapy (response rates ≥50%) generally are appropriate candidates for cancer treatment. As such, patients with acute or chronic leukemia, high- or intermediate-grade lymphoma, GISTs, untreated small cell lung cancer, or breast cancer are usually offered chemotherapy despite poor performance status. Such patients may respond and improve dramatically. These responders usually are debilitated because of the cancer itself rather than severe infection or underlying comorbid medical problems. Not all metastatic sites are equal; some respond better than others For patients with advanced solid tumors, the volume of metastatic disease and the multiplicity of anatomic sites usually are related to both prognosis and likelihood of response to therapy. It is quite easy to understand why a patient with only one small metastatic lesion would have a better prognosis than a patient with bulky disease in multiple sites. However, it is less obvious but equally evident that patients with metastatic disease to visceral sites such as the bone, liver, or brain have a worse prognosis and are less likely to respond to systemic therapy than patients who have involvement of other sites, such as pulmonary parenchyma, lymph nodes, or skin. This observation has been noted for more than 20 years. Early in the cisplatin era, the series of trials using cisplatin-based chemotherapy for germ cell cancer involved the Indiana Staging System.19 This staging system was originally based on the clinical observation that the number of metastatic sites and size of the lesions were important to outcome, but also that visceral sites carry a worse prognosis. As such, patients with bone, liver, or

401

brain metastases were considered to have advanced-extent disease, regardless of their other prognostic factors. Two decades later, this observation was confirmed in a more rigorous, evidence-based update of the staging system for germ cell cancer.20 This same observation also has been made for less responsive solid tumors.8,10,21 Another important observation is that systemic therapy is not as effective for local control of primary sites as it is for treatment of metastatic sites. This also was established more than 20 years ago. Using data from the Eastern Clinical Drug Evaluation Program from 1961 to 1965, Slack and Bross22 reviewed response and location data from six primary tumor sites and six metastatic sites. With the exception of breast cancer, metastases were found to respond better than the advanced primaries from which they were derived. New advances in molecular oncology may eventually yield clues to the biologic basis of this observation. The impact of prior therapy: the first shot is the best shot Medical oncologists tend not to save their bullets – the first attempt at systemic therapy usually is the best opportunity for achieving a response and accomplishing the treatment goal of prolongation of survival and/or palliation of symptoms. Table 21.1 lists the current expectations for response for first-line systemic therapy for adults with metastatic cancer. Nevertheless, medical oncology is a discipline undergoing rapid evolution. The discovery of new molecular targets leads to novel drug development and the realistic expectations for response to treatment may shift for any given disease. Currently, combination chemotherapy remains the first-line choice for most malignancies; in the future, combination targeted therapy will probably be the most efficacious approach. In hormonally responsive tumors such as prostate, breast, endometrial, and papillary thyroid cancers, hormonal manipulations often are appropriate as the initial treatment. RCC and malignant melanoma are somewhat unique in that they share a profound resistance to combination chemotherapy and have a better response rate to biologic therapy using agents such as interferon-␣ or interleukin-2 (alone or in combination). For these tumors, the response rates remain poor despite the partial efficacy of biologic therapy, but a small fraction of patients (5%– 10%) achieve a response that can be amazingly durable (measured in years rather than months).23,24 More recently, oral tyrosine kinase inhibitors such as sorafenib and sunitinib have produced meaningful responses and the prospect for improved survival with far less toxicity compared with biologic therapy for RCC.25–27 This is a good example

402 of the rapidly changing landscape of systemic anticancer therapy. For many tumor types, there are multiple first-line chemotherapy options; choosing the first-line regimen that is most likely to be effective requires careful consideration. A notable predictor of response to first-line palliative chemotherapy is the disease-free interval (DFI), which represents the time period between the patient being rendered ostensibly free of disease (after chemotherapy, surgery, radiation, or any combination thereof) and relapse with distant recurrence or progression. One can reasonably hypothesize that a shorter DFI reflects relative tumor fitness, aggressiveness, and, if the patient received chemotherapy previously, at least some degree of resistance to the previous chemotherapeutic challenge. For example, in breast cancer, a long DFI (⬎5 years) portends a favorable prognosis and predicts responsiveness to hormonal therapy.28 Similarly, in acute myeloid leukemia, duration of first remission lasting less than 1 year suggests an extremely poor prognosis with standard reinduction therapy.29 Data from a number of tumor types corroborate the general principle that a short DFI correlates with worse prognosis. Perhaps more importantly, patients previously treated with curativeintent chemotherapy who subsequently experience a short DFI generally are treated with chemotherapeutic agents possessing an alternative mechanism of action in hopes of overcoming drug resistance. Patients who progress after first-line therapy generally have a poor prognosis, and the expected response rates for further therapy are quite low. Only a handful of metastatic cancers remain at least moderately responsive to secondline systemic therapy (see Table 21.3). In this setting, not only are bulk of disease, multiplicity of sites, and type of metastatic sites important for predicting prognosis and response to therapy, but so is the type of response to firstline therapy and the duration of that response. For example, a patient with advanced breast cancer who achieves a complete remission lasting 14 months with doxorubicin-based chemotherapy is more likely to respond to second-line therapy than a patient who failed to respond to initial therapy or whose initial response lasted only 3 months. There are Table 21.3. Metastatic cancers moderately responsive to second-line systemic therapy Breast carcinoma Ovarian carcinoma Acute and chronic leukemias (most subsets) Lymphoma (some subsets) Germ cell tumors Multiple myeloma

s.m. patel and m.j. fisch dramatically fewer clinical trials that address the use of systemic therapy in the setting of progression after first-line treatment compared with studies of previously untreated patients. As such, it can be difficult to formulate realistic expectations when faced with the choice of salvage therapy. As a general rule of thumb, most solid tumors show response rates to second-line therapy that are one third to one half the response rate in the first-line setting. For example, a patient with advanced transitional cell carcinoma of the bladder with lung metastases might have an expected initial response rate with combination chemotherapy of 40%, and with second-line therapy using an active single agent to which the patient has not been exposed, the expected response rate is less than 25% and the expected duration of response is similarly reduced. It is not clear whether or not this rule of thumb will apply equally well to patients treated with regimens containing one or more novel agents that are distinct from traditional cytotoxic chemotherapy. Age and its impact on treatment outcome Most systemic therapy for advanced cancer carries a significant risk of toxicity. The impact of a patient’s age on the expected outcome of treatment is an area of controversy in medicine. One can argue against age discrimination in medical oncology based on data available from older prospective studies in cancer patients showing that the effect of age is diminished or absent when multiple regression analysis is applied.30,31 More recent prospective studies in cancer patients32 and in seriously ill hospitalized adults33 suggest that there is a modest, independent effect of age on treatment outcome. The underlying explanation for this age effect is related to the fact that treatment risk often increases with age and also because advancing age brings with it other, competing health risks.34 For example, a treatment that can effectively reduce the 5-year mortality from a given cancer from 50% to 25% would have less impact on the average, vigorously healthy 80-year-old man than on a similarly healthy 70-year-old man. The effect of competing risks is important to consider when making a decision about whether or not to pursue systemic anticancer therapy, but once a decision is made to proceed with therapy, older adults with cancer benefit most from full-dose treatment. Attempts to modify the dose and schedule of palliative chemotherapy below standard thresholds have yielded inferior outcomes for older adults. This is evident in various diseases, including small cell lung cancer, non-Hodgkin’s lymphoma, and breast cancer.

Tumor Burden

palliative systemic antineoplastic therapy

A

Curative Chemotherapy

Palliative New Goal: Maximize area under the curve

Time (Length of Treatment)

Adjuvant

Chemotherapy

Progression or Distant Recurrence

Quality of Life

Tumor Burden

Surgery

B

Tumor Burden

Other Palliative Interventions Systemic Chemotherapy

Time (Length of Treatment) D

C

403

Time (Quantity of Life)

Neoadjuvant Chemotherapy Surgery

Time (Length of Treatment)

Fig. 21.1. The goal of chemotherapy and palliative interventions. Panels A, B, and C describe the effect of chemotherapy on tumor burden in various cancer treatment scenarios and in relation to surgery. Panel D illustrates the intended effects of chemotherapy and palliative interventions on the area under the curve for quality of life over time. (See color plate.)

Revisiting the goals of therapy Combination chemotherapy or other aggressive treatment of cancer may bring palliation by virtue of reducing the burden of tumor. Often, the goal of aggressive therapy is cure or prolongation of survival or local control of vital areas, and palliation is a secondary benefit. When cure is the intent, systemic therapy may be administered alone, after surgery, or before surgery (Fig. 21.1A–C). Regardless of nomenclature, the goal in this situation is eradication of all neoplastic cells, and the risk of toxicity often is mitigated by the very real chance of cure. In fact, the toxicity of curative therapy may worsen the overall health of the patient on a temporary or permanent basis. Strictly speaking, palliative therapy of any kind is treatment directed primarily at relief of one or more bothersome symptoms, with the goal of improving the overall quality of life for the patient. The goals of palliative chemotherapy, however, often step outside the typical palliative realm as

in some cases, both symptom relief and prolongation of survival are reasonable and achievable goals (Fig. 21.1D). Although symptom control and survival benefit may sometimes be cooperative goals, the physical costs and psychosocial burden of chemotherapy can place these two goals at odds with one another. For more chemoresistant tumor types, improved survival, objective response, and/or effective local control are less likely outcomes of palliative chemotherapy, and therefore symptom control becomes the primary intent. For most other tumors, the oncologist must judiciously utilize systemic therapy in hopes of prolonging survival while maintaining or improving quality of life (Fig. 21.1D). It is often surprising to nurses and physicians how much risk patients are willing to accept for what appears to be a slim chance of benefit. It is often assumed that the patients have been misled or misinformed by their oncologists. However, data support the conclusion that cancer patients tend to have a more risk-taking style compared with their

404 oncologists, nurses, and radiotherapists, as well as the general public. Slevin and colleagues35 explored this issue in a prospective study of 100 cancer patients with newly diagnosed solid tumors who were surveyed about their preferences with regard to a set of hypothetical chemotherapy treatments. The patients’ responses were compared with those of 100 controls matched for age, sex, ethnic origin, and occupation. Also surveyed were 60 oncologists, 88 radiotherapists, and 790 general practitioners. Patients clearly were most willing to accept chemotherapy for a small chance of benefit. The median benefit cancer patients required to accept mild chemotherapy was a 1% chance of cure, 1% chance of symptom relief, and a 3-month prolongation of survival. The next most aggressive group were oncologists, who required a median of a 10% chance of cure, 25% chance of symptom relief, and 6 months of survival benefit to accept mild chemotherapy. Cancer nurses, general practitioners, radiotherapists, and controls were all substantially more conservative than patients or oncologists. In a similar study performed in 1995, Bremnes and colleagues36 found that patients under age 40 were willing to accept toxic treatment for median benefits of 7% chance of cure, 8% chance of symptom relief, and 3 months of survival. “Palliating” the asymptomatic patient: the importance of symptom assessment The standard nomenclature of “palliative” chemotherapy may be confusing when considering the asymptomatic patient with advanced malignancy. Certainly, chemotherapy with the intent of symptom relief has no role in such a situation. Likewise, a patient with symptoms that are easily manageable with supportive care is not an ideal candidate for palliative chemotherapy either. For example, consider a patient with a head/neck tumor producing pain that is easily relieved with acetaminophen plus codeine given on an occasional basis. Contrast this with a patient whose tumor appears less alarming but who requires high doses of opioids to obtain partial relief from the nociception caused by the tumor. The latter patient might benefit from palliative chemotherapy with the intent of providing better analgesia and possibly reducing the dose of opioids and side effects of the opioids. However, the patient with good pain control on low doses of opioids is much less likely to benefit from chemotherapy with purely palliative intent. Some oncologists contend that chemotherapy may be appropriate for the patient with manageable symptoms to prevent worsening symptoms in the future. This “prophylactic palliation” approach is valid for diseases that are potentially

s.m. patel and m.j. fisch curable or highly sensitive to systemic therapy, or for situations in which there is some published value for maintenance chemotherapy strategies.37 In addition, for metastatic non–small cell lung cancer (NSCLC) and colorectal cancer, diseases classified as moderately responsive to systemic therapy, data support the use of chemotherapy (for good performance status patients) combined with “best” supportive care.38–40 For most other cancers that are either moderately or poorly responsive to systemic therapy, the use of chemotherapy to prevent or delay the onset of symptoms may be appropriate under some circumstances (depending on the patient’s preference style and specific data related to the value of a given regimen in a given disease), but the evidence to support a palliative benefit for most patients with advanced solid tumors is lacking. Likewise, even for specific treatment settings for which use of systemic anticancer therapy is supported by available clinical evidence, the regimen may not be appropriate for individual patients. This is particularly true when there are important comorbid conditions, mitigating social circumstances, or strongly held patient and/or family beliefs that such therapy will not be beneficial. Elegant use of palliative chemotherapy requires the oncologist to identify bothersome symptoms and to assess all symptoms in a disciplined fashion. Without such an assessment, the end point of therapy is unclear and the decisions about the duration of therapy become difficult. Pain is the most significant single symptom in advanced cancer patients, as more than two thirds of outpatients with metastatic cancer report pain or recent analgesia use.41 Guidelines for management of cancer pain stress comprehensive pain assessment at regular intervals, including quantification of pain intensity on a 10-cm visual analogue scale or a 0–10 numerical rating scale.42 A commonly used instrument for pain assessment is the Brief Pain Inventory.43 This instrument was originally developed in 1983 and has been validated in at least seven different languages. The rationale for using chemotherapy to improve pain relief is not simply to reduce tumor burden and to alleviate the mechanical effects of the cancer on normal structures, but also to diminish tumor function and production of nociceptive chemicals. For instance, chemotherapy may be indicated to treat hypercalcemia associated with parathyroid hormone–like protein associated with solid tumors such as squamous cell carcinoma and RCC. For most patients with advanced cancer, pain is just one of several co-occurring symptoms.44–50 Prevalent symptoms other than pain include fatigue, anorexia, constipation, dyspnea, psychological distress, and cognitive disturbances. The number of symptoms tends to increase as

palliative systemic antineoplastic therapy Table 21.4. Multidimensional scales for cancer patients Edmonton Symptom Assessment Scale (ESAS)125 Functional Assessment of Cancer Therapy (FACT)126 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)127 Rotterdam Symptom Check List (RSCL)128 Cancer Rehabilitation Evaluation Systems (CARES)129 Functional Living Index Cancer (FLIC)130 Medical Outcomes Study Short Form (MOS SF)131 Memorial Symptom Assessment Scale (MSAS)132,133

performance status declines. For example, in a series of hospice inpatients with advanced cancer, the median number of symptoms was 3.6 with KPS greater than 60, 5.7 for KPS 30–50, and 7.4 for KPS 10–20.45 Because of the complexity involved in trying to assess palliation in patients with multiple symptoms, it is often helpful to use a multidimensional assessment tool rather than an instrument tailored to assess one symptom. Several reliable and valid instruments are feasible for clinical use as well as for research. Many of these instruments are described as “quality of life” measures, although the appropriateness of that description is sometimes argued.51 Seven of the most widely used multidimensional assessment tools for cancer patients are listed in Table 21.4. Many of these instruments also have been validated in other languages. The Edmonton Symptom Assessment Scale is particularly easy to use in the outpatient setting, because it consists of nine visual analogue scales (which are easily understood by most patients) and it involves only one page. Overall, a disciplined and thorough approach to assessment of patients with advanced cancer allows for rational decision making regarding initiation of palliative chemotherapy or the adjustment of the dosage, frequency, or total duration of therapy. Just as performance status is a valuable predictor of prognosis and response to therapy, so is quality of life as measured by a multidimensional assessment.32,52 There are an increasing number of clinical trials in cancer with patient-reported outcomes measures integrated into the data collection process,53 thus setting the stage for the value of obtaining patient-reported outcomes more frequently in the delivery of quality cancer care.

Ascertainment of patient preferences An important aspect of making treatment decisions regarding palliative chemotherapy is the ascertainment of patient preferences. The patient’s preferences with respect to information style, participation in decision making, and care

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toward the end of life need to be explored in a straightforward manner. Some physicians use a pre-visit questionnaire to elucidate some of these preferences, others simply ask about these issues in the first one or two visits. In the United States, more than 80% of patients are avid for full disclosure of information about their illness,54,55 particularly in the earlier stages of disease, and the courts have upheld the ruling that physicians have a duty to adhere to full disclosure (although a patient can waive the right to information).56 Regarding autonomy in decision making, there is a trend for older and sicker patients to desire less autonomy,55,57 but most patients in the United States prefer some form of shared decision making. Regarding use of chemotherapy, at least in tertiary care settings, older adults are as likely as their younger counterparts to accept chemotherapy, although they are less likely to trade off current quality of life for potential survival benefit.58 One of the most difficult aspects of dealing with patient preferences involves the role of family members in the decision-making process. Most physicians have, at one time or another, faced tensions with families. Common sources of conflict include disagreement between family members and/or between different physicians, misunderstanding of medical facts or misinformation from outside sources, denial of bad news, guilt from family members, issues of secondary gain, and differing religious, ethnic, or cultural traditions.59,60 The most effective physicians are able to develop an ethic of negotiation and accommodation that involves active listening and careful, complete discussion of diagnosis, prognosis, and treatment options.60 Chochinov’s61 framework for dignityconserving care, which includes attention to attitudes, behaviors, compassion, and dialogue (the “A, B, C, and D” that embraces the essence of medicine) is fundamental to effective care in the context of palliative systemic anticancer therapy. Finally, any consideration of systemic anticancer therapy for palliation necessarily involves two very difficult tasks: prognostication and bad-news breaking. Oncologists or palliative care specialists often are the local experts on prognostication and bad-news breaking for advanced cancer patients and may be consulted to deliver that information skillfully. Prognostication refers to outlining the possible outcomes of the disease and the frequency with which they occur, as well as using characteristics of a particular patient to more accurately predict that patient’s eventual outcome.62 Clinicians sometimes use actuarial methods for prediction based on the medical literature. Prognostic information in the cancer literature is most valid when there is a representative and well-defined sample of patients studied

406 at a similar point in the disease, follow-up that is sufficiently long and complete, use of objective and unbiased outcome criteria, and adjustment for important prognostic factors.62 Prognostic data should be reproducible, which means the system is still accurate when it is applied to different patients from the same underlying population. Ideally, these data also are transportable, which refers to a data system that is still accurate when the sample is drawn from a different but related population or the data are collected by slightly different methods.63 When there are no applicable or readily available actuarial data, clinicians often use clinical prediction – a method that arises out of intuition and personal experience alone. For clinical prediction performed by patients, there tends to be an optimistic bias. In data derived from the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT), a subset of 917 cancer patients was examined; the receiver operating characteristic (ROC) curve area developed from the patient estimates of survival was only 66, with the inaccuracies clearly biased toward more favorable outcomes.64 In this study, patients who expected their survival to exceed 6 months were more likely to seek life-extending therapy (odds ratio 2.6; CI, 1.8–3.7), but the actual 6-month survival was not improved for those who favored life-extending therapy.64 Physicians’ clinical prediction of survival produced an ROC curve area of 0.78, which was significantly superior to the patients’ predictions.64 Physicians did not demonstrate an optimistic bias; they were as likely to underestimate survival as to overestimate.65 The mean of the physician estimates was always within 7.5% of the SUPPORT model estimates and always within 9% of actual survival.65 Overall, the ability of physicians or patients to accurately predict survival outcomes is limited. Nevertheless, physicians are in a position to evaluate and utilize published actuarial data and are generally able to produce superior clinical estimates of survival. Disclosure of prognostic information may be useful for patients and families for making treatment decisions in the setting of advanced malignancy. How should physicians communicate difficult information about prognosis or limited treatment efficacy without eradicating hope in a way that is antipalliative? There are established techniques that can be learned for approaching difficult communication tasks in oncology.66–72 General tips for breaking bad news are summarized in Table 21.5. Bad-news breaking is a clinical skill that can be developed through practice, and there are a growing number of workshops available to help physicians improve on this aspect of care.

s.m. patel and m.j. fisch Table 21.5. Techniques for breaking bad news Control of session r Select convenient time with no interruptions r Include presence of significant others to comfort the patient r Provide quiet, comfortable environment r Sit forward and use eye contact Style of delivery r Convey warmth, empathy, respect r Avoid jargon; use simple language r Provide the news at the patient’s pace Content of the message r Ascertain what the patient already knows r Give a warning shot r Provide realistic information and time frame r Acknowledge uncertainty r Provide realistic hope r Allow for the patient’s emotional reactions r Ask patients what they want to accomplish r Recommend taking care of personal and business affairs r Provide realistic assurance of your continuity r Allow for questions

Basic principles of palliative systemic therapy for cancer The field of medical oncology has grown tremendously since 1970, when there were roughly 13 commonly used drugs that could be divided according to four main mechanisms of action.73 In 1971, medical oncology was recognized as a distinct discipline of the American Board of Internal Medicine, and over the past 30 years there has been significant growth in the number of therapeutic agents available. Table 21.6 outlines the general categories of the most widely used anticancer therapeutics, including biotherapy and hormonal therapy. In the past few years, many new therapeutic agents have been introduced, many of which involve “targeted therapy” that takes advantage of newly discovered aspects of basic cellular and cancer biology. Any published list of the anticancer armamentarium is destined to be incomplete in this environment of rapid change in medical oncology. Some of the newer agents are available as oral agents, but most systemic therapy requires parenteral administration. The administration of parenteral systemic therapy requires not only specific cognitive and technical skills acquired by training, but also an appropriate infrastructure. The American Society of Clinical Oncology guidelines for high-quality chemotherapy administration include the following: necessary infrastructure, including physical space and equipment; medical and nursing staff with training and equipment for managing anaphylaxis and cardiopulmonary resuscitation; 24-hour availability of a treating physician; office support for documentation of

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Table 21.6. Categories of common anticancer therapeutics Classic alkylating agents Cyclophosphamide Ifosfamide Carmustine Lomustine Semustine Melphalan Chlorambucil Busulfan Mechlorethamine Thiotepa Antimetabolites 5-Fluorouracil Methotrexate Capecitabine Gemcitabine Pemetrexed Clofarabine Cladribine Cytosine arabinoside Fludarabine 6-Mercaptopurine Deoxycoformycin Hydroxyurea Alkylating agents (other) Procarbazine

Estramustine Dacarbazine Temozolomide Mitotane Streptozotocin Platinum compounds Carboplatin Cisplatin Oxaliplatin Taxanes Docetaxel Paclitaxel Abraxane Anthracyclines Doxorubicin Mitoxantrone Daunorubicin Liposomal doxorubicin Camptothecins Irinotecan Topotecan Vinca alkaloids Vincristine

Vinblastine Vinorelbine Antibiotics Bleomycin Dactinomycin Mitomycin-C Newer agents or classes Retinoids Cancer vaccines Gene therapy Radiation-response modifiers Antisense oligonucleotides Antiangiogenesis targets Tyrosine kinase inhibitors Farnesyl transferase inhibitors Metalloprotease inhibitors Miscellaneous Suramin Asparaginase

Monoclonal antibodies Rituximab Trastuzumab Bevacizumab Alemtuzumab Gemtuzumab ozogamicin Tositumomab Panitumumab Biotherapy Interferon Interleukin-2 Denileukin diftitox Steroids Prednisone Dexamethasone Methylprednisolone Hydrocortisone

Finasteride Flutamide Bicalutamide Nilutamide Liazorole Aminoglutethimide Ketoconazole Androgens Testosterone Danazol Antiestrogens Tamoxifen Raloxifene Droloxifene Toremifene Estrogens Diethylstilbetrol Ethinyl estradiol

LHRH analogues Leuprolide Goserelin

Progestins Megestrol acetate

Antiandrogens Cyproterone acetate Fluoxymesterone

Aromatase inhibitors Anastrozole Letrozole

Abbreviation: LHRH, luteinizing hormone-releasing hormone.

records; and administrative support for supplies and compliance with quality assurance standards.74 Traditional combination chemotherapy regimens are designed by combining active single agents with different mechanisms of action and nonoverlapping toxicity to produce additive or synergistic antitumor effects without producing excessive toxicity. The appropriate doses and dosing schedule are determined in phase I testing, and the feasibility and activity of the regimen are determined by phase II testing. There is a clear relationship for a dose– response effect for cytotoxic drugs when applied to various experimental tumor systems.75,76 In solid tumors, it has been demonstrated that less than optimal dose intensity is suboptimal,77 but high-dose chemotherapy has not been found to improve outcomes.1 New, targeted agents have been developed that do not fit this same model, and the design of phase I and phase II trials is being adapted for agents for which the classic dose–response relationship does not hold.78 Outside an investigational protocol, most oncologists will use single agents or combination chemotherapy in a dose and schedule that have been published previously. The traditional method of individualizing the dose of chemotherapy

is to estimate the body surface area of the patient with regard to height and weight using the DuBois formula.77 The most active regimens tend to require parenteral administration of therapy, but dozens of agents are being developed for oral use. A list of currently available oral chemotherapy agents is shown in Table 21.7. A prospective study of patients with incurable cancer demonstrated that 92 of 103 assessable patients (89%) preferred oral chemotherapy rather than parenteral therapy, but regardless of their initial preference, 70% were not willing to accept a lower response rate and 74% were not willing to accept a shorter

Table 21.7. Systemic therapy agents available orally for cancer Cyclophosphamide Chlorambucil Melphalan Busulfan Hydroxyurea Temozolomide Erlotinib Sunitinib Sorafenib

Mercaptopurine Methotrexate Etoposide Capecitabine Procarbazine Imatinib mesylate

408 duration of response in exchange for the convenience of oral chemotherapy.79 Evaluation of the patient before and after initiation of systemic therapy Once a decision has been made to initiate palliative systemic therapy, the next step is to complete a staging evaluation. The purpose of staging the patient is to evaluate the sites of disease so that a determination about response can be made after the therapy is initiated. For the purpose of evaluating solid tumors, lesions that can be measured in two dimensions by physical examination and/or by imaging are considered measurable. Lesions that can be detected but not measured (e.g., areas of uptake on a bone scan) are considered evaluable. A complete staging evaluation involves documenting the areas of measurable and evaluable disease. As mentioned above, a complete symptom assessment is also important so that the extent of palliation can be assessed. The next step is to proceed with a therapeutic trial, usually 6–8 weeks of systemic therapy, followed by a restaging examination. A complete response is defined as the disappearance of all sites of measurable and evaluable disease. A partial response refers to a ≥50% decrease in the sum of the bidimensionally measurable lesions. When the lesions have decreased or increased by ≤25%, the patient is described as having stable disease. Finally, patients who develop new sites of disease and/or an increase in measurable disease of ≥25% are said to have progressive disease. Because many of the newer, targeted therapeutic agents result in disease stabilization rather than tumor shrinkage, new concepts of response are being developed. Some protocols include traditional responders as well as patients with stabilization of their disease for several months as “responders.” For hematologic malignancies, response criteria generally are developed for the individual disease. For example, the criteria for response in multiple myeloma are distinct from the criteria for chronic lymphocytic leukemia. Overall, tumor response criteria may vary on the basis of the underlying disease or the nature of the therapeutic agent. In addition to assessing the response of the tumor, the oncologist is obliged to assess the pattern and extent of therapy-related toxicities. A common nomenclature for defining toxicities is provided by the National Cancer Institute in the United States, which publishes common toxicity criteria (http://ctep.info.nih.gov/CTC3/default.htm). The toxicities are graded on a scale of 0 (no toxicity) to 4 (severe toxicity). Selected areas of toxicity due to specific anticancer agents are shown in Table 21.8. Skillful supportive

s.m. patel and m.j. fisch care during chemotherapy involves the prevention and management of treatment-related side effects. The treating physician must obtain appropriate intravenous access when necessary and should be able to recognize which agents are vesicants in the event of an extravasation of the chemotherapy into the skin (see Table 21.9). In addition, prevention and treatment of chemotherapy-associated nausea and vomiting are extremely important. The advent of the 5hydroxytryptamine inhibitors has greatly improved the tolerability of combination chemotherapy. In addition, the use of colony-stimulating factors to mitigate the morbidity and mortality due to neutropenic infections for selected patients also is a significant advance that has enabled more patients to tolerate palliative chemotherapy. There are readily available consensus statements that provide guidance for appropriate management of chemotherapy-induced emesis as well as neutropenia.80,81 It should be noted that in addition to the objective toxicities experienced by patients on chemotherapy, the disruption to the patient and family related to the sheer inconvenience of frequent medical visits (e.g., expense, parking, need for babysitting, missed work) often is equally burdensome. In a study of 99 chemotherapy patients with a variety of solid tumors, the nonphysical “toxicities” constituted 54% of the 15 most severe symptoms as reported by the patients.82 Landmark trials with palliative primary end points The response definitions above provide the basis for generalizing data from clinical trials, and the response labels refer to the activity of the regimen against the tumor itself. The criteria for a palliative response have not been formalized and depend on the pretherapy assessment used. Two famous clinical trials paved the way for use of palliative primary end points in major clinical trials. First, in 1996, Tannock and colleagues83 reported the results of a randomized trial comparing mitoxantrone plus prednisone with prednisone alone for patients with symptomatic, hormoneresistant prostate cancer. All patients in the trial had pain, and there was an initial adjustment and stabilization of analgesic medication before beginning treatment. The primary end point was a palliative response, defined as a two-point decrease in pain as assessed using a six-point pain scale (without an increase in analgesic medication) maintained for at least 3 weeks. In this trial of 161 patients, the palliative response rate in the mitoxantrone plus prednisone arm was 29%, compared with 12% in the prednisone-alone arm. This trial provided the basis for the U.S. Food and Drug Administration (FDA) to approve mitoxantrone for

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Table 21.8. Selected areas of toxicity due to anticancer therapya Encephalopathy Methotrexate Ifosfamide Fludarabine Deoxycoformycin Interferon-␣ Interleukin-2 Cerebellar toxicity Cytarabine 5-Fluorouracil Ototoxicity Cisplatin Peripheral neuropathy Cisplatin Paclitaxel Docetaxel Vincristine Vinorelbine Vinblastine Interleukin-2 Pulmonary toxicity Bleomycin Mitomycin-C Carmustine Busulfan Cyclophosphamide Chlorambucil Methotrexate Cytarabine Fludarabine Heart failure Doxorubicin Daunorubicin Mitoxantrone 5-Fluorouracil Interleukin-2 Interferon alpha a

Myalgias/arthralgias Paclitaxel Interferon Interleukin-2 Fever/chills Interferon-␣ Interleukin-2 Bleomycin Etoposide Cladribine Nausea/vomiting Cisplatin Carboplatin Cyclophosphamide Doxorubicin Mechlorethamine Streptozotocin Dacarbazine Carmustine Dactinomycin Stomatitis Methotrexate Doxorubicin Cytarabine 5-Fluorouracil Hydroxyurea Diarrhea Irinotecan 5-Fluorouracil Cyclophosphamide Cytarabine Methotrexate Flutamide Interleukin-2 Interferon-␣

Renal dysfunction Cisplatin Carboplatin Methotrexate Carmustine Streptozotocin Hepatotoxicity Methotrexate Cytarabine Dacarbazine l-Asparaginase Carmustine Myelosuppression Paclitaxel Carboplatin Doxorubicin Daunorubicin Cyclophosphamide Ifosfamide Cytarabine Mechlorethamine Methotrexate Dacarbazine 5-Fluorouracil Fludarabine Chlorambucil Melphalan Busulfan Carmustine Lomustine Depression Prednisone Dexamethasone Interferon-␣ Leuprolide Goserelin Tamoxifen

This list is not comprehensive but represents commonly used therapies that cause common toxicities.

use in metastatic, hormone-resistant prostate cancer. The FDA also approved another cytolytic agent, gemcitabine, based on a trial with a palliative primary end point. In 1997, Burris and colleagues84 reported the results of a randomized comparison of gemcitabine versus 5-fluorouracil for first-line therapy of advanced pancreas cancer. Like the Tannock trial, this study included an initial lead-in period for pain stabilization. However, in this trial, the measure of palliation was not as straightforward in its interpretation. These investigators defined a specific, new efficacy measure called clinical benefit response, a composite of measurements of pain (analgesic consumption and pain intensity) plus performance status and weight. To be considered a responder, a patient had to demonstrate an improvement

in at least one of the three parameters (sustained for ≥4 weeks) without worsening in any of the others. The trial included 126 patients, and the gemcitabine arm showed a

Table 21.9. Agents that damage skin when they extravasate (vesicants) Doxorubicin Daunorubicin Vincristine Vinblastine Mitomycin-C Estramustine Mechlorethamine

410 clinical benefit response for 23.8% compared with 4.8% of 5-fluorouracil–treated patients. Although the aforementioned landmark trials reflect a growing appreciation of palliative end points in trials of systemic chemotherapy, the vast majority of clinical trials are designed with overall survival and/or time to progression as primary end points, with palliative end points typically included as secondary measures. Of note, Tannock et al.85 recently reported the results of the TAX-327 trial, which compared two different schedules of docetaxel/prednisone with mitoxantrone/prednisone. Overall survival was the primary end point, with a statistically significant improvement in median survival of 2.4 months. Secondary palliative end points, including quality of life and pain, also were significantly improved with docetaxel versus mitoxantrone. In pancreatic cancer and other malignancies with low chemotherapy response rates, primarily palliative end points are commonly used in assessing novel treatment strategies, as positive survival end points are difficult to achieve given the resistant nature of the underlying disease and difficulty in accruing sufficient numbers of patients to clinical trials. Duration of therapy for the responding patient For patients who demonstrate a complete or partial response and acceptable toxicity after a 6- to 8-week therapeutic trial of systemic therapy, the oncologist is faced with a decision about the duration of therapy. Although there is sometimes a role for maintenance chemotherapy in hematologic malignancies such as acute or chronic leukemia, most solid tumors are treated with limited chemotherapy. The rule of thumb is to treat with two additional cycles of therapy (usually 8–12 weeks) after the maximal response has been obtained. This translates into a total of 4–8 cycles of therapy for most patients over the course of 4–8 months. There have been numerous attempts to use more prolonged courses of chemotherapy for a variety of advanced solid tumors, and that strategy has been decidedly unsuccessful.86–90 In general, duration of therapy in the responding patient is guided by two fundamental principles: minimizing cumulative toxicities and maximizing duration of treatment response. In advanced NSCLC, multiple studies have demonstrated that first-line therapy limited to 4–6 cycles of treatment offers similar survival and symptom control compared with continuous therapy (i.e., continued chemotherapy until disease progression) or sequential therapy with non–cross-resistant agents.91–95 In metastatic colorectal cancer, the picture is evolving. In the recent past, many patients would receive continuous chemotherapy

s.m. patel and m.j. fisch with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), which after approximately 12 cycles typically causes significant neuropathy. Recent trials designed to investigate the role of lower-toxicity maintenance chemotherapy (5-fluorouracil/leucovorin) after response to first-line FOLFOX have demonstrated an improvement in overall survival with maintenance therapy compared with retreatment with chemotherapy at the time of disease progression.37 There is, however, a growing appreciation in other settings for the role of a “treatment pause” as a valuable strategy to consider as the oncologist strives to achieve the best quality of life over time for each individual patient. Many patients put substantial value on time that they feel well and are not requiring treatment, and few chemotherapy clinical trials assess end points that have distinct meaning with regard to the palliative value of any treatment approach, such as symptom-free intervals, time to symptomatic progression, and chemotherapy-free time intervals. In metastatic breast cancer, three well-known trials evaluated the value of continuous chemotherapy. A trial involving 308 patients from Australia and New Zealand tested the hypothesis that continuous treatment with chemotherapy may be superior to limited-duration therapy. In this trial, the limited-duration arm involved only three cycles of chemotherapy. The study arms were not significantly different with respect to overall survival, but the continuouschemotherapy arm produced longer time to progression and improved quality of life despite the added therapy-related toxicities.96 Similarly, in 1991, Muss and colleagues97 studied a cohort of 250 women with previously untreated metastatic breast cancer. The patients were initially treated with six cycles of cyclophosphamide, doxorubicin, and 5-fluorouracil, and those with stable or responding disease were then randomized to maintenance chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil, or observation until disease progression. In this study, the maintenance therapy patients did not have improvement in overall survival, but they did have increased nausea, vomiting, and mucositis as well as a roughly 6-month prolongation in the time to progression. The interpretation of these data is limited by the fact that both trials may have featured suboptimal initial chemotherapy treatment. The Australian–New Zealand Breast Cancer Trials Group study used only three cycles of initial therapy, whereas most oncologists favor four to eight initial treatment cycles. In the latter study by Muss, the dosing algorithm involved upfront dose reductions for patients over age 60 and those with three or more bone lesions. Again, the trend toward suboptimal initial dosing may have artificially inflated the apparent value of continuous (maintenance)

palliative systemic antineoplastic therapy chemotherapy. A study conducted by Gennari et al. investigated the use of maintenance paclitaxel for eight cycles in patients who had response or stable disease after a firstline anthracycline/taxane regimen. This study was stopped early because the maintenance chemotherapy arm demonstrated no improvement in overall survival or progressionfree survival compared with the no-treatment arm. Novel targeted agents for breast cancer, such as trastuzumab (discussed in detail later), are effective for certain subsets of patients and have complicated the issue of maintenance chemotherapy in this population. Given trastuzumab’s generally mild side effect profile, many physicians and patients opt to continue single-agent trastuzumab indefinitely, despite the fact that few data exist to support its use in this setting. Thus, there is controversy regarding the utility of maintenance chemotherapy in breast cancer, and at present both intermittent and continuous approaches are used, based largely on patient and tumor characteristics and patient and physician preference. In notable contrast to the situation with chemotherapy, it is important to realize that the current standard of care for patients who are responding to hormonal therapy for prostate cancer or breast cancer is to continue that therapy until progression.98,99 Treatment decisions for stable or progressive disease The proper duration of therapy may be very difficult to ascertain for patients who obtain only stable disease with aggressive therapy, and for those who have discordance between their objective and subjective responses. In the case of stable disease, oncologists often will weigh the toxicities and inconvenience of therapy against the change in subjective well-being before recommending whether or not to continue treatment. For “close-call” situations, the patient’s preference is often the determining factor. Sometimes, a patient will experience some degree of disease progression and yet report an improvement in certain symptoms and/or improved overall well-being. It may be argued that the treatment is slowing the rapid pace of progression and that further treatment is worthwhile. Generally speaking, this type of reasoning is worth avoiding. Patients and their physicians share a “good news” bias with respect to the value of therapy. There often is some psychological comfort gained for both the patient and physician for delaying a confrontation with bad news. A style of communication that allows the patient to dictate most of the flow of prognostic information (and even to avoid it or delay it) has been coined “necessary collusion.”100 The challenges for physicians using palliative chemotherapy are to be prepared to

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deliver truthful news about disease progression skillfully (see Table 21.5), to be sensitive to specific patient and family needs, and to guide patients toward other sources of hope rather than continuation (or introduction) of ineffective therapy.

Hormonal therapy: an important treatment for advanced breast and prostate cancer Hormonal therapy has been part of the anticancer arsenal since 1896, when Beatson101 first described the effects of oophorectomy on metastatic breast cancer. In the 1940s and 1950s, other forms of surgical ablation were developed, including bilateral adrenalectomy and hypophysectomy for breast cancer102 and bilateral orchiectomy for prostate cancer.103 Currently, hormonal therapy for metastatic breast cancer and prostate cancer usually is accomplished with medical therapies that were found to be as effective as surgical forms of hormone ablation in randomized trials conducted mostly in the 1970s and 1980s. Although the exact mechanism of action of the various hormonal agents is not completely understood, these agents are known to influence steroid hormones or the steroid receptors found on breast and prostate cancer cells (and sometimes in other tumors) to either arrest cell growth or trigger cell death. There are other diseases for which hormonal therapies are sometimes used (e.g., endometrial cancer and thyroid cancer), but the following discussion focuses on strategies used to treat breast and prostate cancer. Hormonal therapy for advanced breast cancer A significant proportion of metastatic breast cancer patients harbor tumors that are amenable to hormonal manipulation. The prototypic hormonal agent in advanced breast cancer is tamoxifen, a synthetic antiandrogen that has been used since the early 1970s.104 Tamoxifen acts by way of estrogen receptor binding as well as other, nonreceptor interactions. The response rate in unselected patients with metastatic breast cancer is in the 30%–40% range, but it varies depending on whether the individual patient has a tumor that expresses estrogen receptors (ER+) and/or progesterone receptors (PR+). The expected response rate with first-line use of tamoxifen is shown in (Table 21.10).104 In postmenopausal women, estrogens are synthesized primarily in extragonadal sites, where the enzyme aromatase converts androgen precursors to circulating estrogen. Aromatase inhibitors have been proven to result in improved overall survival in first-line therapy of postmenopausal women with hormone receptor–positive metastatic breast cancer

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412 Table 21.10. Response to first-line hormonal therapy for advanced breast cancer Hormone receptor status ER+, PR+ ER−, PR+ ER+, PR− ER−, PR−

Expected response rate (%) 60–70 40–45 25–30 10

compared with tamoxifen, resulting in a shift in practice patterns in recent years.105 For patients with hormone receptor–positive tumors, second-line therapy also is available. Premenopausal women who fail tamoxifen may be offered ovarian ablation (chemical, surgical, or postirradiation) or an aromatase inhibitor.106 Postmenopausal women can undergo a trial of tamoxifen if they received an aromatase inhibitor in the firstline setting. There are women with receptor-positive tumors who respond for 1 year or longer and may benefit from three or four hormonal manipulations.106 Progestins are used for third-line maneuvers, and androgens or estrogens are used for fourth-line therapy in selected patients. Generally speaking, patients who have a major response that is very durable with first-line or second-line therapy are those most likely to benefit from subsequent hormonal maneuvers (“winners win and losers lose”). More recently, new understanding about important categories of breast cancer has emerged since HER-2/neu receptor testing became widely available. In addition, new hormonal agents are being developed. The proper role of hormonal agents in breast cancer continues to evolve rapidly. Hormonal therapy for metastatic prostate cancer Like breast cancer, most prostate cancer cells express a steroid receptor. In prostate cancer, the vast majority of prostate cancer cells in untreated patients are “androgen sensitive,” which means that those cells’ growth and progression depend on continued androgen stimulation. The mainstay of treating metastatic prostate cancer is testicular androgen suppression.107 Androgen ablation can be achieved medically by use of a gonadotropin-releasing hormone (GnRH) analogue, such as goserelin or leuprolide, or surgically by bilateral orchiectomy. Either method will achieve castrate levels of testosterone (⬍20 ng/mL), but this effect is very rapid with bilateral orchiectomy (i.e., within minutes) and may take several weeks with the GnRH analogue. In 5%–10% of patients treated with GnRH analogues, there is a temporary increase in testosterone, which

may be associated with a flare of pain or disease progression (including spinal cord compression or ureteral obstruction in vulnerable patients). This flare can be blocked by shortterm (roughly 14 days) concomitant use of an antiandrogen. The prostate cancer outcomes are the same overall, regardless of whether a GnRH analogue or bilateral orchiectomy is chosen – 80%–90% of men achieve disease stabilization, the duration of response is 12–18 months, and the median survival is 24–36 months.108 In the early 1980s, several trials evaluated the efficacy of treating patients with both a GnRH analogue and an antiandrogen (e.g., flutamide or bicalutamide) to suppress adrenal androgens.109 This strategy of “combined androgen blockade” became the standard of care until a confirmatory phase III trial evaluating bilateral orchiectomy with or without flutamide showed no clinically important survival benefit108 and inferior quality of life for the patients who received the combination therapy.110 The standard of care for patients who respond to androgen ablation but who later progress is to continue the suppression of the testicular androgens. This is based on retrospective data that show a modest survival advantage for this strategy.111 One possible explanation for these retrospective data is the existence of a persistent subpopulation of androgen-sensitive cells, even in patients with disease progression due to androgen-insensitive disease. When patients who have undergone androgen ablation develop disease progression (biochemical, radiographic, or symptomatic), their disease is considered androgen independent or “hormone refractory.” The management of asymptomatic patients without evident metastatic disease but with rising prostate-specific antigen (PSA) levels is controversial. In this setting, the use of androgen ablation is considered acceptable, but observation alone until progression to symptomatic (or at least radiographically evident) metastatic disease also is considered appropriate management.107 Patients with symptomatic progression of hormonerefractory prostate cancer (HRPC) may be candidates for additional hormonal maneuvers. The rationale for this strategy is based on the hypothesis that certain clones of the prostate cancer cells may be stimulated to grow by small concentrations of adrenal androgens that could be medically suppressed. For patients who have not already been exposed to antiandrogens as part of a combined androgen blockade strategy, use of an antiandrogen such as flutamide or bicalutamide can produce a biochemical response and sometimes a symptomatic response. However, these second-line hormonal responses generally are short-lived, with a median response duration of approximately 4 months.112–114 For

palliative systemic antineoplastic therapy HRPC patients who progress while they are still receiving an antiandrogen, the first step should be an antiandrogen withdrawal maneuver. Discontinuing the antiandrogen treatment is associated with response in approximately 20% of patients, with a median duration of response of 3–5 months.114 The mechanism of this withdrawal response is not clear, but it may be a result of mutation of the androgen receptor. Interestingly, the phenomena of hormone withdrawal responses (as well as flare reactions with initiation of hormonal therapy) also are seen sometimes in breast cancer patients. What about prostate cancer patients who progress after androgen ablation and then progress after antiandrogen withdrawal? There are other third- and fourth-line hormonal maneuvers that have been studied, including use of megestrol acetate, ketoconazole plus hydrocortisone, or hydrocortisone or prednisone alone. In this setting, objective responses are uncommon and biochemical responses (i.e., a lower PSA) are infrequent and short-lived.115 Depending on performance status and overall goals of care, systemic chemotherapy with an agent such as docetaxel may be offered to such patients.

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Table 21.11. Toxicities associated with hormonal therapy Drug class

Toxicities

Corticosteroids

Hyperglycemia, hypertension, osteoporosis, peptic ulcer, cataracts, proximal muscle weakness, depression, lymphopenia Nausea/vomiting, sodium retention, breast tenderness, venous thromboembolism, uterine bleeding (women), gynecomastia and loss of libido/impotence (men) Nausea/vomiting, fluid retention, cholestatic jaundice, masculinization (women) Weight gain, fluid retention, withdrawal bleeding (women) Hot flashes, nausea/vomiting, depression, osteoporosis, loss of libido/impotence, and gynecomastia and decreased muscle bulk (men) Nausea/vomiting, hepatotoxicity diarrhea (flutamide) slow visual adaptation to lighting changes (nilutamide), interstitial pneumonitis (nilutamide), facial flushing (bicalutamide) Hot flashes, vaginal discharge, menstrual irregularities, and uterine cancer Nausea/vomiting, skin rash, lethargy, myalgias

Estrogens

Androgens Progestins LHRH analogues Antiandrogens

Antiestrogens Aromatase inhibitors

Abbreviation: LHRH, luteinizing hormone-releasing hormone.

Toxicity of hormonal therapy Hormonal manipulations are appealing because the interventions generally are less cumbersome and less toxic than chemotherapy. Nevertheless, there are some disadvantages to using hormonal therapy. First, except for the surgical ablations, these maneuvers often require 1 or 2 months to achieve a satisfactory response. Hormonal therapy is not always well-suited for rapidly progressive disease. Second, hormonal agents are associated with potential toxicities that may be very burdensome to the patient with advanced cancer. A summary of some common toxicities of hormonal therapy is provided in Table 21.11.

Targeted therapy: new treatment paradigms, new treatment goals Over the past three decades, much progress has been made in our understanding of molecular oncology and the various cellular and genetic abnormalities that allow for unchecked growth of cancer cells. More recently, we have begun to see rapid translation of these laboratory findings into the clinical arena, with the advent of strategies designed to inhibit the molecular workings of the cancer cell. As a number of targeted therapies, used alone or in combination with chemotherapy, already have become mainstays of treatment for a number of malignancies, the goals of treatment for

these patients are rapidly evolving. In some cases, targeted therapy has led to a significant shift in survival and prognosis, whereas in other cases such therapies have led to only marginal or incremental benefits. The rapid evolution of oncologic therapeutics necessitates strong communication links among all members of the multidisciplinary care team so that the goals of care are clear to all involved providers. Monoclonal antibody therapy After many years of being restricted to using either chemotherapy or hormonal therapy as the only classes of systemic agents for advanced cancer, monoclonal antibodies have emerged as a new class of exciting agents. Although numerous antibodies have been discovered and tested for therapeutic use, the two most widely used agents at this time are trastuzumab and rituximab. These drugs are administered by intravenous infusion on an outpatient basis. The targets, indications, and toxicities of these agents are outlined in Table 21.12. Rituximab was the first monoclonal antibody to be approved for therapeutic use in malignancy. The drug was approved by the FDA in November 1997 for management of patients with low-grade B-cell non-Hodgkin’s lymphoma

s.m. patel and m.j. fisch

414 Table 21.12. Toxicities associated with monoclonal antibody therapy

Drug (target)

Current indication

Trastuzumab (anti–HER-2)

Breast cancer

Rituximab (anti-CD20)

Non-Hodgkin’s lymphoma

Toxicities Infusion-associated symptoms (flu-like), anemia/leukopenia, diarrhea, congestive heart failure (with anthracyclines) Infusion-associated symptoms (flu-like), urticaria, nausea

who have not responded to standard therapy.116 It is a chimeric, genetically engineered version of a mouse antibody that contains human IgG1 and ␬ constant regions with murine variable regions. In the pivotal trial, involving 166 patients with relapsed low-grade or follicular lymphoma, use of four weekly intravenous doses of rituximab was associated with a 48% response rate and the median duration of response was 13 months.117 Further studies with rituximab have demonstrated dramatic improvements in response rate and overall survival for a variety of lymphoid malignancies, and it is presently a cornerstone of therapy for B-cell lineage nonHodgkin’s lymphomas.118 Trastuzumab came into the international spotlight in May 1998, after abstract presentations at the annual meeting of the American Society of Clinical Oncology suggested that there was some activity (15% response rate) in a cohort of women with chemotherapy-refractory breast cancer and overexpression of the HER-2/neu growth factor receptor on their tumor.119,120 The drug was approved by the FDA in September 1998. Trastuzumab has since been tested in combination with various cytotoxic chemotherapeutic agents and has demonstrated significant improvement in time to progression compared with chemotherapy alone.121 One concerning observation has been that patients receiving trastuzumab as a single agent as well as in combination with doxorubicin-based chemotherapy have an increased risk of developing dilated cardiomyopathy, particularly with the combined treatment regimen.121 Other than this dreaded complication, treatment with trastuzumab is very well tolerated and has, in fact, led to much debate regarding its continued use after disease progression. Many medical oncologists continue trastuzumab despite disease progression owing to its favorable safety profile and possible synergy with second- and third-line chemotherapy.

Small molecule inhibitors The epidermal growth factor receptor (EGFR) is an important regulator of cell proliferation and angiogenesis, and has been shown to have increased activity in NSCLC, either by overexpression, mutation, or amplification. A rationally designed small molecule inhibitor of EGFR, erlotinib, confers a superior response rate and overall survival compared with placebo in the second- and third-line settings.122 More importantly, a subset of patients in this study seemed to preferentially derive benefit from therapy with erlotinib, namely patients with adenocarcinoma histology, females, nonsmokers, and patients of Asian descent, with some patients achieving complete responses with long remission durations. Further study has revealed that particular mutations of the EGFR molecule confer preferential sensitivity to erlotinib,123 although this remains an area of some controversy. The dramatic response to erlotinib seen in a small subset of patients with NSCLC provides a window to more ambitious therapeutic approaches. Given the vast clinical heterogeneity of diseases such as breast, lung, and colorectal cancer, so-called personalized treatment approaches are being developed. Multivariable models of response to a given therapy, based on molecular, clinical, or pathologic markers, might be able to predict an individual patient’s response to a given therapeutic approach, which may allow for treatments to be provided only to patients who will derive preferential benefit, thereby sparing those unlikely to respond from unnecessary toxicity. Targeted therapies have begun to show promise in tumors previously characterized as chemoresistant. Two such tumors, RCC and hepatocellular carcinoma (HCC), are notoriously resistant to systemic cytotoxic chemotherapy. Until recently, therapy for metastatic RCC consisted of immune-based therapies with relatively modest response rates, and therapy for unresectable HCC often was limited to supportive care alone, as the benefits of systemic therapy have been disappointing at best. Molecular insights into RCC and HCC have revealed that both rely on vascular endothelial growth factor (VEGF) signaling pathways, providing a rationale for the use of sunitinib and sorafenib, both of which are multitargeted small molecule tyrosine kinase inhibitors that inhibit the VEGF receptor. Phase III data in RCC with sunitinib versus standard subcutaneous interferon-␣ demonstrated a dramatic improvement in response rate (39% vs. 8%) and improvement in median progression-free survival (11 months vs. 5 months), leading to sunitinib being approved by the FDA as the new standard of care for first-line management of metastatic

palliative systemic antineoplastic therapy RCC.25 In HCC, recent phase III data in patients receiving sorafenib versus placebo demonstrate a significant improvement in overall survival (10.7 months vs. 7.9 months), with a reasonable toxicity profile.124 Further studies are ongoing to determine whether combining targeted agents with cytotoxic chemotherapy might improve responses in these tumors, previously thought to be treatment refractory.

10.

Hope for the future

11.

There has been an explosion in knowledge related to cancer biology as the tools of molecular biology have been applied to human cancer. Discoveries related to the basic mechanisms of disease have led to new targets and novel therapeutics. Clinicians and patients alike look forward to still more classes of cancer therapies, which may allow for increased individualization of therapy and reduced toxicity. The opportunity to participate in phase I and phase II clinical trials provides not only some element of hope for patients with advanced cancer, but also the chance to contribute to scientific advancement for the benefit of future patients.

9.

12.

13.

14.

15.

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94. Westeel V, Quoix E, Moro-Sibilot D, et al. Randomized study of maintenance vinorelbine in responders with advanced nonsmall-cell lung cancer. J Natl Cancer Inst 97:499, 2005. 95. Sculier J, Lafitte J, Lecomte J, et al. A phase III randomised trial comparing sequential chemotherapy using cisplatinbased regimen and paclitaxel to cisplatin-based chemotherapy alone in advanced non-small-cell lung cancer. Ann Oncol 18:1037, 2007. 96. Coates A, Gebski V, Bishop JF, et al. Improving the quality of life during chemotherapy for advanced breast cancer: a comparison of intermittent and continuous treatment strategies. N Engl J Med 317:1490–5, 1987. 97. Muss HB, Case LD, Richards F, et al. Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. N Engl J Med 325:1342–8, 1991. 98. Kloke O, Klaassen U, Oberhoff C, et al. Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy: results of a randomized trial. Essen Breast Cancer Study Group. Breast Cancer Res Treat 55:51–9, 1999. 99. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol 11:2167–72, 1993. 100. Helft PR. Necessary collusion: prognostic communication with advanced cancer patients. J Clin Oncol 23:3146–50, 2005. 101. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 2:104–7, 1896. 102. Kimmick G. Current status of endocrine therapy for metastatic breast cancer. Oncology 9:877–90, 1995. 103. Huggins C, Hodges CV. Studies on prostatic cancer; the effect of castration, of estrogen and of androgen injection on serum phosphatase in metastatic carcinoma of the prostate. Cancer Res 1:293, 1941. 104. Honig SF. Hormonal therapy and chemotherapy. In: Harris JR, Lippman ME, Morrow M, Hellman S, eds. Diseases of the breast. Philadelphia: Lippincott-Raven, 1996, pp 674–5. 105. Buzdar AU. Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer. Oncologist 8:335–41, 2003. 106. Hortobagyi GN. Treatment of breast cancer. N Engl J Med 339:974–84, 1998. 107. Logothetis CJ, Millikan R. Update: NCCN practice guidelines for the treatment of prostate cancer. Oncology 13:118–37, 1999. 108. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339:1036–42, 1998. 109. Denis L, Murphy GP. Overview of phase III trials on combined androgen blockade in patients with metastatic prostate cancer. Cancer 72:3888–95, 1993. 110. Moinpour CM, Savage MJ, Troxel A, et al. Quality of life in advanced prostate cancer: results of a randomized therapeutic trial. J Natl Cancer Inst 90:1537–44, 1998.

s.m. patel and m.j. fisch 111. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol 11:2167–72, 1993. 112. Joyce R, Fenton MA, Rode P, et al. High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 159:149–53, 1997. 113. Scher HI, Liebertz C, Kelly WK, et al. Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 15:2928–38, 1997. 114. Fowler JE, Pandey P, Seaver LE, Feliz TP. Prostate specific antigen after gonadal androgen withdrawal and deferred flutamide treatment. J Urol 154:448–53, 1995. 115. Small EJ. Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 15:382–8, 1997. 116. McLaughlin P, Hagemeister FB, Grillo-Lopez AJ. Rituximab in indolent lymphoma: the single-agent pivotal trial. Semin Oncol 26(Suppl 14):79–87, 1999. 117. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825–33, 1998. 118. Jacobs SA, Foon KA. The expanding role of rituximab and radioimmunotherapy in the treatment of B-cell lymphomas. Expert Opin Biol Ther. 7:1749–62, 2007. 119. Slamon D, Leyland-Jones B, Shak S, et al. Addition of herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer markedly increases anticancer activity: a randomized, multinational controlled phase III trial [abstract]. Proc Am Soc Clin Oncol 17:98a, 1998. 120. Cobleigh MA, Vogel CL, Tripathy D, et al. Efficacy and safety of herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer [abstract]. Proc Am Soc Clin Oncol 17:97a, 1998. 121. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–92, 2001. 122. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–32, 2005. 123. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–92, 2005. 124. Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): results of a phase III randomized placebo-controlled trial (SHARP trial). J Clin Oncol 25(18S):LBA1, 2007. 125. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 7:6–9, 1991. 126. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 11:570–9, 1993.

palliative systemic antineoplastic therapy 127. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQC30. A quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–76, 1993. 128. Watson M, Law M, Maguire GP, et al. Further development of a quality of life measure for cancer patients. The Rotterdam Symptom Checklist (revised). Psychooncology 1:35–44, 1992. 129. Ganz P, Schag C, Lee J, Sim M. The CARES: a generic measure of health-related quality of life for patients with cancer. Qual Life Res 1:19–29, 1992. 130. Schipper H, Clinch J, McMurray A, Levitt M. Measuring the quality of life of cancer patients: the Functional Living Index-

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Cancer: development and validation. J Clin Oncol 2:472–83, 1984. 131. Ware JE, Sherbourne CD. The MOS 36-Item Short Form Health Status Survey (SF-36): 1. Conceptual framework and item selection. Med Care 30:473–83, 1992. 132. Chang VT, Hwang SS, Corpion C, Feuerman M. Validation of the Memorial Symptom Assessment Scale short form (MSASSF) [meeting abstract]. Proc Am Soc Clin Oncol 16:A165, 1997. 133. Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom Assessment Scale: an instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer 30A:1326–36, 1994.

Innervated peripheral tissue (bone)

Large diameter myelinated fibers (Aβ) Propioreceptors, mechanoceptors

Brain

Small diameter unmyelinated fibers (C) and thinly myelinated (Aδ), Nociceptors

Endothelial cells

Tumor associated immune cells Macrophage

blood vessel

Tumor/ stromal cells

Dorsal Root Ganglia

Mast cell

T cell neutrophil

Spinal Cord

ATP, NGF, PGE 2

ETA R

B2R

B1R

EP

Nav 1.8 &1.9

Nociceptor

TrkA TRPV1

H+

ASIC 2/3

H+ H+

TRPA1

TRPV4

TRPV1

Mechanical distortion of sensory fibers

Osteoclast Plate 2.1. Primary afferent sensory nerve fibers involved in generating bone cancer pain. Primary afferent neurons innervating the body have their cell bodies in the DRG and transmit sensory information from the periphery to the spinal cord and brain. Myelinated A-fibers (A␤) containing large-diameter cell bodies, which project centrally to the dorsal column nuclei and deep spinal cord, are involved in detecting non-noxious sensations including light touch, vibration, and proprioception. Unmyelinated C-fibers and thinly myelinated A␦-fibers contain small-diameter cell bodies that project centrally to the superficial spinal cord. These fibers are involved in detecting multiple noxious stimuli (chemical, thermal, and mechanical). Box: Nociceptors use several different types of receptors to detect and transmit signals about noxious stimuli that are produced by cancer cells (yellow), tumor-associated immune cells (orange), or other aspects of the tumor microenvironment. There are multiple factors that may contribute to the pain associated with cancer. The TRPV1 and ASICs detect extracellular protons produced by tumor-induced tissue damage or abnormal osteoclast-mediated bone resorption. Several mechanosensitive ion channels may be involved in detecting high-threshold mechanical stimuli occurring when distal aspects of sensory nerve fiber are distended from mechanical pressure due to the growing tumor or as a result of destabilization or fracture of bone. Tumor cells and associated inflammatory (immune) cells produce a variety of chemical mediators, including prostaglandins (PGE2 ), NGF, endothelins, bradykinin, and extracellular adenosine 5 -triphosphate (ATP). Several of these proinflammatory mediators have receptors on peripheral terminals and can directly activate or sensitize nociceptors.

C

B

A

E

D

F WB

Sham

2472 E

D

F

ACE-1 H WB

T T

H

H

WB

Plate 2.2. Bone remodeling and tumor growth in 2472 sarcoma– and ACE-1 prostate carcinoma–injected femurs have different characteristics depending on the osteolytic or osteoblastic component of the tumor cells as assessed by ␮CT imaging and hematoxylin and eosin staining. Shaminjected femurs present a relative absence of bone formation or bone destruction (A, D). The 2472 sarcoma–injected femurs display a primarily osteolytic appearance visible as regions absent of trabecular bone at the proximal and distal heads (B) as well as replacement of normal hematopoietic cells by tumor cells (E). The ACE-1 prostate carcinoma–injected femurs mainly present an osteoblastic appearance, which is characterized by pathologic bone formation in the intramedullary space (C) surrounding pockets of tumor cells that generate diaphyseal bridging structures (F). A–F: Scale bar, 0.5 mm. T, tumor; H, normal hematopoietic cells; WB, ACE-1-induced woven bone formation.

Plate 2.4. ATF-3 and galanin are upregulated in primary sensory neurons that innervate the tumor-bearing femur 14 days following injection of osteolytic sarcoma cells into the intramedullary space of the femur. Neurons in the sham-vehicle L2 DRG express low levels of ATF-3 (A) or the neuropeptide galanin (C), whereas 14 days following injection and confinement of sarcoma cells to the marrow space, there is a marked upregulation of both ATF-3 (B) and galanin (D) in sensory neurons in the L2 DRG ipsilateral to the tumor-bearing bone. Many sensory neurons that show an upregulation of galanin in response to tumor-induced injury of sensory fibers in the bone also show an upregulation of ATF-3 in their nucleus (compare parts E and F, arrows). These data suggest that tumor cells invading the bone injure the sensory nerve fibers that normally innervate the tumor-bearing bone. A–D: Scale bar, 200 ␮m; E and F: scale bar, 100 ␮m. Modified from Peters et al.24

Tumor Burden

Plate 2.5. Confocal images showing the increase in the astrocyte marker GFAP in a mouse with bone cancer pain in the right femur. Coronal sections of the L4 spinal cord 21 days following injection of osteolytic sarcoma cells into the intramedullary space of the femur. In part A, GFAP is bright orange; in parts B and C, GFAP is green and the neuronal nuclei (NeuN) staining (which labels neurons) is in red. A low-power image (A) shows that the upregulation of GFAP is almost exclusively ipsilateral to the femur with the intraosseous tumor. Higher magnification of GFAP contralateral (B) and ipsilateral (C) to the femur with cancer shows that on the ipsilateral side, there is marked hypertrophy of astrocytes, characterized by an increase in both the size of the astrocyte cell bodies and the extent of the arborization of their distal processes. Additionally, this increase in GFAP (green) is observed without a detectable loss of neurons, as NeuN (red) labeling remains unchanged. A: Images, from 60-␮m thick tissue, are projected from six optical sections acquired at 4-␮m intervals with a 20× lens; scale bar, 200 ␮m. B and C: Images are projected from 12 optical sections acquired at 0.8-␮m intervals with a 60× lens; scale bar, 30 ␮m. Modified from Schwei et al.22

A

Curative Chemotherapy

Palliative New Goal: Maximize area under the curve

Time (Length of Treatment)

B

Adjuvant

Chemotherapy

Progression or Distant Recurrence

Quality of Life

Tumor Burden

Surgery

Time (Length of Treatment)

Tumor Burden

D

C

Other Palliative Interventions Systemic Chemotherapy

Time (Quantity of Life)

Neoadjuvant Chemotherapy Surgery

Time (Length of Treatment)

Plate 21.1. The goal of chemotherapy and palliative interventions. Panels A, B, and C describe the effect of chemotherapy on tumor burden in various cancer treatment scenarios and in relation to surgery. Panel D illustrates the intended effects of chemotherapy and palliative interventions on the area under the curve for quality of life over time.

Plate 29.5. Subcutaneous needle in the upper back. R Plate 29.2. CADD-Prizm
PCS II. Photo courtesy of Smiths Medical Inc., St. Paul, Minnesota.

Plate 29.3. Subcutaneous insertion.

Plate 29.6. Subcutaneous needle in the abdomen.

Plate 29.7. Edmonton Injector.

Plate 29.4. Subcutaneous needle insertion with dressing.

SECTION VIII

PAIN IN SPECIAL POPULATIONS

22

Cancer pain management in the chemically dependent patient b steven d. passik, a lara k. dhingra, and kenneth l. kirsh c a b

Memorial Sloan-Kettering Cancer Center, Beth Israel Medical Center and Albert Einstein College of Medicine, and c University of Kentucky College of Pharmacy

Introduction There is a potential risk for substance use problems in cancer patients managed in the palliative care setting, the severity of which varies significantly across subgroups. The potential for substance use problems in cancer patients may be manifested in various case scenarios: Patients may increase their dosages of prescribed drugs without informing their physicians, or use their analgesics to treat symptoms other than those intended; other patients helpfully present to the palliative care team with a known history of, or current addiction to, illicit drugs or prescription medications. Accordingly, efforts to appropriately identify, assess, and clinically manage substance-related problems are critical to the optimal treatment of cancer patients in the palliative care setting. In this chapter, we discuss these important issues and describe how clinicians can assert control over opioid prescriptions by closely monitoring drug use and by using specific strategies to structure drug therapy. By implementing these strategies and methods, clinicians can help address substance use problems in cancer patients while ensuring that pain and other symptoms are not undertreated.

Prevalence rates of drug abuse and addiction: general U.S. population versus cancer population In 2006, approximately 50% of people aged 12 and older in the United States reported using illegal drugs at some point in their lives,1 and between 6% and 15% have a current or past substance use disorder.2 Further, rates of controlled prescription drug abuse have risen dramatically in the United States, with rates nearly doubling between 1992 and 2003 from 7.8 million to 15.1 million.3 As a result of the high prevalence rates of substance abuse in the U.S. population and the association between drug abuse and lifethreatening diseases (e.g., AIDS and cancer),4 patients with

substance abuse–related problems are likely to be encountered in the palliative care setting. Much of the research to date evaluating the epidemiology of prescription drug abuse among chronic pain populations has focused on nonmalignant pain populations. Prevalence rates for current drug abuse, dependence, or addiction among nonmalignant pain populations range between 3% and 45%, depending on the variables measured, the population assessed, the history of substance use disorders, psychiatric comorbidities, and the length of exposure to opioids.5–8 Within the tertiary care oncology setting, however, substance abuse problems in cancer patients may not be commonly reported. For example, during a 6-month period in 2005, fewer than 1% of inpatient and outpatient consultations performed by the psychiatry service at Memorial Sloan-Kettering Cancer Center in New York City were requested for substance abuse–related issues, and only 3% of patients who were referred to the psychiatry department for various reasons were subsequently diagnosed with a substance abuse disorder of any type.9 The prevalence rates observed in this small clinical sample are much lower than the frequency of substance abuse disorders among the general adult U.S. population, among general medical populations, and among emergency medical departments.10,11 Potential explanations for these findings may include a low prevalence of actual substance abuse disorders among patients in this clinical sample, the underrecognition of substance abuse disorders among patients in an upper middle-class tertiary care oncology population, oncologists’ unwillingness to refer patients with identified substance abuse problems for psychiatry consultation, and competing demands for clinical attention that were perceived as more important than substance abuse issues. Clearly, the prevalence rates observed in this single-site study may have limited generalizability to cancer patients treated in other settings. Evaluating the nature of substance 423

424 abuse disorders among palliative care patients and identifying characteristics of drug abuse and addiction are areas for additional research.

Aberrant drug-taking behaviors Definition and rationale for assessment Upfront and ongoing assessment and management of aberrant drug-taking behaviors is now recognized as a key component of effective approaches for pain and symptom control. Aberrant drug-taking behaviors are defined as patients’ nonadherence behaviors with prescribed opioid therapy that are “suggestive of drug abuse or addiction.”12 These observable behaviors range in severity from patients’ occasional unsanctioned drug escalations (less severe/less suggestive of abuse) to evidence of deterioration in the ability to function (more severe/more suggestive of abuse).12 Identifying and managing aberrant drug-taking behaviors in patients is consistent with the need to ensure safe and effective administration of opioid therapy.

s.d. passik, l.k. dhingra, and k.l. kirsh to organize the patients’ medications may help improve aberrant drug-taking behaviors. Thus, obtaining a comprehensive medical history in the patient with advanced cancer is essential when managing patients without prior substance use histories as well as patients with substance use histories, who are likely to suffer from a comorbid psychiatric disorder.13 When assessing and rendering differential diagnoses for aberrant drug-taking behaviors, it is useful to consider the degree of severity of the behavior. Specifically, the less severe aberrant behaviors are less likely to reflect addiction-related concerns; conversely, the more severe aberrant behaviors are more likely to reflect true addiction.12 Although there is a need to empirically evaluate whether subtypes of aberrant drug-taking behaviors are predictive of abuse and addiction, this conceptualization may serve as a useful model when evaluating their clinical relevance in this population. In most scenarios, aberrant drug-taking behaviors rarely indicate criminal intent (e.g., patients reporting pain with the explicit intent to sell or divert their prescribed medications). Prevalence and characteristics

Assessment and differential diagnosis When conducting an assessment of aberrant drug-taking behaviors, it is important to consider the underpinnings of these behaviors. First, pseudo-addiction must be ruled out if the patient is reporting significant distress associated with unrelieved pain symptoms. In the case of pseudoaddiction, observable behaviors such as aggressively complaining about the need for higher doses of pain medication or occasional unilateral drug increases indicate desperation that is caused by unrelieved pain and should cease when pain management improves. Further, within the palliative care setting, it is not uncommon for patients with advanced cancer to suffer from heightened psychological distress, hopelessness, or demoralization. Cancer patients who appear to be self-medicating their anxiety symptoms, depression, or even periodic dysphoria and loneliness may demonstrate aberrant drug-taking behaviors. In these cases, the careful diagnosis and treatment of emotional symptoms may diminish the tendency for patients to inappropriately self-medicate their psychological distress using substances. Occasionally, aberrant drug-taking behaviors may be secondary to a mild encephalopathy with confusion regarding the appropriate therapeutic regimen, which may be a potential concern in the treatment of the elderly cancer patient. In these cases, administering low doses of neuroleptic medications, simplifying drug regimens, and attempting

Much of the existing research focusing on the prevalence and characteristics of serious aberrant drug-taking behaviors has been conducted among nonmalignant pain populations. A systematic review recently showed that the prevalence of aberrant drug-taking behavior among chronic nonmalignant back pain patients ranges between 5% and 24%; however, the reliability of this estimate may be limited by the few quality studies to date.14 Several studies have identified significant numbers of patients with at least a few aberrant drug-taking behaviors in chronic nonmalignant pain samples, whereas multiple behaviors (i.e., more than three in a 6-month period) have been found in 20% of samples.15,16 Dunbar and Katz17 examined outcomes and aberrant drug-taking behaviors in a sample of 20 patients with diverse histories of substance use disorders who received long-term opioid therapy for 1 year. In this study, 45% of patients exhibited multiple aberrant drug-taking behaviors.17 Specifically, during the 1 year of opioid therapy, 11 patients adhered to the drug regimen and nine did not. In the subgroup of patients who did not abuse prescribed opioids, patients were abusers of alcohol exclusively (or had remote histories of polysubstance abuse), were in a solid drug-free recovery, or had strong social support. In the subgroup of patients who abused prescribed opioids, patients were either polysubstance abusers, were not participating in 12-step recovery programs, or had poor social support.

cancer pain management in the chemically dependent patient Additionally, Passik and other researchers at a major cancer center18 examined self-reported aberrant drug-taking attitudes and behaviors among patients diagnosed with cancer (n = 52) and AIDS (n = 111). In both groups, patients’ reports of past drug use and abuse were more frequent than current reports of drug use, and current aberrant drugtaking behaviors were rarely reported. Despite this finding, an examination of patients’ attitudes revealed that many patients would consider engaging in aberrant drug-taking behaviors, or possibly excuse them in others, if pain or symptom management was inadequate. Specific risk factors There is a need to identify specific risk factors for the propensity to develop serious aberrant drug-taking behaviors, abuse, or addiction. Studies show that various pain populations without a prior history of substance use disorders and those exposed to therapeutic opioids for a short time period (e.g., during the treatment of acute pain) have a low risk of developing severe aberrant drug-taking behaviors.19–22 Likewise, long-term opioid administration in cancer patients without a previous history of substance abuse is rarely associated with the development of abuse or addiction-related problems.23,24 Despite these data, many inexperienced clinicians, as well as the lay public, appear to have misconceptions that the treatment of cancer pain with opioids will lead to the development of an addictive disorder. Specialists in the fields of pain and palliative care widely agree that the major problem related to addiction is not the phenomenon itself but rather the persistent undertreatment of pain driven by the inappropriate fear that addiction will occur. An evaluation of the scientific literature25,26 yields little support for the view that large numbers of patients with no personal or family history of drug abuse or addiction, no affiliation with a substance-abusing subculture, and no significant premorbid psychopathology will develop abuse or addiction-related problems de novo when patient selection for potentially abusable drugs is informed and the monitoring of those who receive these drugs is appropriate to the level of risk severity. Interestingly, euphoria, a phenomenon of intense positive affect believed to be common during the abuse of opioids, is rare following administration of opioids for pain; instead, dysphoria is observed, especially in patients who receive meperidine.27 However, more information is needed on how and why population subgroups differ in their propensity to develop severe aberrant drug-taking behaviors and what the specific risk factors are. Recently, several studies have indicated

425

that cigarette smoking may be one potential risk factor for aberrant drug-taking behavior among opioid-treated nonmalignant pain patients.28–31 Specifically, current smoking is associated with higher levels of analgesic use32–35 and a greater frequency of aberrant drug-taking behaviors. One study that assessed the prevalence of aberrant drug-taking behaviors during treatment for nonmalignant pain observed more aberrant behaviors among smokers,28 and a second study identified more comorbid substance use disorders among nonmalignant pain patients who smoked compared with nonsmokers.29 Passik and colleagues36 recently evaluated AIDS patients with a history of substance use disorders and cancer patients without this history and found that AIDS patients had more aberrant drug-taking behaviors during opioid therapy for pain, and a larger proportion smoked. Additional research is needed to confirm this linkage and elaborate on the potential mechanisms of the association or a clinical explanation. The following section summarizes additional data on the risk of abuse and addiction for populations with known histories of substance use disorders.

Risk factors for drug abuse and addiction among palliative care patients with a current or previous history of substance use problems For the palliative care patient who presents with a current or previous history of a substance use disorder, there is limited empirical information to date on the risk of drug abuse or addiction during or after the therapeutic administration of a potentially abusable drug. Anecdotal reports have suggested that safe and effective long-term opioid therapy in patients with cancer pain or chronic nonmalignant pain is possible, even if the history of abuse or addiction is remote.17 Indeed, patients suffering from AIDS-related pain have been successfully treated with morphine, regardless of whether they had substance use problems or did not have non–substance use problems.37 In a study by Kaplan and colleagues,37 a major group difference was that AIDS patients with substance use problems required considerably more morphine to reach stable pain control. These data are reassuring but do not obviate the need for caution on the part of clinicians when treating patients with current or past histories of substance use problems. For example, although there is little empirical evidence showing that the use of short-acting drugs or the parenteral route of drug administration is more likely to lead to aberrant drug-related behaviors, it may be prudent to avoid such approaches in patients with known histories of substance

426 abuse. Clinical management strategies for the patient with substance use problems are described later in this chapter. Emerging efforts to optimize patient selection for opioid therapy: screening measures There is a growing interest in predicting which patients can be maintained on opioid therapy without aberrant drugtaking behaviors and which patients will exhibit behaviors representing various degrees of management difficulty, including the development of potential drug abuse and addiction. In an attempt to improve the selection of candidates for opioid therapy, screening measures for patients with chronic pain have been developed and validated. Butler and colleagues38 recently developed a measure to predict future medication misuse in opioid-treated patients. During the content development phase, researchers identified prominent opioid misuse characteristics among chronic pain patients to design a 24-item, self-administered measure called the Screener and Opioid Assessment for Patients with Pain (SOAPP). Further, a recently developed brief version of this measure (i.e., a 14-item short form) shows much promise in screening chronic pain patients for abuse potential and improving the delivery of palliative care interventions for patients who may have a potential risk for drug abuse and addiction. Additionally, Passik and colleagues39 conducted a study to evaluate the relationship between aberrant drug-taking behaviors and pain outcomes during long-term treatment with opioids for nonmalignant pain. In this study, a checklist tool was developed, and although additional validation is needed to determine the extent to which this tool may be applied to palliative care settings, it may be helpful in structuring opioid therapy for patients. The checklist consists of four domains that are most relevant to the ongoing monitoring of chronic pain patients who are receiving long-term opioid therapy (these areas are referred to as the “four A’s”: analgesia, activities of daily living, adverse side effects, and aberrant drug-taking behaviors).40 It is proposed that the monitoring of clinical outcomes in these specific domains over time should inform therapeutic decisions and provide a framework for the clinical use of controlled drugs.

Clinical management of palliative care patients with substance use problems Overview Severe aberrant drug-taking behavior, particularly among palliative care patients (with or without a history of

s.d. passik, l.k. dhingra, and k.l. kirsh substance use problems), is a serious and complex clinical occurrence. Perhaps the more difficult situations involve the palliative care patient who is actively abusing illicit or prescription drugs or alcohol concurrently with medical therapies. Whether the patient is actively abusing drugs, has a history of substance abuse, or is not adhering to his or her therapeutic regimen, the clinician should establish structure, control, and a means of monitoring the patient so that he or she can prescribe freely and without prejudice. To achieve these aims, a multidisciplinary team approach is usually ideal for the management of cancer patients with substance abuse problems in the palliative care setting. If available, behavioral health professionals with specialization in addictions medicine can help palliative care team members to develop strategies for patient management and treatment adherence. It is understandable that providing care to patients with abuse behaviors may sometimes elicit feelings of anger and frustration on the part of health care providers and staff. It is our belief that such feelings can unintentionally compromise pain management outcomes and contribute to feelings of isolation and alienation among patients, thus complicating treatment and recovery. When a judgmental attitude or belief is recognized and addressed, a structured, multidisciplinary team approach can be effective in helping the staff to understand the patient’s needs and develop more effective strategies for controlling pain and aberrant drug use simultaneously. Assessment of substance use problems in the palliative care patient Before the implementation of effective therapeutic strategies for symptom control and comorbid substance use problems, a detailed assessment of the drug use behaviors demonstrated by the patient is essential. As such, the first member of the medical team to suspect aberrant drugtaking behaviors or a history of drug abuse should alert the patient’s palliative care team, thus beginning the assessment and management process.41 Next, it is helpful to have a physician assess withdrawal symptoms or other pressing health concerns. At this point, it is useful to involve other staff, particularly social workers and/or psychiatrists, in initiating and planning long-term management strategies. As much as possible, concurrent with these steps, obtaining a detailed history of the duration, frequency, and desired effects of drug use is critical. Clinicians often avoid asking patients about substance abuse because of concerns or fears that they will anger the patient or that they are incorrect in their suspicion of abuse, which may perpetuate continued problems. In our experience, empathic and truthful

cancer pain management in the chemically dependent patient communication with patients about substance use is the best approach. Further, a careful, graduated interview often is instrumental in assessing the history and patterns of drug use. In this approach, the interview begins with broad questions that assess the role and effects of commonly used drugs (e.g., nicotine and caffeine) in the patient’s life and then gradually becomes more specific to include the use of illicit drugs. Such an approach may be helpful in reducing any denial and resistance in patients. Evaluating the patient’s perception about the positive and negative consequences of his or her substance use as well as the barriers and facilitators to changing maladaptive behaviors is recommended. It is useful to obtain a previous history of substance abuse treatment and recovery and to understand why the patient believes these treatments were effective or ineffective. Additionally, the application of this interviewing approach may assist in the detection of coexisting psychiatric disorders. The identification of comorbid psychiatric disorders is important because psychiatric illness may drive aberrant drug-taking behaviors. For example, studies suggest that 37%–62% of alcohol abusers have one or more coexisting psychiatric disorders.42 As such, the patient’s drug abuse history may be a potential marker of a comorbid psychiatric disorder (e.g., drinking to quell panic symptoms). Anxiety disorders, personality disorders, and mood disorders are commonly encountered conditions in populations with comorbid substance abuse disorders. The assessment and treatment of these comorbid psychiatric disorders can greatly enhance management strategies, reduce the risk of drug relapse, and improve abstinence maintenance. Finally, specific behaviors can be incorrectly regarded as aberrant, particularly when these reflect a paucity of data. For example, patients who request a specific pain medication or a specific route or dose often are considered “suspicious” or drug seeking by clinicians. Other aberrant behaviors may be common among non–drug-addicted patients but have limited clinical relevance to addiction; for example, many nonaddicted cancer patients use anxiolytic medications that were prescribed for someone else.18 This seems to reflect the undertreatment and under-reporting of anxiety in oncology patients, rather than true drug addiction. Development of a treatment plan for palliative care patients with substance use problems: general considerations The articulation of clear treatment goals is essential in managing illicit drug abuse or abuse of controlled prescription drugs. Depending on the individual patient, a complete

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remission of the substance use problems may not be a reasonable goal. For some patients, “harm reduction” may be a better model. This approach aims to enhance social support, maximize treatment adherence, and contain harm that results from episodes of relapse. The goals of care may be difficult to balance, especially when patients’ poor adherence and drug abuse behaviors appear to contradict their reported desire for pursuing cancer therapy. One potential reason for abuse behaviors may be the psychological distress of coping with a life-threatening illness and the availability of prescription drugs for symptom control, which may undermine efforts to achieve abstinence.19 In our experience, clinicians must decide whether to refer the patient with substance use problems to another health care professional for pain and comorbid substance abuse treatment or to continue managing the patient through the establishment of structure and goals for abstinence maintenance. As stated earlier in this section, establishing a therapeutic relationship based on empathic listening and acceptance of the patient’s report of symptom distress is critical to achieving positive outcomes. When managing the patient with substance abuse problems, whenever possible, it is important to use nonopioid and behavioral intervention approaches, although these are not substitutes for appropriate pharmacologic management. When using pharmacologic approaches, issues of tolerance, route of administration, and duration of action should be considered when prescribing medications for pain and symptom control. For example, the degree of preexisting tolerance should be taken into account for patients who are actively abusing drugs or are being maintained on methadone. The failure to address tolerance may result in undermedication in patients and contribute to their attempts to self-medicate their pain and symptoms. Additional considerations for management include the use of medications with a slow onset and longer duration (e.g., the fentanyl patch and sustained-release opioids), which may be helpful therapeutic strategies for mitigating the risk of aberrant behaviors in patients with addictive disorders. Importantly, patients at high risk for substance abuse should not be given short-acting opioids for breakthrough pain as these drugs may lead to a greater likelihood of abuse in vulnerable patients. Finally, the adequacy of the patient’s pain and symptom control should be reassessed frequently. Urine toxicology screening Urine toxicology screening has the potential to be a useful tool to the clinician when diagnosing a potential drug abuse problem in patients and monitoring patients with a known

428 history of drug abuse or addiction. In a recent study, however, an analysis of medical chart reviews showed that urine toxicology screens are infrequently ordered or documented in tertiary care centers.43 Specifically, the results showed that nearly 40% of the medical charts surveyed did not list a reason for obtaining a urine toxicology screen, and the ordering physician for the screen could not be identified in nearly 30% of cases. These findings suggest that staff education may be needed to address these problems and ultimately make urine toxicology screens a viable approach to treating pain and symptoms in oncology patients. Special considerations for treating substance use problems in palliative care patients Managing drug abuse and addiction in patients with advanced cancer is often labor intensive and time consuming. Regardless of abuse and addiction’s negative impact on palliative care outcomes, many clinicians may opt to overlook a patient’s use of illicit substances or alcohol, perhaps viewing these behaviors as a last source of pleasure for the patient. However, the negative consequences of abuse and addiction in palliative care settings may include increased distress for patients and family members, concerns among family members about the misuse of medications, the masking of symptoms important to the patient’s care, poor adherence to the treatment regimen, and diminished quality of life. Although complete abstinence may not be a realistic outcome for all patients, reduction of abuse can certainly lead to positive effects on the well-being of the cancer patient and caregivers.43 It is important to reflect upon clinician attitudes and beliefs that may serve as potential barriers to the use of risk assessment and risk management strategies in the palliative care setting. For example, many clinicians have traditionally assumed that cancer patients are “immune” to problems with addiction or substance abuse. These perceptions may lead clinicians to perform suboptimal documentation on the effects of controlled prescription drugs and become less vigilant in monitoring patients who are given substances such as opioids. In contrast, there has been a growing fear of opioid use among the general population, and this is a growing issue even among oncology populations. Regions of the United States, particularly rural Appalachia and other areas severely affected by the rising rates of prescription opioid abuse, have seen clinicians retreat from opioid prescription altogether, even if this action is medically inappropriate. Clinicians must avoid both these extremes and ensure their due diligence in prescribing medications to patients with potential problematic behaviors. As such,

s.d. passik, l.k. dhingra, and k.l. kirsh good documentation of opioid prescribing should be considered a necessary baseline, but not necessarily sufficient for protecting the clinician and the patient. Outpatient management of substance use problems in palliative care patients There are multiple strategies for encouraging treatment adherence in patients who are managed in an outpatient setting. A written contract between the palliative care team and patient helps to provide structure to the treatment plan, establishes clear expectations of the roles played by both parties, and outlines the consequences of aberrant drugtaking behaviors. Using spot urine toxicology screens and specifying their administration in a written opioid contract may be helpful in promoting treatment adherence. Expectations regarding patient attendance at clinic visits and the patient’s management of his or her supply of medications also should be stated, including holding prescription refills contingent on clinic attendance. The clinician may consider requiring the patient to attend 12-step drug or alcohol recovery programs and may request that the patient document his or her attendance as a condition for ongoing prescribing. With the patient’s consent, the clinician may wish to contact the patient’s sponsor to make him or her aware that the patient is being treated for a chronic illness that requires medications (e.g., opioids). This action may reduce the potential for stigmatization of the patient as being nonadherent to the goals of a 12-step program. Finally, family members and friends should be involved in the patient’s drug abuse treatment to help bolster the patient’s social support and functioning. Behavioral health professionals are encouraged to identify family members who themselves have drug abuse problems and who may potentially divert the patient’s medications. Assisting family members with referrals to drug treatment and codependency groups is a useful approach to helping the patient receive optimal health care. Although some readers may be skeptical of the motivation and ability of palliative care patients to participate in these active recovery steps, we have found that many patients are willing and able to engage in such substance abuse treatment. Inpatient management of substance use problems in palliative care patients The management of patients with active substance abuse problems who have been admitted to the hospital for cancer management includes and expands on the recommendations discussed in the previous section for outpatient settings.

cancer pain management in the chemically dependent patient Most importantly, the patient’s drug use behaviors need to be discussed in a candid manner. Accordingly, it is necessary to reassure the patient that steps will be taken to avoid adverse events such as drug or alcohol withdrawal, which may complicate recovery and decrease patient motivation for abstinence. In the case of the preoperative cancer patient, the patient should be admitted several days in advance for stabilization of the drug regimen. We recommend that the patient be provided with a private room near the nurses’ station to help monitor his or her status and discourage attempts to leave the hospital in an attempt to purchase illicit drugs. To decrease a patient’s access to drugs, visitors should check in with nursing staff before visitation and, in some cases, have their packages searched. Daily urine specimens should be collected from the patient for random toxicology analysis. Although these recommendations may appear adversarial, the majority of caregivers will agree that such steps are necessary and, in most cases, in the best interests of the patient. It is important that patient management strategies are tailored to reflect the clinician’s assessment of the severity of drug abuse and are consistent with ongoing attempts to facilitate open and honest communication with the patient. In some cases, these guidelines may fail to curtail aberrant drug-taking behaviors despite repeated interventions by staff. At that point, the patient should be considered for discharge, but this seems necessary only in the most recalcitrant of cases. In this situation, the clinician should involve members of the staff and administration for discussion about the potential ethical and legal implications of this decision. Alcohol abuse among palliative care patients Alcoholism in cancer patients with terminal illness is a common problem, often with severe consequences, and warrants special attention. In a 1995 survey of patients admitted to a palliative care unit, alcohol abuse was documented in more than 25% of patients.44 A recent literature review documented that the prevalence of alcohol abuse ranges from 7% to 27% in palliative care patients.45 Further, 33.6% of head and neck cancer patients and 13% of lung cancer patients have been shown to meet diagnostic criteria for alcohol dependence.45 Patients with life-threatening illnesses who are alcohol dependent present unique challenges to the clinician and require careful assessment and management. For example, patients with alcohol dependence who are not identified and consequently hospitalized may suffer withdrawal symptoms and experience unexpected complications. In particular, patients at the end of

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life may experience withdrawal symptoms if they decrease their alcohol intake as their physical condition declines. If the extent of the patient’s alcohol use is unknown, alcohol withdrawal symptoms may be mistaken for anxiety symptoms. The first symptoms of alcohol withdrawal usually begin a few hours after the cessation of alcohol intake and consist of tremors, agitation, and insomnia. In mild to moderate cases of alcohol withdrawal, these symptoms lessen within 2 days. Patients with terminal cancer are more likely than patients without terminal cancer to progress from exhibiting these initial symptoms to a state of delirium characterized by autonomic hyperactivity, hallucinations, incoherence, and disorientation.41 Delirium tremens (DTs) represent a serious medical emergency and occur in approximately 5%–15% of patients in alcohol withdrawal, usually within the first 72–96 hours of withdrawal. DTs are self-limiting and usually subside as the patient enters a deep sleep. Patients often experience amnesia during this time period. In surgical settings, alcohol withdrawal can cause up to a threefold increase in postoperative mortality when unrecognized and not treated.46 Because of poor nutrition and prior head trauma and brain injury from excessive alcohol consumption, cancer patients with comorbid alcohol disorders have a heightened high risk for developing delirium postoperatively as a result of the adverse consequences of seizures and DTs, which may be fatal.41 Because of the physical vulnerability of patients with terminal cancer, potential alcohol withdrawal symptoms should be managed aggressively and prevented whenever possible.46 Although there is a lack of research to date that highlights best practices for treating acute alcohol withdrawal in the palliative care setting, basic management steps, including the use of hydration, benzodiazepines, and, in some cases, neuroleptics, may be employed.46 Additionally, the administration of a vitamin–mineral solution helps to counteract the effects of malnutrition that results from alcohol itself and poor dietary habits. Further, the use of thiamine, 100 g intramuscularly or intravenously, should be implemented for 3 days before switching to oral administration to prevent the development of Korsakoff’s syndrome and alcoholic dementia. Finally, a daily dose of folate, 1 mg, also should be given to patients experiencing alcohol withdrawal throughout alcohol treatment. Strategies for management of palliative care patients enrolled in drug and alcohol recovery programs Depending on the structure of the recovery program (e.g., Alcoholics Anonymous, methadone maintenance

430 programs), a patient may fear ostracism from the program’s members or experience considerable fear regarding susceptibility to readdiction. It is best to first explore the use of nonopioid therapies with these patients, and this action may require referral to a pain management center. Alternative therapies may include the use of nonopioid or adjuvant analgesics, cognitive therapies, electrical stimulation, neural blockades, or acupuncture. In some cases in which opioids are required, it is necessary to use opioid management contracts, random urine toxicology screens, and unannounced pill counts. If possible, the patient’s recovery program sponsor should be included to aid successful monitoring of the patient’s status and abstinence maintenance efforts.

Conclusions Although clinicians cannot prevent the risk of all aberrant drug-related behaviors, they must recognize that virtually any drug that acts on the central nervous system, and any route of drug administration, can be abused. We believe that the fundamental problem in addiction is not the nature of the prescription medications themselves. The potential for drug abuse and addiction is not distributed equally across subpopulations, and certain patients may be more susceptible to substance use problems. Thus, the effective assessment and management of patients with pain who engage in aberrant drug-taking behaviors must involve a comprehensive approach that recognizes the biological, chemical, social, and psychiatric aspects of substance abuse while providing a practical means to manage risk, treat pain effectively, and assure patient safety. Unfortunately, there are sparse data to date that focus on the unique issues and concerns related to risk assessment and risk management in palliative care patients. Most available data focus on the risk of severe aberrant drug-taking behaviors during long-term opioid therapy for chronic nonmalignant pain in patients without a history of substance use disorders. Thus, future areas for clinical research include identifying the prevalence and adverse consequences of less severe aberrant drug-taking behaviors in palliative care patients; evaluating the role of risk factors in aberrant drugrelated behaviors, such as smoking, in populations that have a history of drug abuse or addiction; and establishing the risk associated with the potential abuse of prescription drugs other than opioids. This chapter demonstrates that clinicians can assert control by closely monitoring the use of prescribed opioid therapies (i.e., by administering long-acting opioids only, recommending small amounts of drug at any one time, or structuring therapy with frequent visits) in conjunction with maximizing the use of noncontrolled adjuvant

s.d. passik, l.k. dhingra, and k.l. kirsh medications to ensure that pain and other symptoms are not undermanaged. Prescription drug abuse is a growing public health problem in the United States. Thus, researchers and clinicians need to create alliances to shed light on risk factors for drug abuse and addiction and determine the specific strategies that will minimize and prevent these problems. Only through an understanding of the best methods for identifying at-risk patients can we preserve opioid use as a viable modality for the majority of patients with chronic pain. Initial efforts to create screening measures to identify risk potential for drug abuse and addiction in patients have been promising. However, further research is needed to determine which specific risk factors best predict the patients who engage in aberrant drug-taking behaviors. Once the determinants driving this complex problem are clarified, further study will be needed to determine how to best manage and treat at-risk populations with cancer and other chronic medical illnesses.

Acknowledgments We wish to thank Jack Chen and Cami Godsey for their assistance with preparing this chapter. References 1. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Results from the 2006 National Survey on Drug Use and Health: National Findings (DHHS Publication No. SMA 07-4293). Rockville, MD: U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2007. 2. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593–602, 2005. 3. Califano JA. Under the counter: The diversion and abuse of controlled prescription drugs in the U.S. New York: National Center on Addiction and Substance Abuse at Columbia University; 2005. 4. Room R, Babor T, Rehm J. Alcohol and public health. Lancet 365:519–30, 2005. 5. Fishbain DA, Rosomoff HL, Rosomoff RS. Drug abuse, dependence, and addiction in chronic pain patients. Clin J Pain 8:77– 85, 1992. 6. Martell B, O’Conner P, Kerns R, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med 146:116–27, 2007. 7. Fleming M, Balousek S, Klessig C, et al. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain 8:573–82, 2007.

cancer pain management in the chemically dependent patient 8. Edlund M, Steffick D, Hudson T, et al. Risk factors for clinically recognized opioid abuse and dependence among veterans using opioids for chronic non-cancer pain. J Pain 129:355–62, 2007. 9. Passik S. Frequency of substance abuse problems detected by psychiatry in a tertiary cancer center. Unpublished raw data. 10. Groerer J, Brodsky M. The incidence of illicit drug use in the United States, 1962–1989. Br J Addict 87:1345, 1992. 11. Derogatis LR, Morrow GR, Fetting J, et al. The prevalence of psychiatric disorders among cancer patients. JAMA 249:751, 1983. 12. Portenoy R, Payne R. Acute and chronic pain. In: Lowinson JH, Ruiz P, Millman RB, eds. Comprehensive textbook of substance abuse, 4th ed. Baltimore: Williams and Wilkins, 1997. 13. Gonzales GR, Coyle N. Treatment of cancer pain in a former opioid abuser: fears of the patient and staff and their influence on care. J Pain Symptom Manage 7:246, 1992. 14. Martell B, O’Conner P, Kerns R, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med 146:116–27, 2007. 15. Passik S, Kirsh K, Donaghy K. Pain and aberrant drug-related behaviors in medically ill patients with and without histories of substance abuse. Clin J Pain 22:173–81, 2006. 16. Webster L, Webster R. Predicting aberrant behaviors in opioid treated patients: preliminary validation of the opioid risk tool. Pain Med 6:432–8, 2005. 17. Dunbar S, Katz N. Chronic opioid therapy for nonmalignant pain in patients with a history of substance abuse: report of 20 cases. J Pain Symptom Manage 11:163–71, 1996. 18. Passik S, Kirsh, KL, McDonald M, et al. A pilot survey of aberrant drug-taking attitudes and behaviors in samples of cancer and AIDS patients. J Pain Symptom Manage 19:274–86, 2000. 19. Passik S, Portenoy R, Ricketts P. Substance abuse issues in cancer patients. Part 2: evaluation and treatment. Oncology (Williston Park) 12:729–34, 1998; discussion 736, 741–42. 20. Jamison R, Raymond S, Slawsby E. Opioid therapy for chronic noncancer back pain. A randomized prospective study. Spine 23:2591–600, 1998. 21. Moulin D, Lezzi A, Amireh R. Randomised trial of oral morphine for chronic non-cancer pain. Lancet 347:143–7, 1996. 22. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med 302:123, 1980. 23. Zech DFJ, Grond S, Lynch J, et al. Validation of the World Health Organization guidelines for cancer pain relief: a 10 year prospective study. Pain 63:65, 1995. 24. Ad Hoc Committee on Cancer Pain, American Society of Clinical Oncology. Cancer pain assessment and treatment curriculum guidelines. J Clin Oncol 10:1976, 1992. 25. Meuser T, Pietruck C, Radruch L, et al. Symptoms during cancer pain treatment following WHO guidelines: a longitudinal follow-up study of symptom prevalence, severity, and etiology. Pain 93:247–57, 2001.

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26. Potter JS, Hennessy G, Borrow JA, et al. Substance use histories in patients seeking treatment for controlled-release oxycodone dependence. Drug Alcohol Depend 76:213–15, 2004. 27. Walker DJ, Zacny JP. Subjective, psychomotor, and physiological effects of cumulative doses of opioid mu agonists in healthy volunteers. J Pharmacol Exp Ther 289:1454–64, 1999. 28. Michna E, Ross E, Hynes W, et al. Predicting aberrant drug behavior in patients treated for chronic pain: importance of abuse history. J Pain Symptom Manage 28:250–8, 2004. 29. Friedman R, Li V, Mehrotra D, et al. Treating pain patients at risk: evaluation of a screening tool in opioid treated pain patients with and without addiction. Pain Med 4:182–5, 2003. 30. Akbik H, Butler S, Budman S, et al. Validation and clinical application of the screener and opioid assessment for patients with pain (SOAPP). J Pain Symptom Manage 32:287–92, 2006. 31. Coambs R, Jarry J. The SISAP: a new screening instrument for identifying potential opioid abusers in the management of chronic nonmalignant pain in general medical practice. Pain Res Manage 155–62, 1996. 32. Jamison R, Stetson B, Parris W. The relationship between cigarette smoking and chronic low back pain. Addict Behav 16:103–10, 1991. 33. Antonov K, Isacson D. Use of analgesics in Sweden – the importance of sociodemographic factors, physical fitness, health and health-related factors, and working conditions. Soc Sci Med 42:1473, 1996. 34. Antonov K, Isacson D. Prescription and nonprescription analgesic use in Sweden. Ann Pharmacother 32:485, 1998. 35. Corrigall W, Franklin K, Coen K, Clarke PB. The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107:285–9, 1992. 36. Passik S, Kirsh K, Donaghy K. Pain and aberrant drug-related behaviors in medically ill patients with and without histories of substance abuse. Clin J Pain 22:173–81, 2006. 37. Kaplan R, Slywka J, Slagle S, et al. A titrated analgesic regimen comparing substance users and non-users with AIDS-related pain. J Pain Symptom Manage 19:265–71, 2000. 38. Butler SF, Budman SH, Fernandez K, Jamison RN. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain 112:65–75, 2004. 39. Passik SD, Kirsh KL, Whitcomb LA, et al. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther 26:552–61, 2004. 40. Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids. Adv Ther 17:70–80, 2000. 41. Lundberg JC, Passik SD. Alcohol and cancer: a review for psycho-oncologists. Psychooncology 6:253–66, 1997. 42. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 264:2511–18, 1990. 43. Passik S, Schreiber J, Kirsh, et al. A chart review of the ordering and documentation of urine toxicology screens in a cancer

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center: do they influence patient management? J Pain Symptom Manage 19:40–4, 2000. 44. Bruera E, Moyano J, et al. The frequency of alcoholism among patients with pain due to terminal cancer. J Pain Symptom Manage 10:599–603, 1995.

s.d. passik, l.k. dhingra, and k.l. kirsh 45. Miovic M, Block S. Psychiatric disorders in advanced cancer. Cancer 110:1665–76, 2007. 46. Maxmen JS, Ward NG. Substance-related disorders. In: Essential psychopathology and its treatment. New York: W. W. Norton and Company, 1995, pp 132–72.

23

Cancer pain in children richard hain

Cardiff University School of Medicine

Introduction

Diagnosis of pain

Palliative medicine has been slower to develop in the pediatric world than in the adult one. This may partly be simply because fewer children die: The death of a child, even in a busy pediatric oncology department, is a relatively rare event compared with an adult unit. It may also be because most pediatric specialties already have at their heart an approach that is holistic or multidimensional and patient centered. Although it is often more honored in the breach than the observance, this principle means that palliative care has perhaps had to recapture a vision in adult medicine that pediatrics has never quite lost. Most of those practicing palliative medicine among children today are pediatricians. For any specialty involving close clinical contact with children, adequate training and experience in pediatrics is a sine qua non. Faced with a child in pain, a key question is often thought to be, How is pain in children different from that in adults? The more important question is, perhaps, How does the child in pain differ from other children? The child in pain is a child first: A thorough understanding of children is a prerequisite to understanding their pain. But we are still in the vanguard of the development of pediatric palliative care. It will be some years before specialist pediatricians can provide all tertiary palliative medicine necessary for children. In the meantime, pediatricians should be willing to work alongside their adult colleagues in the care of children with life-limiting conditions. When it comes to management, it is important to be able intelligently to extrapolate and/or modify techniques that have been developed in adults. This chapter considers the diagnosis, assessment, measurement, and management of pain in children. It considers both how pain affects children and how being a child affects the nature of pain.

The persistence of professional beliefs that children do not experience pain has been well documented.1 As recently as the early 1990s, one pediatric hematology professor in North America commented to his trainees that “children are like fish – they do not feel pain!” Intended, possibly, as a light-hearted and perhaps even ironic reference, the assertion perfectly articulates the views of generations of professionals working with children. It may stem from an early study2 that concluded that “the neonate’s experience of pain is equivalent to that of a deeply anesthetized adult.” The study was an honest attempt to investigate an important phenomenon, but its interpretation was deeply flawed. It is a measure of the willingness of professionals to believe convenient conclusions of scientific studies, even where they plainly contradict day-to-day clinical experience, that this conclusion seems hardly to have been questioned by the mainstream of pediatrics for some decades. Remnants of the myth persist even today; invasive and highly painful procedures such as circumcision3 and bone marrow aspiration4 are still routinely performed in children in many centers without general anesthesia. It often has been observed that children tolerate pain well in contrast to adults. This is almost certainly true, partly because existential aspects of pain are probably different in children, but mostly because we give them little alternative. For a child to receive analgesia, any expression of pain has to be processed by dilating concentric rings of caregivers, first within the family and then through the hierarchy of professionals, before medication can be made available. Children have no choice but to tolerate pain well. The ethical question is whether children should have to tolerate pain these days, because safe and effective interventions are available to prevent it. It is a genuine and important question. Children rarely die from pain, but they do (rarely)

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434 die under general anesthesia, or after an adverse event from some analgesic. The ethical argument can be made that it is always safer for a child to suffer pain than run the risk, however small, of adequate analgesia or anesthesia. On the other hand, this is also true for adults, and as a society, we do not accept the argument that the certainty of avoidable pain is preferable to the remote possibility of avoidable death. In the absence of evidence that children are more vulnerable to adverse effects, we should surely apply the same moral imperative to the provision of adequate analgesia for children.

Physiology of pain in children Over the last three decades, good scientific evidence has emerged to counter earlier misconceptions regarding the child’s capacity to feel pain. We now know that even at birth,5 the neurological system of the full-term neonate is perfectly capable of experiencing pain. One early theory was that demyelination made a child less able than an adult to feel pain. It is certainly true that myelination is incomplete at birth,6 but it now appears that the nerves most affected are those that mediate analgesia.5 The net effect of demyelination may be to render a neonate more, rather than less, susceptible to pain. The vulnerability of children to analgesic medications also has been exaggerated in the past. There is little evidence to suggest that children are any more susceptible, for example, to the adverse effects of opioid. Outside the neonatal period, it appears that passage of opioids across the blood–brain barrier is comparable with that in adults.7 There is evidence that renal clearance of opioids improves over the first few months and years of life5 and that older children actually clear opioids more quickly than adults.7,8 There is no doubt that the body of published evidence regarding pain in children remains small compared with that available in adults. We do now know, however, that children have in common with adults9,10 the fact that, with appropriate dosing, review, and titration guidelines,11 analgesics can be prescribed safely and with good effect.

Types of cancer pain in children Table 23.1 indicates some of the important characteristics that make cancer pain in children distinct. The range of tumors in children is very different from that in adult oncology, which affects the nature of pain experienced by children with cancer. The major causes of bone pain in adults, such as breast cancer, myeloma, carcinoma of the colon, and lung cancer, simply do not occur in children. Although

r. hain Table 23.1. Cancer pain in children: differences from adults’ pain Spectrum of tumors quite different from adults: leukemias, brain tumors, abdominal and bone tumors predominate Bone pain caused more often by medullary expansion, less often by localized bone metastases Neuropathic pain less common; may arise from tumors themselves (tumors that are neural in origin quite common) Emotional elements of pain very important, particularly among adolescents; may need to address fears of whole family to manage “total pain” Pain and emotional discomfort of procedures often worse than pain from cancer itself, particularly if hospital attendance is required; smaller role for invasive analgesic approaches, such as neurolytic procedures Chemotherapy often continued even once cure unlikely; palliative management may need to be alongside experimental or potentially “curative” chemotherapy Cord compression rare, presents less acutely, often diagnosed too late for radiotherapy to be of benefit

bone pain due to discrete metastases does occur, most notably in osteosarcoma and Ewing’s sarcoma, in children it is more commonly a result of medullary expansion associated with relapsed leukemia. Nonsteroidal anti-inflammatory drugs (NSAIDs) and radiation may play a part, as they do in adults, but a short course of palliative chemotherapy such as steroids or oral antineoplastics may be more effective. The use of “palliative chemotherapy”12–22 in pediatric cancers is contentious. The term should probably be restricted to using chemotherapy specifically for the relief of symptoms. In practice, it is often used instead to describe experimental chemotherapy, or chemotherapy given with the intention of prolonging life, or even as a “last-ditch” attempt at cure. Neuropathic pain, in children as in adults, may be caused by nerve damage or compression due to tumor or treatment. Again, the underlying causes in children are very different. Axillary plexopathy related to breast cancer and celiac axis pain from carcinoma of the head of the pancreas or of the bowel are almost unknown. Neuroblastoma in this region as a cause of celiac axis pain is rare but has been described.23 More commonly, neuropathic pain may complicate terminal management of peripheral neuroectodermal tumors (Ewing’s sarcoma or Askin tumor). As the name suggests, these are tumors of neuroectodermal origin, and the tumors themselves, or metastatic deposits, often are painful. Typically, the pain lacks the dermatomal distribution of classic neuropathic pain but presents with the hallmark of altered sensation and responds to antineuropathic pain measures such an anticonvulsants or antidepressants.

cancer pain in children Pelvic tumors are rarer in childhood than in adults but may arise, for example, as a prostatic rhabdosarcoma or by extension from other intra-abdominal tumors. Reduction of tumor volume, where practical, can be a valuable approach to reducing neuropathic pain. Judicious use of palliative chemotherapy that emphasizes agents with low toxicity that can be taken orally may have an impact. Etoposide24–26 is such an agent. Radiation may be a valuable adjunct but is not always practical because of scatter to adjacent organs. This is particularly true in the pelvis, where radiation proctitis may impose a disproportionate symptom burden.

Assessment and measurement of pain Assessment Verbal expression When possible, verbal expression of pain by children or young people themselves is the preferred way to access their experience. Any articulation of pain that has been processed by others will necessarily be contaminated by objectivity, and is no longer a subjective description. Although they may lack the precise vocabulary used by some adults, children may nevertheless be able to give an accurate pain description. For example, a child who described “toothache in the middle of my arm” was clearly communicating the pain of a bony metastasis. Such descriptions are often precise enough to convey the information and should certainly be solicited if at all possible. In reality, it is not always practical to rely only on the child’s own description of his or her pain. As a general rule, the more time somebody spends with the child, the more reliable his or her report is likely to be that the child is in pain. Thus, parents are more likely to notice pain than nurses, and nurses often are more likely to notice it than doctors. Because there is no absolute means of diagnosing pain, except by report, the burden of proof should be in favor of prescribing analgesia rather than against it. If there is doubt, it is often helpful to explore with the parent or caregiver what behaviors in the child have suggested that he or she is in pain and to initiate a therapeutic trial of an appropriate analgesic. If there is no change in the behavior, it is a good indication that pain was not the cause. In the meantime, a message has been given that professionals have taken seriously the possibility that it was. It is also helpful to consider whether it is inherently plausible that a child is not in pain. Because a child is able to experience pain at least as well as an adult, it is reasonable to assume that a situation or procedure that adults would find painful will cause the child a similar degree of pain. The

435 answer to the question How painful would I find circumcision without general anesthesia? immediately concentrates the mind on the need to abolish such an approach. The question Would paracetamol (acetaminophen) be sufficient for my pain 24 hours after appendicectomy? helps clarify the need for adequate postoperative analgesia in children. Symbolic expression Skilled therapists can access the experience of children through play, art, music, or other symbolic means of expression. These techniques have the advantage of fitting well with a child’s normal experience of life. For a child, they are simply an extension of his or her normal experiences of childhood play. Symbolic expressions of pain can access more than just the physical components. Children often may express anger, fear, sadness, and other elements of “total pain.” The interested reader is referred to more detailed chapters published elsewhere.27 Although symbolic techniques can therefore address the comprehensive experience of pain, they are not as good at quantitating pain. These techniques are useful for indicating that pain is present but are not as good at identifying its precise nature or severity. Behavior: “body language” Experienced pediatric professionals, particularly nursing staff, learn to recognize that a child is in pain simply from “the way he or she looks.” Whereas a normal child will move freely and interact socially, the child who is in pain may demonstrate poverty of movement, speech, and expression. Again, this is a good indication that pain is present, but alone provides only limited information about nature or intensity. One highly innovative measure,28–30 however, allows a more precise quantitation of pain from these behaviors in children with cancer, providing what is in effect a dictionary for their body language. More recently, the Pediatric Pain Profile was developed for children with nonmalignant life-limiting conditions.31 Measurement The measurement of pain in children is one of the few areas of children’s palliative care that has received considerable research attention. There are many scales designed to be accessible to children while providing robust quantitative data. Given the range of tools available, it is perhaps surprising to find that their use is far from routine in many pediatric units. Even where good management of pain in children is given a high priority, assessment often is done using

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436

MOST PAIN

10 9 8 7 6 5 4 3 2 1 0 NO PAIN

Fig. 23.1. Simple color analogue scale. The scale emphasizes increasing pain intensity using increasing width and depth of color (usually red).

tools that have been developed in adults and that have not necessarily been validated in children. It could be argued that this is because, in practice, precise numeric data are not essential to manage pain adequately. Given the variability between one patient and another, approximations in reporting of pain, and the multiple other variables in clinical practice, overemphasis on precisely expressing pain scores may be neither practical nor necessary. At the same time, one of the historical barriers to good pain management in children has been the difficulty in performing clinical research trials to develop techniques that are safe and effective. Such research depends for credibility on reliable quantitative measures of pain. Visual analogue scales A large proportion of pain measurement tools that have been developed for use in children are variations on a visual analogue scale (VAS).32 It is well established that children find little conceptual difficulty in using VAS, although recent evidence suggests they may prefer Likert scales.33 The challenge has been to make them attractive and accessible for children to use and, where possible, to keep to a minimum the need for sophisticated understanding of numbers. Alongside this has been the challenge of developing a single tool that can meet the needs of children at many different stages of development.

The simplest tools are color analogue scales (Fig. 23.1). Alongside a simple vertical VAS, a color analogue scale emphasizes the concept of increasing pain intensity with a color bar that increases in color intensity and in width as pain intensity increases. From a very early age, children engage enthusiastically with facial expression, and this has been the basis for a number of “faces” scales.34,35 The faces are intended to represent how a child feels inside. Too often, however, they are used simply to represent the facial expression of a child who is in pain. For this reason, they have been validated largely in the context of acute pain, particularly postoperative pain. Most facial expression changes (Fig. 23.2) are a short-lived response to acute pain. The faces scales may therefore be less effective in chronic pain. Other scales The color tool36 is an imaginative and practical pain measurement tool. The child is given an outline drawing of a human figure and asked to choose from a selection of crayons four colors to represent no pain, mild pain, moderate pain, and severe pain. The child then simply chooses the appropriate crayon to color in the drawing, indicating both location and intensity of acute pain.37 The tool is ideally designed for young children, combining as it does accessibility and quantitation without the need for numeracy. The Douleur Enfant Gustave-Roussy (DEGR)28–30,38 effectively provides a means to quantify a child’s physical expression of pain. The DEGR consists of a series of observations about the child’s behavior and comportment. The intention is that the observations are made over the duration of an individual nursing shift. The observations are grouped under three headings (Fig. 23.3): r Direct pain related to movement and positioning. This is important because a child may describe him- or herself as being free of pain but be able to maintain analgesia only by remaining preternaturally immobile. r Verbal complaint. As has been seen, when asked directly, children often are able to report both the presence and the nature of pain with surprising accuracy. From a young age, children are able to use a VAS. r Psychomotor atonia. This phenomenon, first observed by the team who developed the DEGR, describes the appearance of a child with pain that has gone on for some time. Although acute pain may induce a vigorous protest in a child, if this does not result in any intervention that helps the pain, the child will gradually resign him- or herself to the pain. The phenomenon of psychomotor atonia describes the appearance of a child who is still in pain but

cancer pain in children

0 No Hurt

437

4 Hurts Whole Lot

3 Hurts Even More

2 Hurts Little More

1 Hurts Little Bit

5 Hurts Worst

Fig. 23.2. Typical faces-type VAS. This scale capitalizes on a child’s interest and rapid engagement in facial expressions. However, facial expressions may not correlate reliably with the severity of pain much beyond the immediate acute event and may not always be suitable for the more chronic pain of cancer.

The pediatric pain profile31 consists of a series of items based on the observation of common behavior patterns in children with severe developmental delay. Again, this is a tool designed for use in the clinical setting. It is based on

has given up hope of its ever being effectively relieved. It is characterized by social withdrawal and by lack of movement and of facial expression, closely resembling the adult syndrome of depression.

8

4

0

4

8

12

(a)

8

4

0

4

8

12

(b)

Fig. 23.3. The DEGR. A: Scores from each of three categories of behavior are plotted on the three axes. In acute pain, voluntary expressions of pain predominate. B: In chronic pain, although direct signs of pain are the same, psychomotor atony predominates.

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438 the observed responses of a large number of children with developmental delay to pain and, in effect, allows those who do not know a child well to have the same capacity to recognize pain as those who do.

Management of pain World Health Organization pain ladder Although children are psychologically, emotionally, and physiologically rather different from adults, the principles that underlie good management of cancer pain are essentially the same. They are summarized simply and clearly in the World Health Organization (WHO) “pain ladder” approach. Although this tool was originally designed for, and validated in, an adult population,9,10 it was soon clear that pain relief in children with cancer needed the same sort of robust and straightforward approach. The WHO, in collaboration with the renowned International Association for the Study of Pain (IASP), published guidelines for cancer pain relief in palliative care in children,11 and although they have never been formally validated, these remain the gold standard. The essence of the WHO pain ladder approach (Fig. 23.4) is that as pain intensity increases, it is not appropriate to cycle through different analgesics of roughly equivalent potency. Instead, once a less potent class of analgesics is no longer adequate to control pain, new medications that are stronger should be added or substituted. In practice, the three “steps” are simple: analgesia, minor opioids, and major opioids. A second fundamental principle is that some attempt should be made to diagnose the nature of the pain, and an appropriate adjuvant prescribed. It has already been seen that cancer may cause pain of a wide variety of types. Adequate history and examination, augmented by appropriate

to sev for moder e ate ± Non re pain o p io ± Adju id vant

Pa or incin persist in reasi ng g Opioid

moder for mild to ± Nonate pain -

04 95

Non ± Ad opioid juva nt

HO

or in in persi crea sting sing

1

± Adj opioid uvan t Pa

W

Quality of life There is an understandable tendency on the part of professionals to recognize more easily phenomena they can measure and for which they can intervene effectively. It is important to remember that achieving good pain relief is necessary but not sufficient for good palliative care. There are at the moment very few well-validated measures of the quality of a child’s life in the palliative phase. In establishing the effectiveness or otherwise of palliative care systems and techniques, the emphasis should be on developing measures not simply of pain, but of the overall quality of a child’s life.

Free cancedrom from pain Opioid

Pain Fig. 23.4. The WHO pain ladder underpins the 1998 WHO/IASP guidelines for management of pain in children, although it has never been formally validated and continues to be subject to debate.

investigations when necessary, usually can elucidate one of a small number of pain syndromes. The importance of this analytical approach is to allow selection of an appropriate adjuvant. At each step of the WHO ladder, an adjuvant should be introduced if one is available to suit the pain. As in adults, the commonest adjuvants in children’s cancer pain are antiepileptics and anticonvulsants for neuropathic pain and NSAIDs or radiation for bone pain. Bisphosphonates are not yet widely used in pediatrics, partly because many of the cancer subtypes that metastasize readily to bone in adults are not found in children. Metastatic bone disease is, in fact, relatively rare in childhood. Many pediatricians are concerned about the effect of bisphosphonates on bone modeling during childhood and adolescence, although current evidence shows they are safe.39 Their use in pediatric palliative medicine largely has been confined to management of pain in osteogenesis imperfecta.40–42 There are a number of “golden rules” associated with the use of the WHO pain ladder. These become even more important in managing children (Table 23.2). Needles should be avoided whenever possible, and the intramuscular route in particular is always contraindicated. The need to make a rational diagnosis of the pain, to prescribe appropriate doses of appropriate medications, and to keep dosage intervals logical (e.g., every 4 hours or less for morphine) is as important in children as it is in adults. Similarly, it is

cancer pain in children Table 23.2. Particular issues to consider in selecting analgesics and adjuvants in palliative pain management in children with cancer a Is it available in a formulation that avoids needles? Is there evidence for its effectiveness in children (even case series)? What are its adverse effects in children? Are there prescribing guidelines in children? Would an alternative drug in the same class be more familiar to pediatricians? Would prescribing it delay discharge or complicate management at home? a

These reflect differences in the way palliative care is delivered to children (e.g., the need to share care with pediatricians) as well as in children themselves. Most important palliative medications can be given to children with appropriate amendments in dosage. If in doubt, contact a pediatric palliative medicine specialist.

important to allow 48 hours to elapse between changing a prescription and reviewing it, to allow realistic assessment of its effectiveness and to allow tolerance to adverse effects to occur. Management of pain in children seems little different from that in adults. So what makes children different? Essentially, children are usually stronger than adults. Even a dying child usually has well-functioning kidneys, heart, and respiratory system and, perhaps above all, a resilient psyche. Taken together, these mean that children often are surprisingly resistant both to beneficial and to adverse effects of palliative medications (Fig. 23.5). Clinical experience suggests that children require a higher dose of opioids per unit of weight than adults. This is supported, but not proven, by some studies.43 These differences also mean that the balance of the benefit of some pharmacological approaches and their burden to the patient is different in the child versus the adult. For example, confusion or delirium caused by the anticholinergic effects of amitriptyline is rare in childhood. On the other hand, the risk of dystonia with haloperidol makes it a less attractive choice for opioid-induced nausea and vomiting than in adults, and certainly is unsuitable for prophylaxis. Anecdotal evidence suggests that children suffer less nausea and vomiting and delirium associated with opioid therapy, but more retention and pruritus. Again, the evidence for this is unclear and may be related to the reluctance of children to volunteer information about adverse effects unless specifically invited to do so. In parallel with discussions in the adult specialty, those working in pediatric palliative medicine have called into question some details of the WHO pain ladder approach. NSAIDs should probably be regarded as step 1 (simple)

439 analgesics rather than true adjuvants, but in practice, they continue to be regarded as adjuvants by most pediatric palliative medicine physicians. The move to describing minor and major opioids as “opioids for mild pain” and “opioids for strong pain” generally has been resisted by most pediatricians. Although pharmacologically a more accurate description, the new terms are unwieldy and add little to most people’s understanding. The bigger question – that is, whether there should be a second step at all – is of considerable practical importance in the pediatric specialty. The introduction of buprenorphine in a transdermal patch has meant that increasingly, children are started on a small dose of buprenorphine instead of codeine. Available buprenorphine formulations effectively encompass steps 2 and 3, arguably rendering minor opioids such as codeine redundant in children. Opioids in children: the evidence In considering what opioid to prescribe, there are some specific aspects that need to be taken into account with respect to children. The importance of an acceptable formulation already has been discussed. The availability of an evidence base in children is a second, extremely important factor that should influence a clinician’s choice. Use of

NOZINAN

Fig. 23.5. Children typically have well-functioning heart, kidneys, lungs, and brain and often are surprisingly resilient to palliative medications. This should not be taken as a dosage recommendation.

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440 unlicensed and off-label medications is widespread in pediatrics and in palliative medicine,44–47 but there is now some research evidence for several major opioids in children. Morphine/diamorphine and fentanyl are the best-researched pediatric major opioids, but there also has been research on hydromorphone, tramadol, and methadone. Pethidine (meperidine), which has received a good deal of attention in the pediatric literature, is now known to be an unsafe drug with little to recommend it. The three main pharmacokinetic phenomena that govern how an opioid should be prescribed are volume of distribution (i.e., the relationship between the dose of a drug that is given and the serum concentration that results), half-life (a measure of how quickly the body eliminates the drug, either by excretion or by conversion to a metabolite), and transformation (i.e., the way in which the body handles the drug). To use opioids safely and effectively in children, it is ideal to know how developmental stage affects these three parameters. Historically, dosage recommendations for morphine in children have relied on the assumption that reducing the dose in proportion to the child’s size would result in similar serum concentrations. In effect, this is equivalent to saying that the volume of distribution is the same in children as it is in adults. If true, it would mean that 10 mg of morphine given to a 25-kg child would result in the same serum concentration as 30 mg of morphine given to a 75-kg adult. Direct comparative evidence is not available, but pharmacokinetic studies in children7,8 seem to indicate that the volume of distribution of morphine in children is indeed similar to that found in studies in adults. It is important to remember that this does not imply that the child’s response to those serum levels will be the same as an adult’s, which is influenced by a number of other factors, including access of the molecules to the mu-opioid receptors themselves. It is not known whether these factors are different in children versus adults, although there is little evidence to support the idea that outside the neonatal period, the blood–brain barrier is any different in children versus adults. The half-life of morphine in children across a range of age groups appears to be around 90 minutes.7,8 This is somewhat shorter than that observed in some studies in adults, but the difference is smaller than the very wide variability among adult patients. It is probably accounted for at least partly by children’s greater capacity to clear drugs renally. This is, of course, not true in children under a year old, whose renal clearance is less than in adults. Like adults, children convert morphine primarily into its 3- and 6-glucuronides (M3G and M6G). There is some

evidence7,8 that the molar ratios of M3G and M6G to morphine are higher in children than in adults. Given the hypothesis that the effectiveness of morphine may depend in part on the production of M6G, and that the adverse effects may depend in part on M3G, there is a theoretical reason to suppose that children will obtain benefits from morphine different from those of adults. Opioids in children: differences from adults Do these differences matter? It could be argued that because good opioid management depends on a cycle of titration and review, the small differences suggested by published evidence may not be clinically significant. Studies have shown that starting doses of 1–2 mg/kg of oral morphine usually result in initial serum concentrations that are a good enough point from which to titrate.8 In practice, oral morphine every 2–4 hours as needed for breakthrough pain offers most children adequate analgesia. Good titration should mean that the difference between a child and an adult is no more significant than the difference between individual children. Adequate review should mean that this effectiveness does not come at too high a price in terms of tolerability. Nonmorphine opioids Oral morphine remains the opioid of first choice in pediatric palliative medicine. In countries where diamorphine is available, it is used effectively as the parenteral form of morphine. The need to avoid needles in children (Table 23.2) means that transdermal formulations such as fentanyl and, increasingly, buprenorphine are second line. Newer opioids, such as oxycodone, have not found a foothold in the pediatric specialty, largely because of the lack of data for their use in children and indeed the lack of evidence for significant benefits over morphine. Morphine, and by direct inference diamorphine, are by far the best-studied opioids in children. Because of their transdermal formulations, the second-line major opioids in children usually are fentanyl and buprenorphine. Fentanyl has been available for longer, and there has been research demonstrating its safety and effectiveness in children.48–52 Interestingly, like morphine, it appears to be cleared somewhat more quickly in children than in adults. The evidence base for buprenorphine in children is currently small and needs to be expanded if this potentially useful drug is to become more widely used in children with cancer. Methadone is not used widely in most pediatric centers, despite some evidence for its effectiveness in children.53,54

cancer pain in children This is because it is a priority of pediatric palliative medicine to ensure the child can be cared for at home during the palliative and dying phases.55 Concern about the variable elimination of methadone56 means that most centers recommend that it should be commenced only in inpatients.57 This makes it less acceptable for use in children. Variable elimination has not been demonstrated in children, however, and it is possible that this potentially useful drug is underused. There are data regarding hydromorphone in children,58 but its benefits over morphine in children are less clear than in adults. Its major advantage is that it is more potent than morphine, and is therefore a suitable alternative for parenteral administration of high opioid doses in countries where diamorphine is not yet available. The need for such high doses is less common in children. Tramadol often is recommended for children with acute postoperative pain, particularly following orthopedic interventions. Evidence for its usefulness in the more chronic pain of palliative care is sparse. Pethidine (meperidine) was traditionally favored by pediatricians, perhaps because of its use in abdominal pain associated with sickle cell crisis. It has little to recommend it59–65 and has been supplanted by opioids that are safer and at least as effective.

Summary Traditionally, physicians have overestimated both the similarities and the differences between children and adults. We now know that children are able to experience pain at least as intensely as adults, and it follows by direct inference that they deserve equally close attention to adequate and rational diagnosis, assessment, and management of pain. Diagnosis of pain may be complex in children, particularly those who are pre- or nonverbal. It is sometimes necessary to accept the word of those who know the child best, usually the family or caregivers. Numerous tools have been devised to assess and measure pain in children. These range from many that are based on a simple VAS to more innovative tools that rely on observation of a child’s “body language.” Despite the ready availability of most of these tools, they are not routinely used in most units. Although perfect relief of pain in children is a laudable aim in principle, and often attainable in practice, it is important to remember that analgesia is only one aspect of good quality of life. Teenagers in particular may choose to remain in a certain amount of pain if the alternative is perfect compliance with the medical team’s instructions. Assessment of the effectiveness of palliative care interventions

441 ideally should be on the basis of observable changes in quality of life. There are, as yet, no measures of quality of life in the palliative phase for children. With respect to treatment, it also is possible to overstate both the similarity and the difference between adults and children. It appears from available research that children handle, and are affected by, opioids in ways that are comparable with adults. Nevertheless, the emotional, social, and spiritual dimensions of a child’s life and dying are very different from those of an adult. As a result, the culture of pediatrics is very different from the culture of adult medicine. For many years to come, pediatricians will need to look to their adult palliative medicine colleagues for support. On occasion, faute de mieux, adult palliative medicine specialists may even find themselves having to take the lead in the medical care of dying children. However, the nature and practice of medicine in adults and pediatric patients are very different, particularly when attempting a holistic or multidimensional approach. Ultimately, pediatric palliative medicine must develop as a branch of pediatrics, not of palliative medicine. References 1. Schechter NL. The undertreatment of pain in children: an overview. Pediatr Clin North Am 36:781–94, 1989. 2. McGraw M. Neural maturation as exemplified in the changing reactions of the infant to pin prick. Child Dev 12:31–42, 1941. 3. Anand KJ, Johnston CC, Oberlander TF, et al. Analgesia and local anesthesia during invasive procedures in the neonate. Clin Ther 27:844–76, 2005. 4. Hain RD, Campbell C. Invasive procedures carried out in conscious children: contrast between North American and European paediatric oncology centres. Arch Dis Child 85:12–15, 2001. 5. Simons SH, Tibboel D. Pain perception development and maturation. Semin Fetal Neonatal Med 11:227–31, 2006. 6. Anand C. The neuroanatomy neurophysiology and neurochemistry of pain stress and analgesia in newborns and children. Pediatr Clin North Am 36:797–822, 1989. 7. Hain RD, Hardcastle A, Pinkerton CR, Aherne GW. Morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children. Br J Clin Pharmacol 48:37–42, 1999. 8. Hunt A, Joel S, Dick G, Goldman A. Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained-release tablets for cancer pain. J Pediatr 135:47–55, 1999. 9. Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the WHO method for cancer pain relief. Cancer 59:850–6, 1989. 10. Zech DF, Grond S, Lynch J, et al. Validation of World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain 63:65–76, 1995.

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11. World Health Organisation. Guidelines for analgesic drug therapy. In: Cancer pain relief and palliative care in children. Geneva: WHO/IASP, 1998, pp 24–8. 12. Kendall C. Forum for Applied Cancer Education and Training. Palliative chemotherapy. Eur J Cancer Care (Engl) 9:243–50, 2000. 13. Ellison N. Palliative chemotherapy. Am J Hosp Palliat Care 15:93–103, 1998. 14. Archer V, Billingham L, Cullen M. Palliative chemotherapy: no longer a contradiction in terms. Oncologist 4:470–7, 1999. 15. Jefford M, Zalcberg J. Palliative chemotherapy: a clinical oxymoron. Lancet 362:1082, 2003. 16. Koedoot CG, de Haan RJ, Stiggelbout AM, et al. Palliative chemotherapy or best supportive care? A prospective study explaining patients’ treatment preference and choice. Br J Cancer 89:2219–26, 2003. 17. Dodwell DJ, Rathmell AJ, Ash DV. Assessment of palliative chemotherapy: a step beyond response. Clin Oncol (R Coll Radiol) 5:114–17, 1993. 18. Cattell E, Arance A, Middleton M. Assessing outcomes in palliative chemotherapy. Expert Opin Pharmacother 3:693–700, 2002. 19. Macbeth FR, Mead GM, Williams CJ, Whitehouse JM. Palliative chemotherapy. Lancet 1:337, 1982. 20. Kay P. Palliative chemotherapy. Northampton: EPL Publications, 1997. 21. Markman M. Does palliative chemotherapy palliate? J Support Oncol 1:65–7, 2003. 22. Andrew J, Whyte F. The experiences of district nurses caring for people receiving palliative chemotherapy. Int J Palliat Nurs 10:110–18, 2004; discussion 118. 23. Hildebrandt T, Venables J, Hain R. Palliative care of a paediatric patient with relapsed neuroblastoma. Eur J Palliat Care 13:101– 2, 2006. 24. Kebudi R, Gorgun O, Ayan I. Oral etoposide for recurrent/ progressive sarcomas of childhood. Pediatr Blood Cancer 42:320–4, 2004. 25. Schiavetti A, Varrasso G, Maurizi P, et al. Ten-day schedule oral etoposide therapy in advanced childhood malignancies. J Pediatr Hematol Oncol 22:119–24, 2000. 26. Davidson A, Gowing R, Lowis S, et al. Phase II study of 21 day schedule oral etoposide in children. New Agents Group of the United Kingdom Children’s Cancer Study Group (UKCCSG). Eur J Cancer 33:1816–22, 1997. 27. Goldman A, Hain R, Liben S, eds. Oxford textbook of palliative care in children. Oxford: Oxford University Press, 2006. 28. Gauvain-Piquard A, Rodary C, Rezvani A, Lemerle J. Pain in children aged 2–6 years: a new observational rating scale elaborated in a pediatric oncology unit – preliminary report. Pain 31:177–88, 1987. 29. Gauvain-Piquard A, Rodary C, Francois P, et al. Validity assessment of DEGR scale for observational rating of 2-6 year old child pain. J Pain Symptom Manage 6:171, 1991. 30. Gauvain-Piquard A, Rodary C, Rezvani A, Serbouti S. The development of the DEGR(R): a scale to assess pain in young children with cancer. Eur J Pain 3:165–76, 1999.

r. hain 31. Hunt A, Wisbeach A, Seers K, et al. Development of the paediatric pain profile: role of video analysis and saliva cortisol in validating a tool to assess pain in children with severe neurological disability. J Pain Symptom Manage 33:276–89, 2007. 32. Huskisson EC. Visual analogue scales. In: Melzack R, ed. Pain measurement and assessment. New York: Raven Press, 1983, pp 33–7. 33. Scott PJ, Ansell BM, Huskisson EC. Measurement of pain in juvenile chronic polyarthritis. Ann Rheum Dis 36:186–7, 1977. 34. Hicks CL, von Baeyer CL, Spafford PA, et al. The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement. Pain 93:173–83, 2001. 35. McGrath PA, Seifert CE, Speechley KN, et al. A new analogue scale for assessing children’s pain: an initial validation study. Pain 64:435–43, 1996. 36. Eland JM. Minimizing pain associated with prekindergarten intramuscular injections. Issues Compr Pediat Nurs 5:361–72, 1981. 37. McConahay T, Bryson M, Bulloch B. Clinically significant changes in acute pain in a pediatric ED using the Color Analog Scale. Am J Emerg Med 25:739–42, 2007. 38. Hain RDW, Devins M, Davies R. Correlation of pain scores in children with cancer using DEGR and Oucher scales. In: Cardiff University School of Medicine; 2007. 39. Ward K, Cowell CT, Little DG. Quantification of metaphyseal modeling in children treated with bisphosphonates. Bone 36:999–1002, 2005. 40. Waterhouse KM, Auron A, Srivastava T, et al. Sustained beneficial effect of intravenous bisphosphonates after their discontinuation in children. Pediatr Nephrol 22:282–7, 2007. 41. Lowing K, Astrom E, Oscarsson KA, et al. Effect of intravenous pamidronate therapy on everyday activities in children with osteogenesis imperfecta. Acta Paediatr 96:1180–3, 2007. 42. Glorieux FH. Experience with bisphosphonates in osteogenesis imperfecta. Pediatrics 119(Suppl 2):S163–5, 2007. 43. Hewitt M, Goldman A, Collins GS, et al. Opioid use in palliative care of children and young people with cancer. J Pediatr 152:39–44, 2008. 44. Conroy S, Choonara I, Impicciatore P, et al.: Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ 320:79–82, 2000. 45. Atkinson CV, Kirkham SR. Unlicensed uses for medication in a palliative care unit. Palliat Med 13:145–52, 1999. 46. RCPCH/NPPG Standing Committee on Medicines. The use of unlicensed medicines or licensed medicines for unlicensed applications in paediatric practice (Report). 2000. 47. McCormack Group. Using licensed medicines for unlicensed indications. Off-Label Rapid Response. 2003. 48. Collins JJ, Dunkel IJ, Gupta SK, et al. Transdermal fentanyl in children with cancer pain: feasibility, tolerability, and pharmacokinetic correlates. J Pediatr 134:319–23, 1999. 49. Sharar SR, Carrougher GJ, Selzer K, et al. A comparison of oral transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound care. J Burn Care Rehabil 23:27–31, 2002. 50. Noyes M, Irving H. The use of transdermal fentanyl in pediatric oncology palliative care. Am J Hosp Palliat Care 18:411–16, 2001.

cancer pain in children 51. Wolfe T. Intranasal fentanyl for acute pain: techniques to enhance efficacy. Ann Emerg Med 49:721–2, 2007. 52. Zernikow B, Michel E, Anderson B. Transdermal fentanyl in childhood and adolescence: a comprehensive literature review. J Pain 8:187–207, 2007. 53. Shir Y, Shenkman Z, Shavelson V, et al. Oral methadone for the treatment of severe pain in hospitalized children: a report of five cases. Clin J Pain 14:350–3, 1998. 54. Miser AW, Miser JS. The use of oral methadone to control moderate and severe pain in children and young adults with malignancy. Clin J Pain 1:243–8, 1986. 55. Vickers J, Thompson A, Collins GS, et al. Place and provision of palliative care for children with progressive cancer: a study by the Paediatric Oncology Nurses’ Forum/United Kingdom Children’s Cancer Study Group Palliative Care Working Group. J Clin Oncol 25:4472–6, 2007. 56. Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 19:13–24, 2005. 57. Shir Y, Rosen G, Zeldin A, Davidson EM. Methadone is safe for treating hospitalized patients with severe pain. Can J Anaesth 48:1109–13, 2001.

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58. Babul N, Darke AC, Hain R. Hydromorphone and metabolite pharmacokinetics in children. J Pain Symptom Manage 10:335– 7, 1995. 59. Pokela ML, Olkkola KT, Koivisto M, Ryhanen P. Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants. Clin Pharmacol Ther 52:342–9, 1992. 60. Hamunen K, Maunuksela EL, Seppala T, Olkkola KT. Pharmacokinetics of i.v. and rectal pethidine in children undergoing ophthalmic surgery. Br J Anaesth 71:823–6, 1993. 61. Kussman BD, Sethna NF. Pethidine-associated seizure in a healthy adolescent receiving pethidine for postoperative pain control. Paediatr Anaesth 8:349–52, 1998. 62. Pryle BJ, Grech H, Stoddart PA, et al. Toxicity of norpethidine in sickle cell crisis. BMJ 304:1478–9, 1992. 63. Kyff JV, Rice TL. Meperidine-associated seizures in a child. Clin Pharm 9:337–8, 1990. 64. Waterhouse RG. Epileptiform convulsions in children following premedication with Pamergan SP100. Br J Anaesth 39:268– 70, 1967. 65. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain 18(4 Suppl):S3–13, 2002.

24

Managing cancer pain in the elderly marvin omar delgado-guay a and david wollner b a b

The University of Texas M. D. Anderson Cancer Center and Metropolitan Jewish Health System

Introduction Western populations are experiencing a progressive increase in median life span, and it is predicted that the percentage of individuals aged 60 years and older will reach 15.2% in 2030.1–3 With aging, there is a decline of organ reserves and functional impairment, contributing to a decreased adaptability to both disease and its treatment. The aging of the population and advances in modern medicine have resulted in chronicity of some illnesses, such as cancer, end-stage heart and lung diseases, and renal insufficiency. Older cancer patients may experience a number of devastating physical and psychosocial symptoms before they die.1,4,5 When symptoms are not recognized and treated appropriately, there is an increase in suffering among elderly patients and their primary caregivers. Cancer pain management in the elderly is truly a public health and quality-of-care issue. Pain in cancer patients is not yet treated effectively.1–3 Most of the cancer patients and cancer survivors are 65 years old or older. Approximately 60% of the estimated 10.8 million cancer survivors in the United States today are older than 65 years.6 Multidisciplinary evaluation of the malignancy and its distressing symptoms and an interdisciplinary approach to the host’s symptoms, including pain, constitute the most effective approach to assessing and treating elderly cancer patients to maximize the best possible quality of life. This book chapter highlights the important issues concerning pain management in elderly cancer patients, the appropriate assessment tools and therapeutic options, and their impact on quality of life.

Cancer pain in the elderly Pain is a common symptom in elderly cancer patients. It may be poorly controlled because it is underreported or patients may have problems with communication or cogni444

tion, and physicians may undertreat it as a result of inherent biases and concerns about use of medications in older patients because of the presence of comorbid diseases and increased risk of adverse drug reactions.2,4,7 It has been documented that 25%–50% of community-dwelling aging individuals may experience significant pain,7 and nearly 50% of severely ill hospitalized patients report that they have pain.7,8 Poorly managed pain increases health care utilization and drives up costs.9 Misconceptions and deficits of knowledge on the part of both patients and health care providers about opioids, including concerns about tolerance and addiction, are other barriers to adequate pain control. Furthermore, many elders and their caregivers expect pain to be a part of aging and do not report it because they think the health care professional is too busy to hear about their complaint.10,11 Patients who experience unrelieved pain have diminished hope and increased depression rates,11 increased sleep and appetite disturbances, and worsening of cognitive dysfunction.3 Pain has a multidimensional nature, and it is extremely important for providers of heath care to older cancer patients to recognize pain, consider the aging factors related to the perception of pain, and treat it appropriately, taking into account other physical, psychosocial, and spiritual symptoms that may greatly influence the pain expression and thereby worsen the pain.1,2,12,13

Pain perception and aging It has been suggested that older patients may report pain less often than young patients because of alterations in the sensorineural apparatus.14 Although nerve conduction appears to be well maintained with age, there is a decrease in the number of nociceptive receptors in the skin and in the amount of afferent fibers with age, causing alteration in

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the perception of pain.15,16 Some laboratory studies have suggested that with increased age, there is a higher threshold for electrical, thermal, and mechanical painful stimuli to the skin; however, these studies lack definitive conclusions because of the low painful stimulus used to produce pain and because several other factors besides age affected the perception of pain.16,17 It has been suggested that older patients have reduced pain perception, especially of visceral pain, evidenced by silent myocardial infarctions16 and the absence of abdominal pain during peritonitis.18,19 Also, elderly people probably report less pain because of stoicism or slowness in responding, but also because of the presence of cognitive impairment, and probably because of language barriers in minority patients.4 Age ⬎85 years and low cognitive performance are predictors of failure to receive analgesics.20 It has been suggested that in elderly cancer patients, the prevalence and intensity of pain decrease.16,21 However, Vigan´o et al.,22 who reported the mean daily pain intensity and daily opioid consumption – measured as the morphine-equivalent daily dose – in 197 advanced cancer patients, concluded that older patients (⬎65 years) had a similar level of pain intensity but required a lower amount of opioid analgesia compared with younger adults. Elderly patients may have increased sensitivity to opioids, which may be related to a reduction in brain volume – approximately 20% – between ages 20 and 80 and the alteration in the ratio of ␮ and ␦ receptors.16,23

nervous system effects or anticholinergic properties. Together with a decline in kidney function, older cancer patients also experience a decrease in hypothalamic vasopressin and in thirst, developing increased susceptibility to volume depletion, which predisposes them to a higher risk of developing nephrotoxicity from medications.1,16 Another factor to consider is that older cancer patients also experience age-related changes in body fat that can affect the metabolism of medications as well as the absorption of transdermal preparations.1 It is important to consider all these age-related changes in the body as well as potential medication interactions to provide comprehensive assessment and management of distressing symptoms affecting older cancer patients.

Aging and changes in pharmacokinetics and pharmacodynamics of analgesics The physiologic changes of aging alter the pharmacokinetics and pharmacodynamics of analgesics. These changes in the metabolism of analgesics cause a decrease in their therapeutic index and an increase in the risks of toxicity and drug–drug interactions.1,2 These changes, accompanied by multiple comorbid conditions, decreased volume of distribution, dehydration, and decreased plasma proteins, make the older cancer patient more vulnerable to drug interactions. Polypharmacy plays an important role in the increased risk of drug interactions.1,2,16 The aging process causes a decrease in the activity of the cytochrome P450 (CYP) system, increasing the risk of interactions due to induction or inhibition of CYP isoenzymes.16 Another important factor to consider is that in persons aged 65 years and older, there is a progressive decline in the glomerular filtration rate,1,16,24 which may lead to accumulation of opioid metabolites. Elderly patients are more sensitive to most medications, especially those with central

Assessment of older cancer patients with pain It is always important to perform a comprehensive assessment in all older cancer patients with pain and other related symptoms (Table 24.1). This comprehensive assessment1,3,25 includes the medical history, which also involves the location, characteristics, and intensity of the pain; any variation in the pain with a change in movement or time of the day; how the pain affects the patient’s activities of daily living (ADL); and the possible cause(s) of the pain.1 The assessment also includes a physical examination; evaluation of performance status (Karnofsky scale or Eastern Cooperative Oncology Group scale)26–29 and ADL (according to the six-item ADL scale of Katz et al.30 or the eight-item instrumental ADL scale of Lawton and Brody31 ); the physical performance test;32 and evaluation of comorbid conditions,33,34 affective status (especially the presence of depression and/or anxiety),35 cognitive status (using the Mini Mental State Examination [MMSE]),36 and geriatric syndromes such as dementia, delirium, failure to thrive, neglect or abuse, falls, and incontinence. Another extremely important component of this comprehensive assessment is the evaluation for conditions that may exacerbate or be exacerbated by pain or other distressing symptoms affecting its expression, such as emotional and spiritual distress, disability, and comorbid conditions (Fig. 24.1). Using the Edmonton Symptom Assessment System (ESAS),37–41 one can identify several other symptoms and better understand the factors related to the expression of pain. Another important tool in assessing older cancer patients with pain is the CAGE questionnaire,42,43 which screens for alcohol abuse at any period of life. This simple tool consists of four questions: Have you ever felt that you should cut down on your drinking? Have you been annoyed by people

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Table 24.1. Comprehensive assessment of older cancer patients with pain and other symptoms Dimension

Assessment

History

Stage of the cancer Recent chemotherapy and/or radiotherapy Self-rated pain scales: vertical, horizontal, and faces pain scales Characteristics, intensity, location, aggravating factors of pain and other symptoms Karnofsky Performance Scale or Eastern Cooperative Oncology Group Scale scores Assessment of ADL (bathing, dressing and undressing, eating, transferring from bed to chair and back, voluntarily control urinary and fecal discharge, using the toilet, and walking) Assessment of IADL (light housework, preparing meals, taking medications, shopping for groceries or clothes, using the telephone, and managing money) ESAS; abdominal radiograph to assess constipation vs. bowel obstruction (consider abdominal CT scan)

Performance status ADL and instrumental ADL (IADL)

Assessment of other physical symptoms related to pain (fatigue, anorexia, nausea, dyspnea, insomnia, drowsiness, constipation) Assessment of psychosocial symptoms: anxiety/depression Family/caregiver’s distress Assessment of delirium

Anxiety/depression (ESAS); identification of mood disorder during interview Assessment for family/caregiver distress during the interview MDAS MMSE CAM Assessment of spiritual distress Spiritual assessment; Spiritual history; FICA; identification of spiritual distress during interview Assessment for chemical coping CAGE questionnaire Evaluation of medications and possible interactions (polypharmacy) Physical examination Abbreviation: FICA, Faith, Importance and Influence, Community, Address or Application.

criticizing your drinking? Have you ever felt bad or guilty about your drinking? Have you ever had a drink to get rid of a hangover, that is, an eye opener? An abnormal score, defined as two or more positive answers to the four questions, has been shown to have prognostic value in opioid management in patients with cancer who experience pain. The CAGE questionnaire helps identify patients who are at high risk of developing chemical coping and subsequently at high risk of opioid dose escalation and overall increased risk of opioid-induced toxicity. Approximately 20% of cancer patients have a positive CAGE questionnaire.42,43

Older cancer patients with pain and cognitive impairment Another factor considered to be one of the greatest barriers to pain assessment and management in advanced cancer patients, especially elderly patients, is delirium. Delirium is defined as a transient and potentially reversible disorder of cognition and attention that frequently complicates care at any stage of the disease. It is important to recognize and diagnose delirium properly because it can make reliable reporting of symptoms difficult for patients, who

frequently present with disinhibition.44,45 If delirium is not recognized, family members as well as health care providers can misinterpret the agitation as a sign of pain, resulting in escalated doses of opioids that may produce toxicity and complicate the delirium. To facilitate the diagnosis of delirium, instruments with adequate psychometric properties have been created, such as the Memorial Delirium Assessment Scale (MDAS),1,2,46–48 the MMSE,36 and the Confusion Assessment Method (CAM).49 The MDAS, a validated tool used in our palliative care practice, was designed to measure the severity of delirium and therefore captures behavioral manifestations as well as cognitive deficits.47 This instrument measures relative impairment in awareness, orientation, short-term memory, digit span, attention capacity, organizational thinking, psychomotor activity, and sleep–wake cycle, as well as perceptual disturbances and delusions. Items are rated from 0 (none) to 3 (severe), depending on the level of impairment, with a maximum possible score of 30. The higher the score, the more severe the delirium. A total MDAS score of 7 out of 30 yields the highest sensitivity (98%) and specificity (96%) for diagnosis of delirium.46

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Painful Stimuli Primary or metastatic cancer Treatment-related stimuli

Pain Receptors Descending Inhibitory Pathways Endorphins

Pain Perception (Somatosensory Cortex)

Neuro-cognitive Status Delirium Dementia

Psychological Factors Depression/Anxiety Chemical Coping

PAIN EXPRESSION Cancer and Treatment-related symptoms

Spiritual Distress Spiritual Pain

Social Factors Culture Family distress

Fatigue, Anorexia, Cachexia, Nausea

Fig. 24.1. Physical, psychosocial, and spiritual factors influence the expression of pain and other distressing symptoms in older cancer patients. The descending inhibitory pathways, including endorphins, contribute to diminishing pain intensity.

It is extremely important to mention that frail elderly cancer patients with baseline cognitive impairment or with dementia may develop delirium secondary to the presence of pain, thus appropriate evaluation of the possible sources of pain, such as fractures, constipation, bowel obstruction, and/or urinary retention, must be done, and therapy should be oriented to treat the underlying cause and the other symptoms accompanying the delirium. Cognitive decline may be a barrier to proper pain assessment, although reliable pain measurements still can be obtained from persons with mild or moderate cognitive impairment.16,50 Pautex et al.51 showed that 61% of 129

severely demented patients (mean age, 83.7 years) demonstrated comprehension of at least one of the three selfassessment tools for pain evaluation (verbal, horizontal visual, and faces pain scales). It was noted that the comprehension rate for the verbal and faces pain scales was better than that for the horizontal visual scale. Furthermore, it was suggested that the observational rating scale may underestimate the severity of pain when compared with self-assessment scales. There are some pain behaviors older patients with cognitive impairment may express that can help with identification of distress in these patients; Table 24.2 summarizes these behaviors.

448 Table 24.2. Common behavioral expressions of pain in older cancer patients with cognitive impairment Facial expressions r Slight frown; sad, frightened face r Rapid blinking r Distorted expression Verbalizations, vocalizations r Grunting, chanting, groaning r Verbally abusive Body movements r Fidgeting, increased pacing, rocking r Restricted movement, gait changes Changes in activity patterns or routines r Refusing food, increase in rest periods r Changes in sleep patterns r Increased wandering, sudden cessation of common routines Changes in interpersonal interactions r Aggressive, combative, decreased social interactions r Socially inappropriate, irritable, or distressed

The main goal of performing a comprehensive assessment in older cancer patients is to provide an interdisciplinary environment that uses both pharmacologic and nonpharmacologic interventions to decrease suffering and improve quality of life for patients and to decrease the distress of family members and/or caregivers.

Pain management Oral analgesics are the most common treatment of cancer pain. The World Health Organization pain ladder, a widely used algorithm in pain management, classifies these agents as a) nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen), and b) opioids.1,4,52 It has been suggested that pain in older cancer patients can be controlled with simple treatments in more than 80% of cases. In the other 20%, a multidisciplinary approach with careful reassessment of the pain syndrome and use of adjuvant medications and/or nonpharmacologic interventions is needed to control pain.52 Pharmacologic management Nonopioid analgesics Paracetamol does not have anti-inflammatory properties, but it has antipyretic and analgesic properties and may be combined with opioids.1,4 Total dose should not exceed 4 g/day, because larger doses may damage the kidneys and liver.1,16 It is well tolerated and not habit forming, and its elimination is not affected by aging. The NSAIDs are a group of medications used for their anti-inflammatory properties and to decrease fever and pain.

m.o. delgado-guay and d. wollner They can be used in combination with opioids. They act in the periphery to decrease prostaglandin synthesis, thus reducing the activity of the N-methyl-d-aspartate (NMDA) receptor in the central nervous system.4 The NSAIDs also may be partially active at the central level via dorsal horn expression of cyclooxygenase (COX)-1 and (COX)-2.1,8,16 NSAIDs may be beneficial in treating inflammatory pain, such as bone metastases. Their activity has a ceiling effect, however, in that increments in the dose over a certain level will result in no further improvement of analgesia.4 NSAIDs may cause several side effects, such as renal toxicity, gastrointestinal bleeding and ulceration, and inhibition of platelet aggregation, which may limit their use in older cancer patients. To decrease the incidence of gastric ulceration secondary to NSAIDs, a proton pump inhibitor may be recommended, although it does not protect against renal toxicity. Opioid analgesics More than 20 different opioids are used in clinical practice. They may be classified as natural opioids (e.g., codeine, morphine), semisynthetic opioids (e.g., buprenorphine, diamorphine), or synthetic opioids (e.g., pethidine, methadone);1,7,16 they also may be categorized as weak (to treat mild to moderate pain) or strong (to treat severe pain).4 Elderly cancer patients are more likely to be affected by the acute and chronic toxicities of opioids, and thus opioids should be administered at a lower dose initially and titrated cautiously.22 Opioids mimic the action of the endogenous opioid peptides at opioid receptors. Opioid receptors are glycoproteins that exist in many organ systems, such as the lungs, cardiovascular system, gastrointestinal tract, and bladder.53 The four major receptor types are the ␮-opioid receptor, ␦-opioid receptor, ␬-opioid receptor, and nociceptin peptide factor. Most of the opioids used clinically are selective for ␮-opioid receptor, although they might interact with the other receptor subtypes if administered in high doses. Evidence from human and animal studies indicates that there are at least seven different variants of ␮ receptors,54 suggesting that incomplete tolerance simply reflects the difference in drug selectivity among those receptors.1,54 Opioid tolerance is defined as a decrease in opioid effect, manifested as a patient requiring an increasing dose of an analgesic to maintain its therapeutic effect. The NMDA receptor plays a central role in the mechanism of tolerance. Antagonism of the NMDA receptor yields better pain control, as seen with administration of methadone, a competitive antagonist of the NMDA receptor.1,2 Opioids have no maximum doses; they can be titrated until pain is

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relieved or adverse effects occur.4 Addiction to opioids is extremely rare in elderly persons.1,4,16 Tramadol and codeine, classified as weak opioids, may have limited efficacy in the management of cancer pain. Tramadol inhibits monoamine uptake. It is highly metabolized in the liver to one active metabolite, O-dimethyl tramadol, and 90% is excreted by the kidneys. The pharmacokinetic properties of the drug do not change in elderly persons.4 Most of the analgesic effect offered by codeine is through its conversion to morphine in the central nervous system, although the morphine yield is relatively small;1,4 the morphine is then converted to metabolites that may accumulate in the presence of renal failure. Codeine undergoes filtration at the glomerulus, tubular secretion, and passive reabsorption.4 Another weak opioid, dextropropoxyphene, is metabolized in the liver to norpropoxyphene and excreted by the kidneys. The metabolite may accumulate in patients with renal impairment; it has a long half-life and may cause toxicity.1,4 Strong opioids, such as morphine, oxycodone, hydromorphone, fentanyl, and methadone, may be of benefit in elderly cancer patients who are experiencing severe pain. Morphine has multiple formulations and is available in oral, rectal, sublingual, and parenteral forms. It is metabolized by glucuronidation to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and then excreted through the kidneys. M6G has a strong analgesic effect because of its ability to penetrate the blood–brain barrier and its high affinity for opioid receptors. M3G antagonizes the effects of morphine and M6G; it does not bind to all opioid receptors. Patients with renal impairment accumulate both metabolites and are more susceptible to neurotoxicity and other side effects; for these reasons, morphine should be avoided in cancer patients with renal failure.1,4,16 Meperidine (pethidine) has a short duration of action, poor oral availability, and increased risk of neurotoxicity due to accumulation of its toxic metabolite, normeperidine; this risk is especially great in patients with renal impairment.4 For all these reasons, meperidine is not recommended in elderly cancer patients. Oxycodone is a semisynthetic opioid receptor agonist. It is metabolized in the liver as noroxycodone, oxymorphone, and conjugated forms, which are eliminated in the kidneys. Like the other opioid metabolites, these substances may accumulate in the presence of renal impairment or liver disease.1,4 Methadone also is used in the treatment of cancer-related pain. It is highly bound to ␣-acid glycoproteins, with significant tissue distribution and high lipid solubility, which allow its sustained plasma levels. Fecal excretion is an important

clearance mechanism of methadone. Methadone’s pharmacokinetics vary among individuals,4 probably because of its hepatic metabolism through the CYP enzyme family. It is considered that at least four CYP proteins are involved in the methylation of methadone.2,55 Caution should be used, especially in elderly cancer patients taking multiple medications, in coadministering medications that inhibit or stimulate the CYP system, to avoid interactions and undesirable side effects.16,55 Methadone presents a rapid and extensive distribution phase (half-life, 2–3 hours) followed by a slow elimination phase; the latter phase may result in accumulation and side effects, as with other opioids.2,4 Methadone has several advantages, however, and may be used as an alternative to other opioids. It may be given orally, intravenously, or rectally, and its oral and rectal bioavailability is more than 85%.2 It may have a role in the treatment of neuropathic pain because of its action as an antagonist of the NMDA receptor.2,55–57 Most of the main metabolite, 1,5-dimethyl-2-ethyl-3,3-diphenyl-1-pyrroline, is excreted in feces, although renal excretion of the unchanged drug also is an important route of methadone elimination.58 Patients with renal impairment on maintenance methadone do not have higher plasma concentrations than those with normal renal function,59 which suggests that fecal excretion might compensate for methadone excretion in patients with renal dysfunction. For this reason and because the possibilities of using other opioids are limited, methadone can be used in patients with kidney impairment.55,59 However, because of its long half-life and propensity to accumulate, elderly patients receiving methadone should be monitored carefully. The optimal conversion method for rotating other opioids to methadone and vice versa has not been established. Following the principle of opioid rotation, the total daily dose of any newly introduced opioid is calculated from the equivalent dose of the current opioids using equianalgesic dose ratios. The dose of the new opioid should be reduced by 30%–50% to allow for incomplete cross-tolerance between opioids. The total calculated 24-hour dose of the new opioid should be divided in appropriate dosing intervals, and the dose for breakthrough pain should be one sixth or one tenth of the daily dose.1,2 Another opioid used frequently to control cancer pain is hydromorphone, an analogue of morphine that is metabolized in the liver to hydromorphone-3-glucuronide and dihydroisomorphine glucuronide and does not have a 6glucuronide.59,60 The metabolites are excreted by the kidneys. Hydromorphone-3-glucuronide is about 2.5 times as potent as M3G as a neuroexcitant. These metabolites may accumulate in patients with renal impairment,

450 causing toxic effects, including myoclonus, allodynia, and seizures.16,60,61 Fentanyl is a synthetic opioid, a potent ␮ receptor agonist. It can be delivered as an intravenous, transdermal, or oral transmucosal preparation. Transdermal fentanyl and buprenorphine are used in patients with stable pain, those with compliance problems, and those who cannot tolerate medications by mouth. Fentanyl is metabolized in the liver by CYP3A4 to compounds that are inactive and nontoxic and are excreted in the urine.16 Fentanyl may be used with caution in elderly patients with renal impairment. Patches should be used cautiously in older cancer patients because these patients have a relatively low ratio of lean body mass to fat, which alters absorption and increases chances of drug accumulation once fat and muscle stores are saturated.4 Buprenorphine is a ␮ receptor agonist with analgesic properties similar to those of morphine.4 It is metabolized in the liver to weakly active metabolites, which are excreted in the biliary system. Buprenorphine may be used in patients with renal impairment.3 Buprenorphine has the advantage of being available in transdermal, sublingual, and injectable preparations in the United Kingdom and some other countries.62 Oxymorphone, a semisynthetic -opioid receptor agonist structurally similar to hydromorphone, has an oral bioavailability of approximately 10%. Oxymorphone is extensively metabolized to oxymorphone-3-glucuronide and the active 6-hydroxyoxymorphone. Rapid clearance mandates every 4- to 6-hour dosing (immediate release [IR]) and every 12-hour dosing (extended release [ER]). Hepatic impairment, renal impairment, and aging enhance systemic exposure. Oxymorphone IR was superior to placebo and oxycodone IR (acute pain studies). Oxymorphone ER was superior to placebo and equivalent to oxycodone controlled release (CR) and morphine CR (one acute and five chronic pain studies). Oxymorphone exhibits the expected opioid side effects, being comparable with oxycodone and morphine in clinical trials.63–65 Elderly patients may experience a 40% increase in plasma concentrations, whereas renally impaired patients may have a 57%–65% increase in bioavailability. Food may increase the rate of absorption by as much as 50%, necessitating dosing either 1 hour before or 2 hours after a meal. Oxymorphone’s primary adverse effects are similar to those of other opioids: nausea, vomiting, pruritus, pyrexia, and constipation.64,65 Local anesthetics, such as transdermal lidocaine, may be considered in cases of dermatomal pain and/or neuropathic pain.16 Older cancer patients may be more susceptible to neuropathic complications of cancer treatment, especially radiation and chemotherapy.16 Neuropathic pain

m.o. delgado-guay and d. wollner is characterized by a heavier intensity and a longer duration compared with non-neuropathic chronic pain. Its frequency is estimated at around 9% of the population aged 65 years and over. Cancer, diabetes, shingles, surgery, radiculopathies, and stroke are frequent in the elderly and may lead to neuropathic pain. The management of neuropathic pain is a real challenge in elderly patients. Besides the difficulties in pain evaluation and choice of a therapeutic strategy, comorbidities associated with aging and polypharmacy require a complex drug treatment strategy. The leading role of cognition, emotion, and physical activity in autonomy preservation as well as the dynamic interaction among these domains in the old, oldest old, and most fragile persons imply that any pharmacological treatment must be integrated into a non-pharmacological approach.66,67 However, very few studies have been specifically devoted to neuropathic pain in the elderly. Epidemiological studies and controlled clinical trials are necessary to optimize pain treatment and could result in multimodal therapeutic strategies, which until now have been only evidence based or intuitively developed.66,67 Opioids also can help control neuropathic pain. Special consideration should be given to using methadone in such cases because of its action on the NMDA receptor. Treatment of neuropathic pain sometimes includes antiepileptic drugs such as gabapentin, which has a good safety profile and has been shown to be superior to amitriptyline in treating diabetic neuropathy.16 In some older patients, however, gabapentin has a prolonged half-life (⬎24 hours) and may interact with other medications.16 Opioids may cause several adverse effects. Sedation is the most common adverse effect of the opioids, although it is extremely important to search for other possible causes contributing to sedation, such as infection, central nervous system neoplastic involvement, renal or hepatic impairment, electrolyte abnormalities (e.g., severe hyponatremia or hypercalcemia), and the use of other sedatives, such as benzodiazepines, tricyclic antidepressants, and alcohol.3 Among patients receiving strong opioids for cancer pain, 7%–10% have persistent opioid-induced sedation.68 Alternative agents for the patient who has pain but cannot tolerate opioid-related sedation include adjuvant opioid-sparing drugs such as NSAIDs, bisphosphonates, and corticosteroids; use of one or more of these adjuvants should allow the opioid dose to be decreased, with better control of the pain.2 Use of a psychostimulant, such as methylphenidate, may counteract the opioid-induced sedation, but psychostimulants should be used with caution in elderly cancer patients because they may cause adverse effects such as delirium or psychosis.1,2

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Constipation is a common and expected adverse effect of long-term opioid use; it is associated with nausea in approximately 25% of cases. Electrolyte imbalance, autonomic failure, decreased oral intake, immobility, history of abdominal surgery, malignant peritoneal involvement, and other medications (e.g., tricyclic antidepressants) contribute to the development of constipation.2 In advanced cancer patients in whom the diagnosis of constipation is unclear, an abdominal radiograph may be required.68 Management includes prevention and aggressive treatment of the constipation, addressing factors contributing to the constipation, and including laxatives, rectal suppositories, enemas, and manual disimpaction. A prokinetic agent such as metoclopramide should be considered to improve and control the related nausea and vomiting. Another approach in refractory constipation is changing to another opioid, specifically methadone, which appears to cause less constipation than other opioids.2 Recent research has shown that the use of subcutaneous methylnaltrexone, a peripherally acting quaternary opioid antagonist, can relieve opioid-induced constipation at doses of more of 5 mg in patients with advanced illness, without reducing analgesia or causing opioid withdrawal symptoms.69,70 Respiratory depression is the most feared opioid-related side effect, yet research on the topic is inconclusive. Estfan et al.71 showed that the use of titrated parenteral opioids for relief of cancer pain was not associated with respiratory depression, as evinced by nonsignificant changes in endtidal CO2 or oxygen saturation in non–oxygen-dependent cancer patients. Clemens and Klaschik,72 in a nonrandomized trial in 11 dyspneic palliative care patients (10 with advanced cancer and one with amyotrophic lateral sclerosis), showed that opioids significantly improved the intensity of dyspnea, without significant increase in Pco2 (measured transcutaneously) or decrease in oxygen saturation.

nonpharmacologic means of pain management include psychological interventions, rehabilitation medicine interventions, neurosurgical techniques, palliative radiotherapy, and anesthesiologic procedures; each intervention must be considered individually, with the main goal of improving the patient’s quality of life.

Nonpharmacologic management Older cancer patients with pain and other symptoms should be treated in an interdisciplinary environment, combining pharmacologic and nonpharmacologic measures that include topical agents, heat and cold packs, informal cognitive strategies, massage, and some home remedies. Having an interdisciplinary team on board allows practitioners to better understand and respond to patients’ and family members’ experience of the illness, with the mutual goal of relieving patients’ and family members’ suffering. The members of the interdisciplinary team provide different management skills and varied perspectives to improve patients’ quality of life and decrease suffering.2,73 Other

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19. Wroblewski M, Mikulowski P. Peritonitis in geriatric inpatients. Age Ageing 20:90–102, 1992. 20. Landi F, Onder G, Cesari M, et al. Pain occurs daily, remains untreated among elderly patients in community settings. Arch Intern Med 161:2721–4, 2001. 21. Curless R, French JM, Williams GV, et al. Colorectal cancer: do elderly patients present differently? Age Ageing 23:102–8, 1994. 22. Vigan´o A, Bruera E, Suarez-Almazor ME. Age, pain intensity, and opioid dose in patients with advanced cancer. Cancer 83:1244–50, 1998. 23. Fuse PG. Opioid analgesic drugs in older people. Clin Geriatr Med 17:479–85, 2001. 24. Repetto L, Balducci L. A case for geriatric oncology. Lancet Oncol 3:289–97, 2003. 25. Hurria A, Lachs M, Cohen H, et al. Geriatric assessment for oncologists: rationale and future directions. Crit Rev Oncol Hematol 59:211–17, 2006. 26. Coates A, Gebski V, Signorini D, et al. Prognostic values of quality of life scores during chemotherapy for advanced breast cancer. J Clin Oncol 10:1833–8, 1992. 27. Miller F. Predicting survival in the advanced cancer patient. Henry Ford Hosp Med 391:81–4, 1991. 28. Schag C, Heinrich R, Ganz P. Karnofsky performance status revisited: reliability validity and guidelines. J Clin Oncol 2:187– 93, 1984. 29. Yates J, Chalmer B, McKegney F. Evaluation of patients with advanced cancer using the Karnofsky performance status. Cancer 45:2220–4, 1980. 30. Katz S, Ford AB, Moskowitz RW, et al. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychological function. JAMA 185:914–19, 1963. 31. Lawton MP, Brody EM. Assessment of older people: selfmaintaining and instrumental activities of daily living. Gerontologist 9:179–86, 1969. 32. Reuben DB, Siu A. An objective measure of physical function of elderly out-patients. The physical performance test. J Am Geriatr Soc 38:1105–12, 1990. 33. Charlson M, Pompei P, Ales K, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 40:373–83, 1987. 34. Miller M, Paradis C, Houck P, et al. Rating chronic medical illness burden in gero-psychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 41:237–48, 1992. 35. Hickie C, Snowdon J. Depression scales for the elderly: GDS. Clin Gerontol 6:51–3, 1987. 36. Folstein M, Folstein S, McMugh P. Mini mental state: a practical method for grading the cognitive state of patients for the clinician. J Psych Res 12:219–26, 1975. 37. Chang V, Hwang S, Feuerman M. Validation of the Edmonton Symptom Assessment Scale. Cancer 88:2164–71, 2000. 38. Chochinov H, Tataryn D, Clinch J, Dudgeon D. Will to live in the terminally ill. Lancet 354:816–19, 1999. 39. Philip J, Smith W, Craft P, Lickiss N. Concurrent validity of the modified Edmonton Symptom Assessment System with the

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58. Murtagh F, Chai MO, Donohoe P, et al. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother 21:5–16, 2007. 59. Kreek MJ, Schecter AJ, Gutjahr CL, Hecht M. Methadone use in patients with chronic renal disease. Drug Alcohol Depend 5:197–205, 1980. 60. Murray A, Hagen N. Hydromorphone. J Pain Symptom Manage 29:S57–66, 2005. 61. Zheng M, McErlane KM, Ong MC. Hydromorphone metabolites: isolation and identification from pooled urine samples of cancer patient. Xenobiotica 32:427–39, 2002. 62. Boger RH. Renal impairment: a challenge for opioid treatment? The role of buprenorphine. Palliat Med 20:s17–23, 2006. 63. Guay DR. Use of oral oxymorphone in the elderly. Consult Pharm 22:417–430, 2007. 64. Chamberlin KW, Cottle M, Neville R, Tan J. Oral oxymorphone for pain management. Ann Pharmacother 41:1144–52, 2007. 65. De Leon-Casasola OA. Current developments in opioid therapy for management of cancer pain. Clin J Pain 24(Suppl 10):S3–7, 2008. 66. Pickering G, Capriz-Ribi`ere F. Neuropathic pain in the elderly. Psychol Neuropsychiatr Vieil 6:107–14, 2008.

67. McGeeney BE. Adjuvant agents in cancer pain. Clin J Pain 24:S14–20, 2008. 68. Donnelly S, Davis MP, Walsh D, et al. Morphine in cancer pain management: a practical guide. Support Care Cancer 10:13–35, 2002. 69. Portenoy RK, Thomas J, Moehl Boatwright ML, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom Manage 35:458–68, 2008. 70. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 358:2332–43, 2008. 71. Estfan B, Mahmoud F, Shaheen P, et al. Respiratory function during parenteral opioid titration for cancer pain. Palliat Med 21:81–6, 2007. 72. Clemens K, Klaschik E. Symptomatic therapy of dyspnea with strong opioids and its effect on ventilation in palliative care patients. J Pain Symptom Manage 33:473–81, 2007. 73. Sinclair S, Raffin S, Pereira J, Guebert N. Collective soul: the spirituality of an interdisciplinary palliative care team. Palliat Support Care 4:13–24, 2006.

SECTION IX

DIFFICULT PAIN PROBLEMS

25

Cancer pain and depression william s. breitbart, a wendy g. lichtenthal, a hayley pessin, a and gloria c. lee b a b

Memorial Sloan-Kettering Cancer Center and The State University of New York Downstate College of Medicine

Introduction Effective management of pain in patients with advanced cancer may benefit from a multidisciplinary approach, enlisting expertise from a wide variety of clinical specialties, including neurology, neurosurgery, anesthesiology, and rehabilitation medicine.1–3 The use of psychiatric interventions in the treatment of cancer patients with pain also has become an integral part of such a comprehensive approach.1–5 This chapter reviews the assessment and management of one of the most common psychiatric disorders, depression, which has been shown to interact with and exacerbate pain among cancer patients.

Multidimensional concept of pain in cancer Pain, especially in advanced cancer, is not a purely nociceptive or physical experience, but rather, it involves complex aspects of human functioning, including personality, affect, cognition, behavior, and social relations.6 Dame Cecily Saunders7 coined the term total pain to capture the all-encompassing nature of the suffering and discomfort that individuals with a terminal illness often experience. Given the conceptualization of pain as a multidimensional construct, it perhaps is not surprising that the use of analgesic drugs alone does not always lead to complete pain relief.8 As the interactions of cognitive, emotional, socioenvironmental, and nociceptive aspects of pain are difficult to separate, effective pain treatment often involves a multimodal intervention.3 Disentangling and addressing both the physical and the psychological issues underlying each patient’s pain are essential to developing rational and successful management strategies. Applying psychosocial and somatic therapies in conjunction can lead to reciprocal effects. Treatments targeting psychological variables

can have a profound impact on nociception, and therapies directed at nociception can improve psychological aspects of pain. Ideally, a multidisciplinary approach to cancer pain management includes the simultaneous use of psychosocial and somatic interventions.4

Psychological factors in pain experience Cancer patients may face many stressors during the course of illness, including dependency, disability, and fear of a painful death. Although these stressors are common, not all patients confronted with these issues develop depression. There are several psychosocial factors that may contribute to an individual patient’s vulnerability, including medical factors, social support, coping capacities, and personality style. Pain similarly can have profound effects on the risk and severity of depression, and in turn, psychological factors such as anxiety, depression, and the meaning of pain can intensify cancer patients’ pain experience. A substantial amount of research demonstrating how psychological factors and pain reciprocally influence one another has been conducted. Daut and Cleeland9 found that cancer patients who attribute a new pain to a benign cause unrelated to their illness reported less interference with their activities and pleasure than cancer patients who believed their pain represented progression of disease. Spiegel and Bloom10 found that severity of pain among women with metastatic breast cancer was predicted in part by the belief that their pain represented spread of their cancer and by total mood disturbance; these two variables were better predictors of pain intensity than was the site of metastasis. Syrjala and Chapko11 also demonstrated that psychological factors play a modest but important role in the perception of pain intensity.

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Pain may result in profound disability and distress. Increased pain intensity has been associated with patients’ perception of marked impairment in activities of daily living,12 and interference appears to be more significant at moderate levels than at levels on either the low or high ends of the severity continuum.13,14 In studies of empirically defined symptom clusters (three or more concurrent and related symptoms), the presence of high levels of both depression and pain (in addition to fatigue and insomnia) has been associated with decreased quality of life.15 Quality of life may be affected by pain in numerous ways. Padilla et al.16 identified three pain-related quality-of-life domains (physical, interpersonal, and psychological) through interviews with cancer patients experiencing chronic pain. The authors found that patients’ psychological well-being was affected by affective factors, cognitive factors, spiritual factors, communication, coping, and the meaning of their pain or cancer.16 Studies have suggested that the interference of pain on various aspects of functioning has more of a negative impact on mood than does the severity of pain.13,14,17 Measures of emotional disturbance have been reported to be predictors of pain in late stages of cancer, and cancer patients with less anxiety and depression are less likely to report pain.18,19 Patients who report negative thoughts about their personal or social competence have reported increased pain intensity and emotional distress.12 In a prospective study of cancer patients, it was found that maladaptive coping strategies, lower levels of self-efficacy, and distress specific to the treatment or disease progression were modest but significant predictors of reports of pain intensity.11 Psychological variables, such as the amount of control people believe they have over pain, emotional associations and memories of pain, fear of death, depression, anxiety, and hopelessness, contribute to the experience of pain in people with cancer and may increase suffering. All too frequently, psychological variables are proposed to explain continued pain or lack of response to therapy when in fact medical factors have not been adequately addressed. However, the psychiatrist is often the last physician to consult for a cancer patient with pain. In that role, one must be vigilant that an accurate pain diagnosis is made and be able to assess the adequacy of the medical analgesic management provided. Depression among terminally ill patients with pain must initially be assumed to be the consequence of uncontrolled pain. Personality factors may be quite distorted by the presence of pain, and relief of pain often results in the disappearance of a perceived psychiatric disorder.20,21

Prevalence of depression in cancer patients with pain Cancer patients experiencing pain appear to be at increased risk of developing psychiatric disorders.22 Epidemiological studies of the prevalence of depression among cancer patients have yielded mixed results, varying with the diagnostic system and assessment methods used, as well as with factors such as disease site and stage.23–27 In their 1983 report on the prevalence of psychiatric disorders among cancer patients, the Psychosocial Collaborative Oncology Group28 found that 39% of the patients who received a psychiatric diagnosis reported significant pain, whereas only 19% of patients without a psychiatric diagnosis had significant pain. The most common psychiatric disorders among cancer patients with pain include adjustment disorder with depressed or anxious mood (69%) and major depression (15%).29,30 Bukberg, Penman, and Holland31 reported that 25% of all cancer patients experience severe depressive symptoms. More recent studies have suggested that approximately 20%–40% of oncology patients experience clinically significant depressive symptoms during their illness.27,32 Grassi, Malacarne, Maestri, and Ramelli32 found that 31% of patients met criteria for depression within the first year of cancer diagnosis. In advanced cancer populations, prevalence rate estimates have ranged from 5% to 27%,33,34 with a median of 15%.25 The prevalence of depression among cancer inpatients varies widely, with reported rates ranging from 23% to 60%.35 In general, the highest rates of depression have been found in patients with pancreatic, oropharynx, and breast cancers.35 It is important to note that a substantial number of patients experience more mild depressive symptoms that are not captured by many epidemiological studies, which often assess patients using formal diagnostic criteria for major depression and do not report findings on subclinical cases.24,36

Prevalence of depression and pain in advanced cancer Cancer patients with advanced disease are a particularly vulnerable group. Not only does the incidence of pain increase with greater debilitation and advanced stages of illness, but also the incidence of delirium.31 The prevalence of organic mental disorders such as delirium requiring psychiatric consultation has been found to range from 25% to 40% in cancer patients, and to be as high as 85% during the terminal stages of illness.37 In addition, opioid analgesics, such as morphine sulfate, can cause confusional states, particularly in the elderly and terminally ill,38 which

cancer pain and depression can in turn hinder adequate pain management. In a study of anxiety and depressive disorders in a palliative care setting, Wilson et al.36 found that major depression was the most common diagnosis, and patients carrying a psychiatric diagnosis were significantly more likely to report pain. Patients with advanced disease also are more likely to experience painful symptoms of their illness. For example, epidural spinal cord compression (ESCC), a neurological complication of systemic cancer, occurs in 5%–10% of patients and often presents with severe pain. Treatment of ESCC may result in the onset of depression, as it is routinely treated with a combination of radiotherapy and high-dose dexamethasone. Stiefel, Breitbart, and Holland39 found that 22% of cancer patients being treated for ESCC had a major depressive syndrome diagnosed, as compared with 4% in the comparison group. Also, delirium was much more common in the dexamethasone-treated patients with ESCC, with 24% diagnosed with delirium during the course of treatment, as compared with only 10% in the comparison group. Peng et al.40 found that pain was present in 87% of an advanced-stage cancer patient sample and, similar to earlier studies,1,9,29 that it increased as patients approached death. In contrast, in their systematic review of research on symptom prevalence, Teunissen et al.41 found lower rates of pain among cancer patients who were closer to death. Although 74% of all pooled study participants reported pain, only 45% of patients in the last 1–2 weeks of life endorsed this symptom.41

Other clinical correlates of depression and pain A growing body of evidence has identified psychosocial variables that are distinct but associated with depression and pain among cancer patients. Mystakidou et al.14 found that increased hopelessness and depression as well as decreased cognitive functioning were correlated with the degree to which pain interfered with advanced-cancer patients’ mood. Researchers also have found a link between patients’ desire for hastened death and both depression and pain.42,43 Desire for hastened death has been associated with elevated levels of depression and pain among advanced-cancer patients who are not imminently dying,42 and among terminally ill patients, it appears to be more strongly associated with depression than with pain.43 Associations between different types of sleep disturbances and depression (i.e., sleeping more hours and early awakening) as well as pain (i.e., difficulty falling asleep, difficulty staying asleep, early awakening, more nights with sleep problems, and more hours per night awake) have been found among cancer patients under palliative care.44 In fact, many factors associated with

459 advanced disease can exacerbate levels of depression and pain as well as the intensity of their interaction with one another.

Assessment of depression in cancer pain Diagnosing depression among cancer patients is often challenging because of the overlap between the somatic symptoms resulting from their physical disease and the depressive syndrome. It is important to appreciate that at different points along their disease trajectory, patients with a lifethreatening illness are likely to suffer from one or more of the symptoms that, if combined, would render a diagnosis of a major depressive disorder (e.g., sad mood, eating and sleep disturbances, decreased libido). To address this challenge, clinicians have applied different diagnostic classification systems in oncology settings. The use of different diagnostic criteria has resulted in varying estimates of the prevalence of depression. Kathol and colleagues45 found that rates of major depression differed as much as 13% when using criteria of the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III; 38%) and the DSM-III, revised (DSM-III-R; 29%), and Research Diagnostic Criteria (RDC; 25%).

Differentiating major depression from mood disorders due to cancer and uncontrolled pain There are two core criterion symptoms for major depression in the DSM, fourth edition, text revision (DSM-IV-TR): depressed mood and anhedonia (Table 25.1). To qualify for the diagnosis, one of these core symptoms must be present, along with at least four other symptoms from the criterion list. In evaluating the presence of anhedonia in advancedcancer patients, it is important to consider that all patients will ultimately experience a functional decline that restricts their physical ability to participate in activities. Disengagement from areas of interest would be common among these individuals, who may then refocus their priorities into areas of deeper significance. When anhedonia is pervasive, however, and extends to a loss of interest or pleasure in almost all activities, including the social comforts of interaction with family and friends, then this symptom criterion may be considered present in the assessment of depression.46,47 The question of causality in the diagnosis of depression in cancer patients is almost inevitable. How is a medical condition determined to cause depression? A causal relation is postulated if the clinician demonstrates the presence of a medical condition known to cause depression, and if symptoms improve as the medical condition is treated.

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Table 25.1. DSM-IV-TR criteria for major depressive episode A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either i. Depressed mood or ii. Loss of interest or pleasure Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood. 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) 3. Significant weight loss when not dieting or weight gain (e.g., a change of ⬎5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains. 4. Insomnia or hypersomnia nearly every day 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6. Fatigue or loss of energy nearly every day 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms do not meet criteria for a mixed episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). E. The symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.

When a depressive syndrome is clearly caused by the direct physiological effect of a medication or other psychoactive substance, or by metabolic or neurochemical disturbances created by the disease process, the diagnosis of mood disorder resulting from the general medical condition would be more appropriately applied. However, these diagnoses are very general and require only that dysphoric mood or decreased interest or pleasure is present.

The concept of secondary depression, which several authors48–50 have credited Munroe51 with developing, addresses this issue. The RDC defined secondary depression as “a depression occurring in a person who has a preexisting nonaffective psychiatric disorder or a life-threatening medical illness that precedes and parallels the symptoms of depression.”52 The RDC, outlined by Spitzer et al.,53 contained criteria independent of etiology and based on a temporal distinction between primary and secondary depression. It also included minor depression as a diagnostic category, defining it as “nonpsychotic episodes of illness in which the most prominent disturbance is a relatively sustained mood of depression without the full depressive syndrome, although some associated features must be present.”53 Patients with depression resulting from medical illness tend to have an older age of onset than depressed patients in general.54 They are more likely to respond to electroconvulsive therapy (ECT), to be improved at discharge, to show “organic” features in the mental status examination, and to have a much lower incidence of family history of alcoholism and depression (19% of medically ill vs. 36% of psychiatrically ill), and are less likely to have suicidal thoughts and to commit suicide (10% death by suicide in medically ill sample vs. 45% in psychiatrically ill group).54

Methods for the assessment of depression Table 25.1 lists the DSM-IV-TR criteria for a diagnosis of major depressive episode, and at least one major depressive episode is required for a diagnosis of major depressive disorder.55 Five different approaches to the diagnosis of major depression in cancer patients have been described:56,57 1) an inclusive approach, which includes all symptoms whether or not they may be secondary to illness or treatment; 2) an exclusive approach, which deletes and disregards all physical symptoms from consideration, not allowing them to contribute to a diagnosis of major depressive syndrome; 3) an etiologic approach, whereby the clinician attempts to determine if the physical symptom is the result of cancer illness or treatment (and so does not include it) or of a depressive disorder (in which case it is included as a criterion symptom); 4) a high diagnostic threshold approach, which requires that patients have seven DSM-IV-TR criteria symptoms for major depression; and 5) a substitutive approach, in which physical symptoms of an uncertain etiology are replaced by other nonsomatic symptoms. The latter approach is best exemplified by the Endicott Substitution Criteria58 (Table 25.2), which include replacing 1) change in appetite or weight with tearfulness or depressed

cancer pain and depression Table 25.2. Endicott substitution criteria Physical/somatic symptom

Psychological symptom substitute

Change in appetite/weight

Tearfulness Depressed appearance Social withdrawal Decreased talkativeness Brooding, self-pity Pessimism Lack of reactivity

Sleep disturbance Fatigue Loss of energy Diminished ability to think or concentrate Indecisiveness

appearance; 2) sleep disturbance with social withdrawal or decreased talkativeness; 3) fatigue or loss of energy with brooding, self-pity, or pessimism; and 4) diminished ability to think or concentrate or indecisiveness with lack of reactivity. Chochinov and colleagues24 studied the prevalence of depression in a terminally ill cancer population and compared low versus high diagnostic thresholds, as well as Endicott Substitution Criteria. Interestingly, identical prevalence rates of 9.2% for major depression and 3.8% for minor depression (total = 13%) were found using RDC high-threshold criteria and high-threshold Endicott criteria. In another study, Chochinov and colleagues59 reported that a single-item screening measure (i.e., asking, in effect, “Are you depressed?”) was as accurate a diagnostic strategy as the use of a structured clinical interview for depression. Table 25.3 lists a number of available assessment methods for depression, including diagnostic classification systems, structured diagnostic interviews, and screening instruments. Unfortunately, few studies of depression in terminally ill or advanced cancer patients have used such research assessment methods to date. Additionally, further work is necessary in adapting to the limitations of such methods in their application to populations with advanced Table 25.3. Research assessment methods for depression in cancer patients Diagnostic classification systems Diagnostic and Statistical Manual (DSM-IV-TR) Endicott Substitution Criteria Research Diagnostic Criteria (RDC) Structured diagnostic interviews Schedule for Affective Disorders and Schizophrenia (SADS) Diagnostic Interview Schedule (DIS) Structured Clinical Interview for DSM-IV (SCID) Screening instruments (self-report) General Health Questionnaire-30 (GHQ) Hospital Anxiety and Depression Scale (HADS) Beck Depression Inventory–Short Form (BDI-SF) Rotterdam Symptom Checklist (RSCL) Carroll Depression Rating Scale (CDRS)

461 cancer.34 Several options have been proposed for handling the issue of confounding somatic symptoms.56 The DSMIV-TR recommends that symptoms should be excluded from consideration if they are caused directly by a medical condition. In practice, however, this discrimination may be a difficult one to make. Technically, it also makes the standard for fulfilling diagnostic criteria more stringent.59 For example, when all symptoms are included, a diagnosis of major depression requires that five of nine criterion symptoms be present. If four symptoms are then excluded because of possible confounding with medical illness, then a patient must have all five of the remaining symptoms before the diagnostic criteria for major depression are met. This is a very strict standard that would identify only the most severely depressed patients. Cassem48 pointed out that the risks of failing to treat depression because of false-negative diagnoses are more harmful, on balance, than the risks of initiating unnecessary therapy based on a false-positive diagnosis. Hence, he suggested that it would be better for clinicians to err on the side of caution, and include somatic symptoms in their diagnostic assessments of the medically ill. When this approach is used, however, there is the possibility that the prevalence rates of depressive disorders among medical patients will be exaggerated.48

Criterion-based diagnostic systems Assessment procedures for depression include criterionbased diagnostic systems, diagnostic interviews, and self-report measures. Criterion-based diagnostic systems include approaches such as DSM-IV-TR or its predecessors (DSM-IV; DSM-III; DSM-III-R), and the RDC.53 These systems are based on the assumption that depression is a distinct syndromal disorder characterized by a constellation of symptoms that have a certain minimal level of severity and duration. These symptoms are associated with impairment in functional and social roles.

Diagnostic interviews For research purposes, diagnostic assessments are usually conducted using structured interviews such as the Diagnostic Interview Schedule (DIS),60 the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I),61,62 or the Schedule for Affective Disorders and Schizophrenia (SADS).63 These interviews differ in the extent to which they are structured and in their coding formats. The DIS is highly structured and can be used by lay interviewers in epidemiological studies. The SCID-I and SADS are

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semistructured and are intended for use by clinicians. With the DIS and the SCID-I, the interviewer is required to code specific symptoms as being either present or absent, whereas with the SADS, the interviewer rates the severity of symptoms on ordinal scales. All these interview protocols have been subjected to extensive checks of their reliability and validity.60–63 If administered in their entirety, these interviews cover a broad range of common mental disorders. However, they may be very time consuming, which is a serious limitation when they are used in palliative care settings. More commonly, investigators administer only the modules within an interview that address the problem of depression in advanced-cancer populations. For example, Chochinov and colleagues24 administered the depression module of the SADS to patients with advanced cancer in an inpatient palliative care unit. They found good levels of interrater reliability for the RDC diagnosis of major or minor depression (kappa = 0.76). Spitzer and colleagues64 developed a brief screening protocol for use by primary care clinicians that would seem to have good applicability to palliative care. The Primary Care Evaluation of Mental Disorders (PRIME-MD) uses a twostage approach to review the DSM-IV criteria for major depression, minor depression, and dysthymia. In addition, it addresses the common anxiety syndromes of panic disorder and generalized anxiety disorder, and provides a brief screen for alcohol abuse. In the first stage, the patient completes a one-page self-report checklist that covers only the most central symptoms of each disorder, using a simple yes/no response format. Using a structured interview guide, the clinician follows up on the symptoms acknowledged on the checklist (ensuring that they meet DSM-IV severity and duration criteria) and probes the remaining symptoms required to make a diagnosis. Spitzer et al.64 found that the PRIME-MD showed good concordance with independent diagnoses made by mental health professionals and that it could be completed within 20 minutes for 95% of patients. Thus, its brevity and comprehensiveness suggest that the PRIME-MD would be a suitable choice for both research and clinical use in cancer, although the self-report component would have to be replaced with an interview administration for the most severely ill patients. Investigators have constructed their own semistructured interviews for use with cancer patients, modifying the diagnostic criteria to account for the unique circumstances of this group of patients.31,65 This approach has some disadvantages, however. The purpose of structured interviews is to enhance the reliability of clinical diagnostic assessments.

When well-tested and psychometrically sound protocols are already widely available, new interviews must be tested rigorously for their reliability to support claims for improvement over existing measures. This seldom has been done in cancer care research. Hence, an expert panel on the neuropsychiatric aspects of advanced cancer has recommended the use of existing validated tools in prevalence and intervention research.66

Self-report measures A considerable body of research has examined the extent to which self-report measures can assist clinicians in diagnosing depression. A review of studies of depression among advanced cancer patients found that the most commonly used assessment tool was the 14-item Hospital Anxiety and Depression Scale (HADS).25,67 Other measures that have been used in this context are the 11-item short form of the Beck Depression Inventory;68 the 60-item General Health Questionnaire;69 the eight-item psychological symptoms subscale of the Rotterdam Symptom Checklist;70 and the 11-item short form of the Carroll Depression Rating Scale (CDRS).71,72 Golden and colleagues71 validated CDRS for use in cancer patients. Although many other self-report measures of depressive symptoms are available in the literature, the advantages of these particular scales are that they have been developed or adapted for use in medical populations and have been tested in various groups of patients with cancer. Hence, information is available regarding the optimal cutoff scores for maximizing their concordance with structured interview diagnoses made by mental health professionals. Several studies with cancer patients have examined selfreport measures to determine their respective sensitivity (proportion of clinically diagnosed patients who score above the optimal cutoff on the questionnaire) and specificity (proportion of nondepressed patients who score below the cutoff).59,73–77 There are two main findings from these studies. First, even those that used the same screening questionnaire (i.e., the HADS) identified different optimal cutoff scores. The discrepancies appear to be related to the characteristics of the patients, the type and stage of disease, and, more importantly, the range of depressive syndromes that are included in the criterion-standard diagnosis. For example, studies that included adjustment disorders identified much lower cutoff scores than those that screened only for the more severe major depressive episodes. Second, none of the available questionnaires provides perfect concordance with structured interviews. Although

cancer pain and depression some studies have reported marginally higher sensitivities associated with certain questionnaires, the tradeoff is a lower degree of specificity.24,73–79 Empirical studies have suggested that the questionnaires are roughly comparable in their performance in screening depressed patients. Therefore, considerations such as a scale’s brevity, simplicity, and specific item content should factor into decisions about which ones to select for screening purposes. Whether or not these error rates are acceptable depends on the purpose for which the screening is being done. For clinical purposes, a high false-positive rate is not necessarily a problem if screen-positive patients receive a follow-up interview to confirm the diagnosis. A high false-negative rate, on the other hand, presents a greater difficulty because a significant number of depressed patients will not be identified. There are many reasons to explain the lack of concordance between questionnaire assessments of depression and criterion-based diagnostic systems.80 With questionnaires, for example, different patients can achieve similar summary scores from strongly endorsing only a few items, or from weakly endorsing many items. The content of the specific items in a questionnaire also is important. With some, it could be possible for a patient to score above the scale cutoff without endorsing any individual symptoms that would actually contribute to the diagnosis of depression in a criterion-based system. Finally, most depression rating scales are correlated highly with measures of anxiety as well as depression. Because of the poor divergent validity of the most common self-report measures of depression, some investigators caution that they should really be used as indices of general distress.80 In patients with advanced cancer, questionnaires also may pose a burden for patients whose medical circumstances make it difficult for them to read. For this reason, visual analogue scales, such as the Edmonton Symptom Assessment System (ESAS), have come into common use in cancer patient settings.81 The ESAS utilizes individual visual analogue scales to assess the severity of each of nine symptoms, including depression and pain. The other symptoms evaluated by the ESAS are fatigue, nausea, anxiety, drowsiness, appetite, well-being, and shortness of breath, and higher scores indicate greater severity.81 Chochinov and colleagues24,82 described the screening characteristics of a 100-mm visual analogue scale of depressed mood (anchored at the end points with the descriptors 0 = “worst possible mood” and 1 = “best possible mood”) while using the Memorial Pain Assessment Card.24,82 The patients comprised a mixed group of inpatients with advanced cancer,

463 and the criterion-standard diagnoses were major and minor depressive episodes defined according to structured interviews. The investigators found that the optimal cutoff score (55 mm) provided less accurate screening than the Beck Depression Inventory–Short Form. Thus, visual analogue scales seem to provide a rather crude substitute for a careful diagnostic interview.24 Chochinov et al.24 additionally examined a brief interview-based screening for depression, which consisted simply of two questions addressing the core criterion symptoms of depressed mood and loss of interest or pleasure in activities. They found that this method was actually quite accurate in identifying patients who qualified for a diagnosis based on the administration of a full interview that covered all the criterion symptoms of depression. Hence, they recommended that this type of brief screening be incorporated more routinely into clinical contacts. In summary, the limitations of assessments with the self-report measures of depression should be recognized. Self-report and visual analogue scales can provide gross assessments when direct interviews are not feasible. They are useful in providing additional information for difficult cases, quantifying the severity of a depressive syndrome, and monitoring change over time. However, diagnostic interviews remain extremely valuable for direct psychiatric assessments of patients with cancer.

Other depressive disorders In addition to major depression, there are other diagnoses that have depressed mood as a central presenting feature. Minor depression as described in the RDC is similar to major depression, but requires fewer symptoms to qualify for a diagnosis (two to four symptoms in total). Like major depression, minor depression is considered an episodic disorder. Dysthymia, in contrast, is defined as a chronic condition characterized by low-grade depressive symptoms that persist for at least 2 years. The diagnosis of adjustment disorder with depressed mood describes a relatively shortlived maladaptive reaction to stress. To meet criteria for this diagnosis, a patient’s depressive response to the stressor must be “in excess of a normal and expectable reaction.” Because evaluation involves subjective judgment as to what is a “normal and expectable response” to catastrophic medical circumstances, adjustment disorder is a controversial diagnosis in cancer care.83 If applied loosely, clinicians risk overpathologizing the experience of some patients and placing a potentially stigmatizing psychiatric label on what may be a normal response to adverse circumstances.

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Cancer pain and suicide Uncontrolled pain is a major factor in suicide and suicidal ideation in cancer patients.84 The public perceives cancer as an extremely painful disease when compared with other medical conditions. In Wisconsin, a study revealed that 69% of the public agreed that cancer pain could cause a person to consider suicide.85 The majority of suicides observed among patients with cancer had severe pain, which was often inadequately controlled or tolerated poorly.86 Although relatively few cancer patients commit suicide, they are at increased risk.85,87 Patients with advanced cancer are at highest risk and are the most likely to have the complications of pain, depression, delirium, and deficit symptoms. Psychiatric disorders are frequently present in hospitalized cancer patients who attempt suicide. A review of the psychiatric consultation data at Memorial Sloan-Kettering Cancer Center showed that of cancer patients evaluated for suicide risk, approximately 33% received a diagnosis of major depression, 20% met criteria for delirium, and more than 50% were diagnosed with an adjustment disorder.84 Fleeting thoughts of suicide appear to be common, particularly in the setting of advanced cancer,88,89 and seem to act as a steam valve for feelings often expressed by patients who may think, “If it gets too bad, I always have a way out.” In a study of 200 terminally ill patients, Chochinov et al.43 found that 44.5% endorsed having a fleeting desire for hastened death, and 8.5% reported experiencing a more persistent wish for hastened death. Examination of psychiatric consultations conducted at Memorial SloanKettering Cancer Center demonstrated that 8.6% were suicide risk evaluations, which were usually requested by staff in response to patients verbalizing suicidal wishes.84 In the 71 cancer patients who had suicidal ideation with serious intent, significant pain was a factor in only 30% of cases. In striking contrast, virtually all 71 suicidal cancer patients had a psychiatric disorder (mood disturbance or organic mental disorder) at the time of evaluation.84 Pain has adverse effects on patients’ quality of life and sense of control and impairs the family’s ability to provide support and therefore has the potential to contribute to patients’ vulnerability to suicide. Cancer patients exhibiting pain in addition to other suicide risk factors, such as mood disturbance, delirium, loss of control, and hopelessness, should be carefully assessed for suicidality. It has been our experience working with terminally ill pain patients that once a trusting and safe relationship develops, patients almost universally reveal that they occasionally have had thoughts of suicide as a means of escaping the threat of being overwhelmed by pain.

Inadequate pain management: assessment issues in the treatment of pain Studies suggest that cancer pain is still being undertreated.81,90 Although it is acknowledged that opioid analgesics are not sufficiently utilized, it is also clear from our work and the work of others that adjuvant agents, such as the antidepressants, are also dramatically underused. Inadequate management of pain is often the result of the inability to properly assess pain in all its dimensions.1,4,91 All too frequently, psychological variables are proposed to explain continued pain or lack of response to therapy, when in fact medical factors have not been adequately appreciated. Other causes of inadequate pain management include lack of knowledge of current pharmacotherapeutic or psychotherapeutic approaches, focus on prolonging life rather than alleviating suffering, lack of communication between doctor and patient, limited expectations of patients to achieve pain relief, limited capacity of patients impaired by organic mental disorders to communicate, poor opioid availability, doctors’ fear of causing respiratory depression, and, most important, doctors’ fear of amplifying addiction and substance abuse. Specifically, in advanced cancer, several factors have been noted to predict the inadequate management of pain, including a discrepancy between physician and patient in judging the severity of pain, the presence of pain that physicians did not attribute to cancer, better performance status, age ≥70 years, and female sex.92 Fear of addiction affects patient adherence to and physician management of pharmacotherapy, and may result in the undermedication of pain among cancer patients.3,91,93 Addiction is a behavioral pattern of compulsive drug abuse characterized by craving for the drug and overwhelming involvement in obtaining and using it for effects other than pain relief. Studies of the patterns of chronic opioid analgesic use have demonstrated that, although tolerance and physical dependence commonly occur, addiction among cancer patients is rare and almost never occurs in an individual without a history of drug abuse before cancer illness.94 Rather, escalation of opioid analgesic use by cancer patients is usually a means of managing symptoms related to the progression of disease. The management of pain in the cancer patient with an active addiction is challenging, particularly if the addiction includes opioids or is accompanied by a comorbid psychiatric disorder. Specialized substance abuse consultation services may be helpful in the team approach to these patients. When persistent cancer pain does not respond to treatment attempts, it is often ascribed to a psychological cause. Staff members who believe the etiology of a patient’s pain

cancer pain and depression is largely psychological may have difficulty empathizing. In our clinical experience, we have noted that patients who report their pain as “severe” are more likely to be viewed as having a psychological contribution to their complaints. Grossman et al.95 found that although there is a high degree of concordance between patient and caregiver ratings of patient pain intensity at the low and moderate levels, this concordance breaks down at high levels. This suggests that a clinician’s ability to assess a patient’s level of pain may become unreliable once a patient reports elevated pain (e.g., an intensity rating of ⬎7 on a visual analogue scale of 0–10). Physicians must be educated about the challenges of objectively assessing the severity of a patient’s subjective pain experience. Patient education also is often useful. Patients may be taught ways to request pain relief that are less intense and more likely to elicit prompt and adequate responsiveness from care providers.

Management of depression in patients with cancer pain General principles Over the past 30 years, numerous studies have compared the relative effectiveness of psychotherapy, pharmacotherapy, and concurrent therapeutic approaches in the treatment of common psychiatric disorders, such as depression and anxiety. Generally, these studies have demonstrated that medication and psychotherapy combined is somewhat more effective in reducing symptoms as well as in preventing relapse than either treatment approach alone. However, the majority of these investigations have been in physically healthy individuals; special considerations must be given to medically ill patients. The relationship with the primary medical caregiver is the most important component of psychotherapeutic support for many patients with a serious illness. Optimally, these relationships are based on mutual trust, respect, and sensitivity. The ability to acknowledge a patient as a “whole person” and to respond in a manner that takes into account the patient’s individual needs and personal style tends to work best. For patients who are terminally ill, maintaining ongoing contact is particularly important. This not only ensures that patients will be continually reevaluated, but also provides patients with reassurance that they will not be abandoned and that care will be forthcoming and available throughout their terminal course. Supportive psychotherapy with medically ill patients consists of active listening with supportive verbal interventions and occasional interpretations.96 Despite the

465 seriousness of the patient’s plight, it is not necessary for the clinician to appear overly solemn or emotionally restrained. Often it is only the psychotherapist, of all the patient’s caregivers, who is comfortable enough to converse lightheartedly and to allow the patient to talk about his or her life and experiences, rather than solely focusing on impending death. The dying patient who wishes to talk or ask questions about death should be allowed to do so freely, with the therapist maintaining an interested, interactive stance. The mainstay of treatment of patients experiencing cancer pain who have severe major depressive disorder involves psychopharmacological interventions (i.e., antidepressant medications).97 The efficacy of antidepressants in the treatment of depression in cancer patients has been well established;33,98–100 however, depression among patients with cancer pain is optimally managed using a combination of psychotherapy and antidepressant medication.101 There is a variety of psychosocial interventions with proven efficacy for patients with cancer who are suffering from major depression, adjustment disorder, or dysthymia, including individual psychotherapy, group psychotherapy, hypnotherapy, psychoeducation, relaxation training and biofeedback, and self-help groups.35 Psychotherapeutic interventions, in the form of individual or group counseling, have been shown to effectively reduce psychological distress and depressive symptoms in patients with cancer pain.83,102,103

Psychosocial treatment of depression in cancer pain patients The goals of psychotherapy in cancer patients experiencing pain, both depressed and nondepressed, are to offer support, knowledge, and skills. By using short-term supportive psychotherapy focused on the crisis created by the medical illness, the therapist provides emotional support, continuity, and information while assisting the patient with adaptation to the effects of the disease and treatment. The therapist may emphasize past strengths, support previously successful coping strategies, and teach new coping skills, such as relaxation, cognitive coping, use of analgesics, selfobservation, documentation, assertiveness, and communication skills. The ability to communicate is of paramount importance for both patients and their families, particularly around pain and analgesic issues. Continuity of care consisting of long-term, supportive relationships within the health care system is optimal so that providers have opportunities to learn about patient and family preferences for care. Exploration of reactions to the cancer experience in general often involve insights into earlier, more pervasive life issues, whereas psychotherapy in the cancer pain setting

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focuses on current issues and tends to be less dynamically oriented. Dying patients may require a psychiatrist, psychologist, social worker, chaplain, or nurse to implement specific psychological techniques to help manage pain and related palliative care issues. Supportive psychotherapy with palliative care patients can be extremely helpful. The dying patient also may benefit from pastoral counseling. If a chaplaincy service is available, it should be offered to the patient and family. As the dying process progresses, psychotherapy with the individual patient may become limited by cognitive and speech deficits. It is at this point that the focus of supportive psychotherapeutic interventions shifts primarily to the family. In our experience, the patient’s level of alertness often becomes an issue among family members. Attempts to control pain often result in sedation, which can limit communication between patient and family. This can sometimes become a source of conflict, with family members disagreeing among themselves or with the patient about what constitutes an appropriate balance between comfort and alertness. It may be helpful for the physician to clarify the patient’s preferences, as they relate to these issues, early on in treatment so that conflict may be avoided and preparing for the patient’s death may begin. Numerous treatment outcome studies have demonstrated the benefits of psychotherapy and its efficaciousness in reducing depressive symptoms.23,104–110 Cognitive– behavioral interventions, such as relaxation and distraction with pleasant imagery111 and cognitive–behavioral stress management,112 also have been shown to decrease depressive symptoms among cancer patients who exhibit mild to moderate levels of depression. Psychotherapeutic interventions integrating multiple therapeutic approaches may be most useful. A prospective study of cancer pain demonstrated that cognitive–behavioral and psychoeducational techniques designed to increase support and self-efficacy and provide education may help patients manage increased pain.113 Another treatment modality shown to reduce both depressive and pain symptoms is acceptance and commitment therapy, which combines variations of cognitive– behavioral and mindfulness approaches and emphasizes acceptance of pain to decrease distress levels and increase activity.114,115 Empirically, using psychotherapy to diminish symptoms of anxiety and depression, factors that can intensify pain, has beneficial effects on the cancer pain experience. In a controlled randomized prospective study, Spiegel and Bloom102 demonstrated positive outcomes related to supportive group therapy for metastatic breast cancer patients. Their support group focused on a series of themes related

to the practical and existential problems of living with cancer, rather than concentrating on common support group topics, such as interpersonal processes or self-exploration. Patients were divided into two treatment groups (supportive therapy with and without self-hypnosis training for pain management) and a control group. The treatment patients experienced significantly less pain sensation and suffering than the control patients, with the patients trained in selfhypnosis reporting the greatest reductions in pain sensation. The authors also found that changes in ratings of pain were associated with changes in ratings of depressed mood.102 Group interventions with individuals, such as the groups of advanced cancer patients examined by Spiegel and Bloom,102 spouses, couples, and families are a powerful means of sharing experiences and identifying successful coping strategies. The limitations of using group interventions for patients with advanced disease are primarily pragmatic. The patient must be physically comfortable enough to participate and must have the cognitive capacity to be aware of group discussion. It is often helpful for family members to attend support groups during the terminal phases of the patient’s illness.

Pharmacological treatment of depression in patients with cancer pain Pharmacotherapy is the mainstay for treating cancer patients meeting diagnostic criteria for major depression.97 Factors such as prognosis and the timeframe for treatment may play an important role in determining the type of pharmacotherapy selected. A depressed patient with several months of life expectancy can afford to wait the 2–4 weeks it may take to respond to a tricyclic antidepressant (TCA). The depressed dying patient with less than 3 weeks to live may do best with a rapid-acting psychostimulant. Patients who are within hours to days of death and in distress are likely to benefit most from the use of sedatives or opioid analgesic infusions. Antidepressant medications The efficacy of antidepressants in the treatment of depression in cancer patients has been well established.22,97,116,117 Furthermore, antidepressants, particularly tricyclics, venlafaxine, and bupropion, are also useful in the management of pain.22 However, antidepressants are prescribed for the treatment of depression in only 1%–3% of hospitalized cancer patients and only 5% of terminally ill cancer patients.118 A survey of antidepressant prescribing in the terminally ill found that of 1046 cancer patients, only 10% received

cancer pain and depression Table 25.4. Antidepressant medications used in advanced cancer patients

Generic name Second-generation antidepressants Selective serotonin reuptake inhibitors Fluoxetine Paroxetine Citalopram Fluvoxamine Sertraline Serotonin and norepinephrine reuptake inhibitors Venlafaxine Duloxetine 5-HT2 antagonists/serotonin and norepinephrine reuptake inhibitors Nefazodone Trazodone Norepinephrine–dopamine reuptake inhibitor Bupropion ␣2 -antagonist/5-HT2 antagonist Mirtazapine Tricyclic antidepressants Secondary amines Desipramine Nortriptyline Tertiary amines Amitriptyline Doxepin Imipramine Clomipramine Heterocyclic antidepressants Maprotiline Amoxapine Psychostimulants Methylphenidate Dextroamphetamine Modafinil Monoamide oxidase inhibitors Isocarboxazid Phenelzine Tranylcypromine Atypical antipsychotics Olanzapine Lithium carbonate Benzodiazepines Alprazolam

Approximate daily oral dosage range (mg)

10–40 10–40 20–40 50–300 50–200 37.5–225 30–60 twice daily 100–500 150–300 200–450 7.5–30 25–125 25–125 25–125 25–125 25–125 25–125 50–75 100–150 5–30 5–30 50–400 20–40 30–60 20–40 600–1200 0.75–6.00

antidepressants, 76% of whom did not receive them until the last 2 weeks of life.119 Table 25.4 outlines the antidepressant medications frequently used with cancer patients. To date, imipramine,120,121 mianserin,122,123 trimipramine,121 amitriptyline and paroxetine,124 alprazolam (a benzodiazepine with antidepressant effects),111,125 fluoxetine,126,127 and desipramine127 have been studied and shown to be effective in reducing depressive symptoms among cancer patients

467 in controlled trials. All these studies used observer-rated or self-report measures to assess depression, distress, or anxiety rather than conducting structured interviews based on the standardized diagnostic criteria of major depression. There are a number of controlled studies of antidepressant drug treatment for depressive disorders in cancer patients in general,120–123,126–128 but fewer that focus on the terminally ill.22,23 Traditional antidepressants such as the tricyclic and tetracyclic drugs may be inappropriate for the treatment of depression in terminally ill cancer patients because of their unfavorable side effect profiles and because they require a substantial amount of time to take effect. Instead, second-generation antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), are preferred. It is important to be mindful of a patient’s cancer treatment regimen in the selection of an antidepressant. For example, several antineoplastic agents use the hepatic cytochrome P450 system, especially the 3A4 isoenzyme.35 Nefazodone and fluvoxamine inhibit the 3A4 isoenzyme, and therefore their use requires careful monitoring for increased toxicity if the patient is receiving a chemotherapy regimen that is metabolized through the same isoenzyme. Drug interactions can also be mediated through competition for protein binding. Highly protein-bound antidepressants can displace the chemotherapeutic agent and leave patients vulnerable to serious toxicity. Venlafaxine is the least protein bound.35 Selective serotonin reuptake inhibitors SSRIs are commonly the first line of treatment because of their safety and low side effect profile. They also may be effective as adjunct analgesic drugs, especially for neuropathic pain. It is good practice “to start low and go slow” in cancer patients to reduce gastrointestinal side effects of nausea and transient weight loss. Initially, the short-term addition of a benzodiazepine helps prevent anxiety and jitteriness. The SSRIs are safe with chemotherapeutic agents. However, they should be avoided in patients receiving procarbazine, a monoamine oxidase inhibitor (MAOI) used to treat some hematological malignancies. The SSRIs have been found to be as effective in the treatment of depression as the tricyclics105,106 and have a number of features that may be particularly advantageous for cancer patients. The SSRIs have a very low affinity for adrenergic, cholinergic, and histamine receptors, thus accounting for negligible orthostatic hypotension, urinary retention, memory impairment, sedation, or reduced awareness. They have not been found to cause clinically significant alterations in cardiac conduction and are generally favorably tolerated

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along with a wider margin of safety than the TCAs in the event of an overdose. Therefore, they do not require therapeutic drug level monitoring. Most of the side effects of SSRIs result from their selective central and peripheral serotonin reuptake properties. Side effects include diarrhea, nausea, vomiting, insomnia, headaches, and sexual dysfunction. Some patients may experience anxiety, tremor, restlessness, and akathisia (the latter is relatively rare, but it may be problematic for the terminally ill patient with Parkinson’s disease).99 These side effects tend to be dose related and may be problematic for patients with advanced disease. The most commonly used SSRIs in the United States are sertraline, fluoxetine, paroxetine, citalopram, and fluvoxamine. With the exception of fluoxetine, whose elimination half-life is 2–4 days, the SSRIs have an elimination halflife of about 24 hours.129 Fluoxetine is the only SSRI with a potent active metabolite, norfluoxetine, whose elimination half-life is 7–14 days. Fluoxetine and norfluoxetine do not reach a steady state for 5–6 weeks, compared with 4– 14 days for paroxetine, fluvoxamine, and sertraline. These differences are important, especially for the terminally ill patient in whom a switch from an SSRI to another antidepressant is being considered. If a switch to a monamine oxidase inhibitor is required, the washout period for fluoxetine will be at least 5 weeks, given the potential drug interactions between these two agents. Paroxetine, fluvoxamine, and sertraline require considerably shorter washout periods (10–14 days) under similar circumstances. Since fluoxetine entered the market, there have been several reports of significant drug–drug interactions.119 For example, mild serotonin syndrome has been observed when fluoxetine and linezolid, which was used to treat infection resulting from chemotherapy complications, were administered concurrently.130 Until it has been studied further in cancer, fluoxetine should be used cautiously in the debilitated patient. All the SSRIs have the ability to inhibit the hepatic isoenzyme P450 11D6, with sertraline and fluvoxamine being least potent in this regard. Because SSRIs are dependent on hepatic metabolism, this ability becomes significant with respect to dose/plasma level ratios and drug interactions. For the elderly patient with advanced disease, the dose response curve for sertraline appears to be relatively linear. With the other drugs, particularly paroxetine (most potent inhibitor of cytochrome P450 11D6), small dosage increases may result in dramatic elevations in plasma levels. Paroxetine and fluoxetine inhibit the hepatic enzymes responsible for their own clearance.131 These medications should be coadministered cautiously with other drugs that are dependent on this enzyme system for their

catabolism (e.g., tricyclics, phenothiazines, type IC antiarrhythmics, quinidine). Fluvoxamine has been shown in some instances to elevate the blood levels of propranolol and warfarin by as much as twofold and should thus not be prescribed together with these agents. For cancer patients, SSRIs can be started at approximately half the usual starting dose used in an otherwise healthy patient. Titration of fluoxetine can begin with 5 mg (available in liquid form) given once daily (preferably in the morning). The usual effective range is 10–40 mg/day. Given the long half-life of fluoxetine, some patients may require this drug only every second day. Paroxetine can be started at 10 mg once daily (either morning or evening) and has a therapeutic range of 10–40 mg/day. Fluvoxamine, which tends to be somewhat more sedating, can be started at 25 mg (in the evenings) and has a therapeutic range of 50–300 mg. Sertraline can be initiated at 50 mg, morning or evening, and titrated within a range of 50–200 mg/day. If patients experience activating effects on SSRIs, these drugs should not be given at bedtime but rather moved earlier into the day. Gastrointestinal upset can be reduced by ensuring the patient is not taking the medication on an empty stomach. Serotonin and norepinephrine reuptake inhibitors Venlafaxine and duloxetine fall into the class of antidepressants know as SNRIs. Venlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and appears to have no significant affinity for muscarinic, histamine, or ␣1 -adrenergic receptors. Some patients may experience a modest sustained increase in blood pressure, especially at doses above the recommended initiating dose. Compared with the SSRIs, its protein binding (⬍35%) is very low; thus, few protein binding–induced drug interactions are expected. Like other antidepressants, venlafaxine should not be used in patients receiving MAOIs. Its side effect profile tends to be generally well tolerated, with few discontinuations. Although there currently are no data addressing its use in depressed cancer patients, its pharmacokinetic properties and side effect profile suggest it may be effective. Similar to venlafaxine, duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine that has been found to effectively treat depression and neuropathic pain.132 The dosage is 60 mg twice daily with meals. To date, however, there are no trials examining the effects of duloxetine in cancer populations. Other atypical antidepressants Nefazodone and trazodone are chemically related antidepressants. Nefazodone is much less sedating than trazodone but more likely to cause gastrointestinal activation.

cancer pain and depression It usually does not impair sexual functioning. Nefazodone may be started at 50 mg at bedtime and titrated within a range of 100–500 mg/day. It increases the serum levels of alprazolam and triazolam but does not have any clinically significant interactions with lorazepam. Nefazodone has been demonstrated to potentiate opioid analgesics in an animal model.133 If given in sufficient doses (100–300 mg/day), trazodone may be an effective antidepressant. Although its anticholinergic profile is almost negligible, it has considerable affinity for ␣1 -adrenoceptors and thus may predispose patients to orthostatic hypotension and its problematic sequelae (i.e., falls, fractures, and head injuries). Trazodone is very sedating and in low doses 100 milligrams taken nightly (100 mg qhs) is helpful in the treatment of depressive symptoms occurring among cancer patients with adjustment disorders134 as well as those with depression and insomnia. It is highly serotonergic with antinociceptive properties, and its use should be considered when the patient requires adjunct analgesic effect in addition to antidepressant effects.135 Trazodone has little effect on cardiac conduction but may cause arrhythmias in patients with premorbid cardiac disease.99 Trazodone also has been associated with priapism and should therefore be used with caution among male patients.136 Trazodone may be used alone or in combination with SSRIs, although there is a risk of serotonin syndrome.135 Sedation and weight gain are favorable side effect profiles among patients with insomnia and anorexia. The lack of anticholinergic side effects is helpful for patients prone to delirium and cognitive dysfunction. Bupropion is commonly used in the cancer setting, and one might consider prescribing bupropion if patients have a poor response to a reasonable trial of other antidepressants. Because of its analgesic effects, it may be especially useful in the depressed patient with pain.22 Bupropion is an aminoketone that inhibits reuptake of norepinephrine and dopamine. It may have a role in the treatment of the psychomotor-retarded, depressed cancer patient, as it has energizing effects similar to those of the stimulant drugs.137 Because of the increased incidence of seizures, however, bupropion should be used cautiously in patients with disorders of the central nervous system. The dopaminergic profile of bupropion may be used to counteract the sexual dysfunction caused by other medications. Mirtazapine is the 6-aza analogue of the tetracyclic antidepressant mianserin. Mirtazapine enhances central noradrenergic and serotonergic activity with blockade of central presynaptic ␣2 -inhibitory receptors and postsynaptic serotonin 5-hydroxytryptamine (5-HT)2 and 5-HT3 receptors. Although mirtazapine compares favorably with

469 amitriptyline and trazodone, further studies are needed to compare its clinical efficacy with that of SSRIs. The drug mainly affects serotonin (5-HT) receptors of the 5-HT2 and 5-HT3 subtypes, possessing low affinity for 5-HT1A , 5-HT1B , and 5-HT1C receptors. Mirtazapine improves appetite, resulting in weight gain, which is desirable in cancer patients. In addition, the marked sedative effect of this medication proves quite useful in patients with sleeping difficulties.138 Tricyclic antidepressants The use of TCAs in depressed cancer patients requires a careful risk–benefit ratio analysis. Although nearly 70% of physically healthy patients treated with TCAs for nonpsychotic depression can anticipate a positive response, the side effect profile of these agents may be troublesome for cancer patients.139 The multiple pharmacodynamic actions accounting for these side effects include blockade of muscarinic cholinergic receptors, ␣-adrenoceptors, and H1 histamine receptors. The tertiary amines (amitriptyline, doxepin, and imipramine) have a greater propensity to cause side effects than do secondary amines (nortriptyline, desipramine).131,139 The secondary amines are thus often a preferable choice in the cancer setting. The anticholinergic side effects of TCAs may include constipation, dry mouth, and urinary retention. To avoid exacerbating symptoms associated with genitourinary outlet obstruction, decreased gastric motility, or stomatitis, less anticholinergic tricyclics, such as desipramine or nortriptyline, are reasonable choices. Patients who are receiving medication with anticholinergic properties (such as diphenylhydramine or a phenothiazine) are at risk for developing an anticholinergic delirium. Antidepressants with potent anticholinergic properties should be avoided in these patients. The anticholinergic actions of TCAs can also cause serious tachycardia. Their quinidine-like effects may lead to arrhythmias by delaying the conduction through the HisPurkinje system. These effects are associated with nonspecific ST-T changes and T waves on the electrocardiograph. TCAs should be avoided in cancer patients with preexisting conduction defects or second- or third-degree heart block. ␣1 -Blockade is associated with postural hypotension and dizziness, which may be of particular concern for the frail, volume-depleted patient who is at risk for falls and subsequent fractures. Nortriptyline and protriptyline are the TCAs least associated with ␣1 -blockade. H1 -histamine receptor blockage is associated with sedation and drowsiness. For dying patients already exposed to a variety of sedating agents (e.g., opioids, antiemetics, anxiolytics, and neuroleptics), TCAs such as amitriptyline and doxepin are

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the most likely to accentuate the overall cumulative sedating effects of these medications. Tricyelic antidepressants (TCAs) should be started at low doses (10–25 mg qhs) and increased in 10- to 25-mg increments every 2–4 days, until a therapeutic dose is attained or side effects become a dose-limiting factor. Both depression and pain in cancer patients respond to significantly lower doses of TCAs (25–125 mg) than are necessary in the physically well (150–300 mg). To minimize TCA toxicity, plasma levels must be carefully monitored during titration, as well as during steady state. The choice of TCA depends on a variety of factors, including the nature of the underlying medical condition, the characteristics of the depressive episode, past responses to antidepressant therapy, and the specific drug side effect profile. For depressed cancer patients, the choice of TCA often is made on the basis of a side effect profile that will be the least incompatible with a patient’s overall medical condition. Most TCAs are available as rectal suppositories for patients who are no longer able to take medication orally. Outside the United States, certain TCAs are given as an intravenous infusion. Amitriptyline, imipramine, and doxepin are available intramuscularly. Therapeutic response to TCAs, as with all antidepressants, has a latency time of 3–6 weeks. Thus, for patients with advanced cancer, psychostimulants may offer a more viable, rapid response alternative. Many antidepressants have analgesic properties. There is no definite indication that any one drug is more effective than the others, although the most experience has been accrued with amitriptyline. Heterocyclic antidepressants The heterocyclic antidepressants have side effect profiles similar to those of the TCAs. Maprotiline should be avoided in patients with brain tumors and in those who are at risk for seizures, as the incidence of seizures is increased with this medication.140 Amoxapine has mild dopamineblocking activity. Hence, patients who are taking other dopamine blockers (e.g., antiemetics) have an increased risk of developing extrapyramidal symptoms and dyskinesias. Mianserin (not available in the United States) is a serotonergic tetracyclic antidepressant with adjuvant analgesic properties that is used widely in Europe and Latin America.141 Costa and colleagues122 showed mianserin to be a safe and effective drug for the treatment of depression in cancer. Psychostimulants Psychostimulants currently approved for use in cancer patients include methylphenidate, dextroamphetamine,

mazindol, and modafinil. They have been shown to be rapidly effective antidepressants,142 especially in the cancer setting.143–152 Psychostimulants are also useful in diminishing excessive sedation secondary to opioid analgesics. Bruera et al.153–155 demonstrated that a regimen of 10 mg of methylphenidate with breakfast and 5 mg with lunch significantly decreased sedation and potentiated the analgesic effect of an opioid in patients with cancer pain. Several investigators also have demonstrated the efficacy of methylphenidate in the treatment of depression in advanced cancer patients, reporting rapid onset of action (1–3 days) and response rates as high as 85%.145,146 Dextroamphetamine has been reported to have additive analgesic effects when used with morphine in postoperative pain.156 Bruera and colleagues144 studied the effects of mazindol on depression in advanced cancer patients using a double-blind design, demonstrating its efficacy in treating pain but not depressive symptoms. Before being removed from the market because of several cases of irreversible liver function abnormalities, the chewable form of pemoline was especially helpful in those who could no longer tolerate the oral route but could utilize buccal absorption.143 Treatment with dextroamphetamine or methylphenidate usually begins with a dose of 2.5 mg at 8:00 am and at noon. The dosage is slowly increased over several days until a desired effect is achieved or side effects (overstimulation, anxiety, insomnia, paranoia, and confusion) intervene. Typically, a dose greater than 30 mg/day is not necessary, although occasionally patients require up to 60 mg/day. Patients usually are maintained on methylphenidate for 1–2 months, and approximately two thirds will be able to be withdrawn from methylphenidate without a recurrence of depressive symptoms. If symptoms do recur, patients can be maintained on a psychostimulant for up to 1 year without significant abuse problems. Tolerance may develop, and adjustment of dose may be necessary. Common side effects of stimulants include nervousness, overstimulation, mild increases in blood pressure and pulse rate, and tremors. More rare side effects include dyskinesias or motor tics, as well as a paranoid psychosis or exacerbation of an underlying and unrecognized confusional state. Pemoline is a unique psychostimulant that is chemically unrelated to amphetamine and that was available until the U.S. Food and Drug Administration (FDA) banned it because of its potential to cause irreversible liver damage. It is no longer manufactured or marketed, although unsold stock may still be available. There were several advantages for using pemoline in cancer patients. Pemoline did not have any abuse potential and did not require special

cancer pain and depression prescriptions. In addition, as described earlier, its chewable tablet form was very useful in cancer patients with difficulty swallowing or with intestinal obstruction. Pemoline was as effective as methylphenidate and dextroamphetamine in the treatment of depression in cancer patients.143 However, it was better tolerated because of its mild sympathomimetic effects. Pemoline was started at a dose of 18.75 mg in the morning and at noon, and increased gradually over days. Typically, patients require 75 mg/day or less. Pemoline produced before the FDA ban is potentially still available for sale but should be used with caution in patients with liver impairment, and liver function tests should be monitored periodically with longer-term treatment.157 Another mild stimulant frequently used in palliative care settings is modafinil, a wakefulness agent that was FDA approved to treat excessive daytime sedation resulting from sleep disorders such as narcolepsy and sleep apnea.158 Modafinil is often used to reduce fatigue, a common symptom of cancer and its treatment,159 such as sedation resulting from opioids that are given to manage pain. DeBattista et al.160 found that patients with major depression who were partial responders to antidepressants exhibited improvements in depressive symptoms, fatigue, and aspects of cognitive functioning when modafinil was given as an adjunctive treatment. Doses range from 50–400 mg. The mechanism of action of modafinil differs from that of classic psychostimulants and is not entirely understood. Unlike amphetamines, it is not sympathomimetic and does not result in euphoria; therefore, there are few concerns about dependence, tolerance, and abuse with the use of modafinil.158 Several clinical trials have demonstrated that psychostimulants are quite helpful in the treatment of depression in the cancer setting,143–146,155,161 especially in patients with dysphoric mood associated with severe psychomotor slowing and even mild cognitive impairment. Psychostimulants have been shown to improve attention, concentration, and overall performance on neuropsychological testing in the medically ill.162 In relatively low doses, psychostimulants stimulate appetite, promote a sense of well-being, and improve feelings of weakness and fatigue in cancer patients. Monoamine oxidase inhibitors In general, MAOIs are rarely used in the cancer setting. Patients who receive MAOIs must avoid foods rich in tyramine, sympathomimetic drugs (amphetamines, methylphenidate), and medications containing phenylpropanolamine and pseudoephedrine. The combination of these agents with MAOIs may cause hypertensive crisis.

471 MAOIs in combination with opioid analgesics have also been reported to be associated with myoclonus and delirium and must therefore be used together cautiously.163 The use of meperidine while taking MAOIs is absolutely contraindicated and may lead to hyperpyrexia, cardiovascular collapse, and death. MAOIs also may cause considerable orthostatic hypotension. Avoiding these adverse interactions may be particularly problematic for patients with cancer. It is not surprising that MAOIs tend to be reserved in this patient population for those who have shown past preferential responses to them. Among the MAOI drugs available, phenelzine has been shown to have adjuvant analgesic properties in patients with atypical facial pain and migraine.164,165 The new reversible inhibitors of monoamine oxidase-A (RIMAs) may reduce some of the problems associated with the older MAOIs. There are no studies on the role of RIMAs in depressed cancer patients, but there are interesting theoretical reasons to suggest they may eventually have a larger role to play than the nonselective MAOIs. RIMAs selectively inhibit MAO-A enzyme, therefore leaving MAO-B enzyme available to deal with any tyramine challenge. Moclobemide, a RIMA recently introduced onto the Canadian market, appears to be loosely bound to the MAO-A receptor and is thus relatively easily displaced by tyramine from its binding site. It has a very short half-life, which further reduces the possibility of any prolonged adverse effects (e.g., hypertensive crisis). Dietary restrictions avoidant of tyramine-containing foods thus are not required. The side effect profile of moclobemide is far more favorable than that of nonselective MAOIs and tends to be well tolerated. Agents such as meperidine, procarbazine, dextromethorphan, and other ephedrine-containing agents are still best avoided. Although RIMAs may offer some advantages over tranylcypromine and isocarboxazid in depressed cancer patients, they likely will remain a second-line choice to other available non-MAOI antidepressants. Lithium carbonate Patients who have been receiving lithium carbonate before a cancer illness should be maintained on it throughout their cancer treatment, although close monitoring is necessary in the preoperative and postoperative periods, when fluids and salt may be restricted.166 Maintenance doses of lithium may require reduction in seriously ill patients. Lithium should be prescribed with caution for patients receiving cis-platinum because of the potential nephrotoxicity of both drugs. Several authors have reported possible beneficial effects from the use of lithium in neutropenic cancer patients. However, the functional capabilities of these leukocytes have not been

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determined. The stimulation effect appears to be transient; no mood changes were noted in these patients.167 Atypical antipsychotics Second-generation antipsychotics such as amisulpride and olanzapine have demonstrated antidepressant effects.168 Atypical antipsychotics have a higher affinity for 5-HT2 serotonin receptors than to D2 dopamine receptors. Studies have suggested the promise of olanzapine, a thiobenzodiazepine, in reducing depressive symptoms in other populations, though there has been little formal research examining its impact on depression in cancer patients.138 Clinical experience suggests its value for alleviating depression, and there is empirical evidence of its efficacy in treating cancer pain.169 At low doses, amisulpride has been efficacious in decreasing depressive symptoms and well tolerated in patients undergoing chemotherapy treatment.170 No clinical studies of this drug have been conducted in the United States, however, and it is primarily marketed in Australia and Europe. Benzodiazepines and other anxiolytics The triazolobenzodiazepine alprazolam has been shown to be a mildly effective antidepressant as well as an anxiolytic. Alprazolam is particularly useful in cancer patients who have mixed symptoms of anxiety and depression. Holland et al.111 reported strong treatment effects for alprazolam (as well as progressive muscle relaxation) when comparing its efficacy in reducing depression and anxiety among cancer patients in a randomized controlled trial, with pharmacological treatment resulting in a greater reduction in depressive symptoms than the relaxation intervention. The starting dose of alprazolam is 0.25 mg three times a day, and effective doses are usually in the range of 4–6 mg daily. Benzodiazepines have not been thought to have direct analgesic properties, although they are potent anxiolytics and anticonvulsants.171 Some authors have suggested that their anticonvulsant properties make certain benzodiazepine drugs useful in the management of neuropathic pain. A study of the use of midazolam by patient-controlled dosage found no reduction in the use of postoperative morphine requirements or in the patient’s perception of pain.172 However, both alprazolam, a unique benzodiazepine with mild antidepressant properties, and clonazepam may be useful in treating neuropathic pain.173,174 Hydroxyzine is a mild anxiolytic with sedating and analgesic properties that are useful in the anxious cancer patient with pain.175 This antihistamine has antiemetic activity as well.

Electroconvulsive therapy Occasionally, it is necessary to consider ECT for depressed cancer patients who have depression with psychotic features or in whom treatment with antidepressants poses unacceptable side effects. Although there are special considerations regarding the administration of ECT under certain circumstances (e.g., increased intracranial pressure), this treatment has the potential to be both safe and effective in the medically ill.97,176

Summary The management of depression associated with cancer pain may be a challenging task for clinicians. A thorough assessment of and familiarity with both pharmacological and nonpharmacological modalities are critical to help distinguish between the distress of unrelieved pain and depression. Successful management of both depression and pain can have a dramatic impact on patients’ suffering and significantly improve their quality of life. References 1. Foley KM. The treatment of cancer pain. N Engl J Med 313:84–95, 1985. 2. Foley KM. Pain syndromes in patients with cancer. In: Bonica JJ, Ventafridda V, Fink RB, et al., eds. Advances in pain research and therapy, vol. 2. New York: Raven Press, 1975, pp 59–75. 3. Breitbart W, Holland J. Psychiatric aspects of cancer pain. In: Foley KM, Bonica JJ, Ventafridda V, eds. Advances in pain research and therapy, vol. 16. New York: Raven Press, 1990, pp 73–87. 4. Breitbart W. Psychiatric management of cancer pain. Cancer 63:2336–42, 1989. 5. Massie MJ, Holland JC. The cancer patient with pain: psychiatric complications and their management. Medical Clin North Am 71:243–58, 1987. 6. Stiefel F. Psychosocial aspects of cancer pain. Support Care Cancer 1:130–4, 1993. 7. Saunders CM. The management of terminal illness. London: Hospital Medicine Publications, 1967. 8. Hanks GW. Opioid responsive and opioid non-responsive pain in cancer. Br Med Bull 47:718–31, 1991. 9. Daut RL, Cleeland CS. The prevalence and severity of pain in cancer. Cancer 50:1913–18, 1982. 10. Spiegel D, Bloom JR. Pain in metastatic breast cancer. Cancer 52:341–5, 1983. 11. Syrjala K, Chapko M. Evidence for a biopsychosocial model of cancer treatment-related pain. Pain 61:69–79, 1995. 12. Payne D, Jacobsen P, Breitbart W. Negative thoughts related to pain are associated with greater pain, distress, and disability in AIDS pain. In: American Pain Society. Miami, 1994.

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Neuropathic pain ricardo a. cruciani, e. alessandra strada, and helena knotkova Beth Israel Medical Center

Introduction Effective pain management in patients with cancer is an essential component of care during active treatment, as well as in palliative and end-of-life care. Chronic pain occurs frequently in patients with cancer, with an estimated prevalence that ranges from 40% to 60%.1 Pain may be caused by direct tumor infiltration of neural structures or by treatment sequelae. Although the prevalence of pain in the outpatient setting is 20%–40%, it may rise to 80% for patients at the end of life.2 However, several prospective studies suggest adequate pain control could be achieved in 90% of patients by following the World Health Organization guidelines.3,4 Because pain is ultimately a perceptual construct within the central nervous system (CNS), a patient’s experience of pain is a result of complex somatosensory processing. Developing understanding of the physiological and biochemical processes involved in pain, combined with an appreciation of the cognitive, emotional, and cultural framework of the patient offers the best opportunity to provide treatment of underlying mechanisms and relief of suffering. Even though most patients initially report somatic or visceral pain, they also frequently experience painful neuropathic components. Management of neuropathic pain presents a number of challenges, because it is often more resistant to conventional analgesic approaches. Mixed pain problems, in which neuropathic pain is combined with elements of somatic or visceral pain, are also common. Neuropathic pain may also signal progressive and often incurable disease. Here, in addition to the physical component of pain, patients may experience significant psychological and spiritual suffering related to the meaning of the pain. Over the past few years, research has been directed toward developing a better understanding of the pathophysiology of neuropathic pain in patients with cancer and identifying treatment strategies that allow improved outcome.5,6 478

Classification of pain Pain symptoms in cancer patients are usually described as primarily nociceptive or neuropathic. However, many patients report mixed pain problems, in which both types are combined. Nonetheless, the underlying mechanisms are different and may result in different treatment selections. Nociceptive cancer pain is considered to result from direct tumor involvement of visceral or somatic tissues. Nociceptors are specialized terminal nerve endings in the injured tissues. They can be activated directly (by electrolyte or pH changes) or by an associated inflammatory reaction (bradykinin, substance P). These nerve impulses are then transmitted to the pseudobulbar dorsal root ganglion (DRG) neurons and then to the dorsal horn of the spinal cord. These primary afferent neurons synapse with a projection neuron that sends pain signals up the spinothalamic tract to the postero-ventricular-lateral nucleus and postero-ventricular-medial nucleus of the thalamus, where pain is sensed. At that level, the pain sensations can be felt but not localized. From the thalamus, a third-order neuron transmits the information to the somatosensory cortex, where, with the participation of association areas, the pain sensation can be localized to a specific body region. This physiologic response allows perception of noxious stimulation and permits a directed protective response. After a stroke that involves parts of the somatosensory cortex, it is not uncommon for patients to feel painful stimulation (because the pathways to the thalamus are intact), but in response to painful stimuli, they move randomly, failing to identify the area where the pain has originated. Neuropathic cancer pain occurs as a result of peripheral nervous system and CNS mechanisms. It is a consequence of: A. Direct tumor infiltration of nerve tissue B. Tumor effects on structures near nerve tissue

neuropathic pain C. Inflammatory and other biochemical processes that affect neurological activity D. Neurotoxic effects of treatment of the neoplasm Management of neuropathic pain presents a number of challenges. As the underlying mechanisms in nociceptive and neuropathic pain are different, they may result in different treatment selections. Neuropathic pain often is more resistant than nociceptive pain to conventional analgesic approaches. The International Association for the Study of Pain defines neuropathic pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.” This definition is enhanced by the concept of abnormal processing of sensory information. The symptoms of allodynia (pain elicited by non-noxious stimuli) and hyperalgesia (an exaggerated pain response to a mildly noxious stimulus) are an example of pain that develops as a result of qualitative alteration and quantitative enhancement of sensory information. From a clinical perspective, perhaps defining neuropathic pain as “abnormal persistent pain that results from a direct injury to the nervous system” may be the characterization that affords the best initial clinical direction.

Clinical overview of neuropathic pain Neuropathic pain is the result of processes that involve the peripheral nervous system, autonomic nervous system, and CNS. In the classic neuropathic pain syndromes, sustained symptoms are present, reflecting evolving processes often with multiple parts of the nervous system participating. Patients often may focus on the reporting of nociceptive pain, as this represents the usual and more familiar experience of pain. However, they may frequently experience significant neuropathic pain either as an isolated experience, or as a component of somatic or visceral pain. Having less experience with neuropathic pain and less familiarity with its descriptive vocabulary may decrease the spontaneous reporting of neuropathic pain. Compression of a vertebral body as a complication of trauma, osteoporosis, or metastatic cancer often causes nociceptive (somatic) pain and often creates pressure on nearby nerve roots or the spinal cord itself, resulting in neuropathic pain also. A radicular distribution of continuous or intermittent pain with electric, burning, or lancinating sensations is typical of early nerve compression. Pain after peripheral nerve injury may occur through a variety of mechanisms. Nerve compression or distention can activate the nervi nervorum, the normal nociceptive afferents that innervate the nerve sheaths themselves. As a result, nerve trunk pain may occur.7 Damage to these

479 primary nociceptive afferents may result in spontaneous and recurrent nerve activation, called ectopic activity. The DRG may represent an additional site of ectopic activity.8 If abnormal processing of sensory information also develops, then pain often becomes more persistent with added classic neuropathic symptoms, such as allodynia and hyperalgesia. Peripheral neuropathic pain may involve individual nerves (as a mononeuropathy, as a polyneuropathy, or simply stated as a peripheral neuropathy) or an entire plexus of nerves (e.g., brachial, lumbar, sacral). Peripheral neuropathic pain associated with oncologic diseases has been observed in patients with lymphoma, head and neck malignancies causing cranial neuropathies, pelvic malignancies causing lumbosacral plexus neuropathies, and metastatic disease in spinal roots or meningeal tissue.9 Although the inciting lesion may occur in the peripheral nervous system, the pain may be generated in the periphery, in the CNS, or both. This distinction often has significant implications for treatment and prognosis. Peripheral neuropathic pain that responds to interventional techniques, such as nerve block, radiation, or direct injection of local anesthetic, generally has a better prognosis. Central neuropathic pain is the result of a lesion in the CNS and has been associated with tumors, myelopathy, and stroke, and as a postradiation syndrome. It is not frequently seen in cancer patients, and it generally is more difficult to treat than peripheral neuropathic pain. Mechanisms of central pain have not yet been determined. With the recent development of animal models, molecular and neurohumoral abnormalities in central pain are being explored. Central disinhibition and central sensitization leading to neuronal hyperexcitability have been considered as possible mechanisms of central pain.10,11 Also, functional imaging studies suggest that functional plasticity and reorganization within somatosensory centers and the motor cortex play an important role in the development of central pain.12 The multitude of potential mechanisms for neuropathic pain may explain individual variations in response to treatment. Even for a given individual, more than one mechanism may be at work. Also, because injury in one part of the nervous system can trigger dysfunction at other levels of the nervous system, the mechanism of pain generation for any one individual may change over time, further complicating attempts at management.13

Pathophysiology The pathophysiology of neuropathic pain is highly complex and may present with multiple types of sensory abnormalities, suggesting the presence of multiple underlying

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mechanisms. After an injury to the peripheral nervous system or CNS, the following pathophysiologic changes may occur: Nociceptors acquire new characteristics; regenerating nerve sprouts may discharge spontaneously (which may be associated with spontaneous dysesthesia); activation thresholds may be decreased (resulting in pain after non-noxious stimuli or allodynia); the stimulus–response function may shift to the left (such that a noxious stimulus causes more pain than normal or hyperalgesia). Although all these events are usually considered to drive any type of neuropathic pain, newer research suggests that specific types of sensory abnormalities, such as allodynic responses or cold hyperesthesia, may be associated with specific abnormalities in neural processing.14 Membrane components relevant to pathophysiology Numerous membrane components and neurohumoral changes are relevant in the development and maintenance of pathologic pain. These neural structures represent potential targets for analgesic drugs and therapeutic interventions designed to relieve pathologic pain: Receptors Purine receptors Purinergic receptors (P2X3, P2X2/3) are localized on peripheral sensory afferents. They are involved in the development of hyperalgesia and mechanical allodynia in neuropathic pain.15 Proteinase-activated receptor-2 Proteinase-activated receptor-2 (PAR-2) is a member of the G protein–coupled, seven-transmembrane domain receptor family, and it is activated by mast cell–derived tryptase and other proteinases. PAR-2 appears in primary sensory neurons and is involved in hyperalgesia.16 This receptor is a recently discovered potential treatment target.17 Cannabinoid receptors An increasing body of evidence supports the hypothesis of the role of the cannabinoid receptors CB1 and CB2 in central and peripheral mechanisms of nociception, particularly during inflammation and neuropathic pain.18,19 Recent research results suggest a potential role for CB1 and CB2 as anti-inflammatory and antihyperalgesic agents, and in the potentiation of opioid analgesia.20 Bradykinin receptors Expression of B1 receptors is induced by tissue injury, and B1 contributes significantly to inflammatory hyperalgesia. The B2 receptor, which acts via a pertussis toxin–sensitive G protein that stimulates phospholipase C B1, is a key player in inflammatory hyperalgesia.21,22

Adenosine receptors (A1, A2A, A2B, and A3) Spinally injected adenosine induces antinociception in animal models of neuropathic pain, and intrathecal adenosine appears to induce some degree of analgesia and relieve neuropathic pain in humans.23–27 Most conditions of neuropathic pain develop after partial injury of the peripheral nervous system. Research on animal models reveals that both injured and neighboring uninjured nerve fibers contribute to the generation of neuropathic pain.28 Ion Channels Proton-gated ion channels Proton-gated ion channels (acid-sensing ion channel-1 [ASIC1], ASIC3, and ASIC/dorsal root ASIC [DRASIC]) are amiloride-sensitive channels activated by low pH and play a role in the development of bone pain. ASICs are activated by the acidic microenvironment produced by osteoclasts during bone resorption.29,30 Transient receptor potential vanilloid channels Transient receptor potential vanilloid channel (TRPV)-1 plays a crucial role in inflammatory pain and thermal hyperalgesia. Activation of TRPV-1 leads to the release of neuropeptides, including substance P, which can also activate osteoclasts and mast cells.31 Voltage-gated sodium channels The tetrodotoxin (TTX)-R Nav 1.8 channel is expressed exclusively in primary nociceptive sensory neurons, and it plays a crucial role in inflammatory pain. TTX-S Nav 1.7 also may contribute to pain associated with inflammation,32 and both TTX-S and TTX-R sodium channels are upregulated during chronic inflammation. Mutations in the gene encoding the TTX-S Nav 1.7 sodium channel contribute to neuropathic pain related to a disorder known as primary erythermalgia, an autosomal dominant genetic disorder characterized by episodic attacks of reddening of the skin as a result of vasodilation of the dermis.33 Voltage-gated calcium channels The role of calcium channels in the control of transmitter release from nociceptive terminals is well known. However, there is evidence that some anticonvulsant drugs (gabapentin, pregabalin) that have been used to treat neuropathic pain act via voltage-gated calcium channels. Both gabapentin and pregabalin bind with high affinity to the ␣2 ␦ subunit of the N- and P/Q-type voltage-gated calcium channels and decrease intracellular calcium influx.34–36 After trauma or compression of a neural structure, some fibers may be injured or sectioned, but a variable number remain intact. This concept is very important because

neuropathic pain neuropathic pain is a complex phenomenon caused by the changes that occur not only in the distal part of the sectioned or injured axons but also in the proximal segment, the DRG neurons where these axons originate, and the remaining intact fibers. Soon after the injury, the distal part of the injured fibers undergoes wallerian degeneration whereas the proximal part of the axon starts the regenerating process within hours. When the newly generated axons (smaller, thinner fibers) find their way into the myelin sheet, successful regeneration occurs. The resultant nerve will be thinner, wrapped by a characteristically abnormal myelin sheet, and will show abnormal conduction velocities. On the other hand, the axons that do not find the myelin sheet produce a chaotic number of fibers at the end of the proximal sectioned axon, known as “Medusa’s head.” These structures, called neuromas, may be a source of abnormal impulses, which are initially mediated by A␦- and later by C-fibers. Such abnormal electrical activity, also known as “injured nerve currents,” can be increased by mechanical and chemical stimulation, including a decrement in pH that occurs during the inflammatory response. The mechanism underlying this electrical activity has not been elucidated. Changes in sympathetic fibers, including sprouting of sympathetic fibers into DRG neurons, has been observed. However, ␣2 -receptor blockers have been shown to be ineffective, indicating that the changes observed in neuroma formation may occur independently from the sympathetic system. The observation that excitability increases in the remaining intact fibers has been a topic of great interest. The most important modifications seem to be at the level of the sodium channels. Sodium channels transport positively charged sodium atoms across cell membrane. These ions subsequently produce the upstroke velocity of action potentials. Thus, the generation of action potentials depends on sodium channels. Two main types of sodium channels have been described: TTX sensitive and TTX resistant. Although the sodium channels remain unchanged in the DRG cell body, they are redistributed on the cell membrane, which results in the generation of “nerve injury discharges.” Ultimately, the sympathetic efferent fibers sprout into the A␤-fiber cell bodies, forming basket-like structures that are responsible for sympathetically mediated pain. Preclinical studies in mice have shown that when the effect mediated by nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin (NT-3) is blocked, sympathetic sprouting is decreased. This finding suggests that early intervention following injury could have an important impact on the outcome of neuropathic pain. However,

481 the role of the sympathetic fibers in the development of neuropathic pain remains unclear. Transgenic mice lacking functional ␣2 -adrenoceptors respond similarly to the wild-type phenotype. Although it has been suggested that sympathetic changes (sprouting, increased expression of the presynaptic ␣2 -receptors) are transient phenomena producing no long-term impact on neuropathic pain, it is currently accepted that such changes are responsible, at least in part, for the development of sympathetically mediated neuropathic chronic pain. After an injury occurs, there are changes in the properties of sodium channels as well as the expression of different types of sodium channels, among other changes. Those localized in the neuronal body remain the same, whereas the sodium channels that are in the axons are redistributed and accumulate. These changes seem to be responsible for some, but not all, of the symptoms observed in neuropathic pain. Indeed, intrathecal application of antisense oligodeoxynucleotides reverses thermal hyperalgesia and hypersensitivity but does not alter thermal or mechanical nociception. As a result, neural activity may occur independently from peripheral noxious stimuli and fire spontaneously. P2X is the receptor for adenosine 5 -triphosphate, which is released after injury along with potassium and other intracellular elements. P2X is also upregulated and has been correlated with the development of allodynia. In addition, vallinoid receptors (now known as TRPV-1), which are structures activated by heat and localized in C- and A-fibers, are also upregulated, but their role in neuropathic pain has not been clearly established. It has been observed that glial cells and immune cells experience activation and produce cytokines. In contrast, Schwann cells and keratinocytes release BDNF and NGF, increasing the excitability of the remaining normal fibers. In normal conditions, these neurons are activated by their physiologic neurotransmitter (substance P, glutamate) or by the application of voltage (∼10 mV). However, changes in the surrounding tissue make them very excitable so that they can spontaneously fire action potentials. Schwann cells seem to play an important role in the development of these changes, as manifested by the increased expression of NGF and NT-4. The changes that result from injury to a neural structure are not limited to the vicinity of the lesion and can extend to the cell bodies of the DRG. These neurons increase the expression of NGF, which has a pivotal role in the development of the postinjury sequelae. After NGF binds the TrkA receptors, they are internalized as a complex and transported to the cell body, where they initiate gene transcription of sodium channels, receptors, and the neuropeptides

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that participate in pain transmission. It has been shown that NGF has a tonic effect on the expression of substance P in nociceptors. Neurohumoral changes secondary to neural injury The microenvironment of nerve fibers changes substantially after injury as a result of wallerian degeneration of lesioned fibers and responses in Schwann cells, satellite cells around the cell bodies of primary sensory neurons in the DRG, and various components of the immune system. Cellular changes, including dedifferentiation and proliferation of Schwann cells, promote regrowth of surviving neurons in the proximal stump of a lesioned nerve. In the distal part of a damaged nerve, macrophages are recruited to clear axonal and myelin tissue. Neurotrophic factors, cytokines, and their receptors are upregulated during this process. As a result, primary sensory neurons become hyperexcitable and may exhibit spontaneous activity. Neurotrophic factors Transection of a peripheral nerve leads to an increased expression of NGF in skin keratinocytes within the area of the damaged nerve. In Schwann cells, an increased transcription of BDNF occurs, together with enhanced production of NGF and NT-4. In DRGs, neurotrophic factors contribute to pain hypersensitivity that develops after the injury. It was shown that inactivation of NGF, BDNF, and NT reduces the development of mechanical allodynia. Signaling between sensory neurons and the sympathetic nervous system Following injury, efferent sympathetic fibers sprout into DRG and form compact structures around the cell bodies of large-diameter A␤-fibers. The release of NTs critically contributes to the creation of this abnormal connection. A blockade of the action of BDNF, NGF, and neurotrophic factor decreases the sprouting of sympathetic efferents.37 Cytokines The cytokine tumor necrosis factor (TNF)-␣ has been shown to play a role in pain hypersensitivity that occurs following a neural injury.38 There is also an upregulation of interleukin (IL)-1␤, IL-6, and IL-10, with a different temporal pattern. TNF-␣ accumulates at the site of injury after release from Schwann cells, and this increase coincides with the invasion of macrophages and T lymphocytes. Proliferating satellite cells represent another potential source of the increase of TNF-␣ in DRG.

Upregulation of ion channels After a neural injury, the proportion of sensory neurons expressing the purinoreceptor (P2X3) transiently increases, and intense immunoreactivity occurs at the injury site. Knockdown of the P2X3 receptor reduces mechanical hyperalgesia and allodynia related to neuropathic pain.39 Pathologic changes in cell bodies of injured neurons The ectopic discharge from injured fibers exhibits a rhythmic pattern that is caused by the emergence of sinusoidal subthreshold membrane potential oscillation and is maintained by depolarizing afterpotentials. Hyperpolarizationactivated “pacemaker” channels in the membranes of cell bodies of injured neurons are responsible for the spontaneous activity of neural A␤-fibers. These channels, which are permeable for sodium and potassium ions, also are responsible for part of the spontaneous activity in A␦-fibers. Blockade of these pacemaker channels reduces mechanical allodynia.

Physical examination and diagnosis A careful and detailed neurological examination is of crucial importance, because the diagnosis of neuropathic pain can be derived only from a detailed history and physical examination. Neuropathic pain generally has distinctive characteristics that can be elicited by a thorough pain history, thereby differentiating it from nociceptive pain. Patients frequently describe their pain as tingling, burning, stabbing, or electrical. On occasion, patients mention that they cannot tolerate contact with clothing and women may stop using a bra to avoid the pressure and contact to their skin.40 A careful medical history and sensory examination should be directed toward discovering abnormal sensations that include hypoesthesia (a numbness or lessening of feeling), paresthesias (spontaneous abnormal nonpainful sensations such as tingling, cold, or itching), dysesthesias (spontaneous abnormal painful sensations such as burning, stinging, shooting, lancinating, or shock-like feelings), hyperalgesia (increased perception of painful stimuli), hyperpathia (exaggerated pain response), and allodynia (pain induced by nonpainful stimuli such as light touch, cool air).41 These abnormal sensations are outlined in Table 26.1. Reduced vibration sense or decreased proprioception may reveal involvement of long fibers, as seen with cisplatin chemotherapy. The presence of mechanical allodynia can be determined by a gentle stroke with a cotton ball. Thermal allodynia can be tested with a cool reflex hammer or a tuning fork gently applied to the putatively affected area

neuropathic pain Table 26.1. Somatosensory abnormalities commonly seen in neuropathic pain Dysesthesias

Paresthesias Hyperalgesia Hyperpathia

Hypoesthesia Allodynia Numbness Prolonged after sensations

Abnormal sensation to normal stimuli. It can be provoked by touch and cold and in occasions can be painful. Patients refer to these as shooting, burning, stinging, lancinating, and shock-like. Abnormal sensations that occur in the absence of a stimuli. They are painless, spontaneous, and intermittent. Increased perception of painful cold, heat, or mechanical stimuli. Abnormal pain sensation evoked in an area with increased threshold for other sensory modalities. It is described as explosive and severe. Decreased feeling to sensory stimuli, sometimes accompanied by increased pain threshold. Pain induced by nonpainful stimuli (e.g., light touch, cool air, contact with clothing) Abnormal sensation to touch. May occur with normal threshold to touch. More common in central pain.

for a few seconds. Mechanical hyperalgesia can be tested with a disposable safety pin used to gently prick the area in question. With a careful examination of the affected region, two distinct areas can be delineated in some patients. The area of primary hyperalgesia is characterized by the presence of heat and mechanical allodynia, but not cold allodynia, which delineates the area of the lesion. The presence of cold allodynia in addition to mechanical and heat hyperalgesia/allodynia in the periphery of the area of primary hyperalgesia suggests the presence of central sensitization, which is called secondary hyperalgesia. Deep tendon reflexes may be decreased or absent. The motor examination may be significant for distal weakness, which is more common in peripheral neuropathies, as opposed to proximal weakness, which is more characteristic of myopathies (e.g., corticosteroids). A foot drop is another common finding in peripheral neuropathies. Shingles or zoster (herpes zoster) is a painful cutaneous blistering eruption that occurs more frequently in cancer patients. It is the result of reactivation of a prior varicella (chickenpox) infection. The quality of the pain (e.g., lancinating, burning, itching) and the dermatomal distribution help define it as neuropathic. It is occasionally followed by a chronic neuropathic pain called postherpetic neuralgia (PHN). These acute and chronic neuropathic pain syndromes illustrate the importance of locating the distribution of pain. The dermatomal distribution of the rash and the pain

483 are defining characteristics, as the reactivated virus travels from the spinal nerve root to the skin. Another pain syndrome that occurs in a band distribution on the chest is caused by a nerve root being compressed by a collapsed vertebral body secondary to metastatic disease. The collapsed vertebral body creates pressure on the spinal nerve roots, resulting in this radicular distribution of pain. If the lesion is in the lumbar spine, it may cause pain radiating to the internal aspect of the thigh (L2–3), the posterior aspect of the leg down to the dorsum of the foot involving the big toe (L4–5), or the bottom of the foot (L5–S1). When the cervical spine is involved, the pain radiates in the internal aspect of the arm to the small finger (C8) or the thumb (C6). The pain in patients with a lesion to the CNS (e.g., stroke, myelopathy) does not follow a dermatomal or a radicular distribution but tends to involve the entire limb. This type of pain is called central, and patients may complain of pain in the entire hemibody contralateral to the site of the lesion. A glove-and-stocking distribution of pain and sensory abnormality may be seen in patients undergoing chemotherapy with cis-platinum, carboplatin, or vincristine. This syndrome characteristically involves the long axonal fibers, and accordingly, although light touch and proprioception are affected, temperature and pinprick sensation are spared. These patients may have a clear worsening of gait with frequent falls. Paraneoplastic syndromes also may present with a glove-and-stocking distribution of sensory symptoms but tend to affect both long and short fibers. Inquiry should be made regarding variation in the quality and intensity of the pain over the course of the day. As pain is usually worse at night, this should be a factor when administering medications over a 24-hour period. When there is sympathetic involvement, patients may complain of “freezing” of the limb, whereas objective changes in temperature may be only minimal. The opposite, increased temperature in the limb, is also sometimes reported.

Impact of neuropathic pain on quality of life Neuropathic pain generally has been associated with a negative impact on patients’ quality of life. Because it is pain that may be challenging to treat, it may require patients to learn to cope either with some degree of discomfort that may not be fully relieved by treatment or with undesired side effects from treatment.42 A cross-sectional study of a Spanish patient population investigated the impact of neuropathic and mixed pain under standard care conditions on overall functioning and health-related quality of life (HRQOL).43 Results showed a significant association between both neuropathic and mixed pain and impaired

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physical and mental functioning. A recent review44 examined 52 studies exploring the relationship between neuropathic pain and HRQOL. Results showed that neuropathic pain is associated with impairment in a number of domains related to quality of life. However, the severity of impact depends on the sensitivity of the measures used and the domains assessed. The implications of these findings indicate the importance of selecting appropriate measures that can fully reflect the quality of patients’ experience in various domains of physical and emotional functioning related to quality of life. A British study45 used qualitative methodology to explore the impact of pain on patients’ daily activities and gathered information on the strategies they use to deal with pain. It was found that although the use of conventional medicine was the most common management strategy, many patients reported use of complementary and alternative therapies, even when they were ineffective. Additionally, some patients reported that a lack of psychological and social support prevented them from being able to learn to accept their pain and live with it. The aforementioned studies indicate the importance of an accurate psychosocial assessment of patients to identify those who may benefit from structured psychological interventions and/or psychosocial support.

Neuropathic pain syndromes caused by direct tumor involvement

Malignant plexopathy Cervical, axillary, para-aortic, or retroperitoneal lymph nodes may infiltrate their respective plexus, resulting in cervical, brachial, or lumbosacral plexopathy. Because of the close proximity of lymph nodes and the nerve plexus, plexopathy is a common feature of patients with advanced lymphoma. Pain is the most common symptom, followed by muscle weakness and sensory abnormalities.48 Rapidly developing excruciating pain and neurologic deficit usually point to a neoplastic etiology, whereas a more insidious onset of mild symptoms may indicate radiation-induced plexopathy.

Disease-related peripheral neuropathy Peripheral neuropathy is a classic complication in the course of IgM paraproteinemia such as Waldenstr¨om’s macroglobulinemia, occurring in 5%–10% of patients.49 The paraprotein reacts with neural antigens, resulting in demyelination. The resultant neuropathy manifests as a sensory syndrome with distal numbness, paresthesias, reduced proprioception, and Romberg sign, and progresses gradually. Tremor, generalized areflexia, and gait ataxia also are common findings. Limb weakness develops in most cases but rarely overshadows the sensory findings.50,51 Between 3% and 5% of patients with multiple myeloma develop a diffuse, progressive sensorimotor polyneuropathy; 50% of these cases are associated with amyloid production.

Spinal cord compression Spinal cord compression is a relatively common occurrence in patients with vertebral metastases. Involvement of vertebral bodies with extradural compression of the spinal cord or its nerve roots is also an important complication of multiple myeloma. Paraspinal or retroperitoneal lymph node involvement may lead to spinal cord compression in lymphoma patients. Approximately 4% of lymphoma and 11% of myeloma patients develop spinal cord or cauda equina compression during the course of their illness.46,47 Radicular pain (often aggravated by coughing, sneezing, or straining), night pain, and an exacerbation of known back pain are early signs that occur in approximately 50% of patients before the development of muscle weakness. This condition is a medical emergency that requires immediate investigation via MRI. Because neurological outcome is determined by the level of impairment before treatment, early recognition is critical. Once motor weakness is established, it may be irreversible.

Neuropathic pain syndromes secondary to cancer treatment Neuropathic pain syndromes secondary to cancer treatment are listed in Table 26.2. Postmastectomy pain syndrome Postmastectomy pain syndrome may occur after any surgical procedure on the breast, including lumpectomy, mastectomy, or axillary node dissection.52 The prevalence of pain after such procedures is caused by the injury to the intercostobrachial nerve, a cutaneous branch of T1–2. Pain may begin immediately after surgery or after a pain-free interval, and may persist for years. Patients typically describe aching or burning pain in the axilla, medial upper arm, and/or anterior chest wall, often with superimposed shock-like pains and allodynia.

neuropathic pain Table 26.2. Neuropathic pain syndromes secondary to cancer and cancer treatment Chemotherapy-induced neuropathy Cisplatin Oxaliplatin Paclitaxel Thalidomide Vincristine Vinblastine Cranial neuropathies Jugular foramen syndrome Complex Regional Pain syndrome (CRPS) Type I (RSD) Type II (Causalgia) Direct nerve lesion (tumor infiltration, compression) mononeuropathies Plexopathies Brachial Lumbosacral Radiculopathy Leptomeningeal disease Neuralgia post herpetica Radiation induced plexopathy Post-surgical procedures Phantom pain Post-mastectomy syndrome Post-thoracotomy syndrome Radical neck dissection Neuroma formation

Postradiation plexopathy In patients who have been treated with radiotherapy, the appearance of plexopathy may be a result of irradiation and not the underlying disease. Symptoms usually do not occur until after a latent period of 6 months, although the interval may be much longer, sometimes many years. Slowly progressing symptoms, electromyographic recording of myokymic discharges, and absence of a space-occupying mass in MRI-imaging studies suggest radiation-induced plexopathy. Pain is usually milder than in disease-related plexopathy. Pain syndromes resulting from chemotherapy Several chemotherapeutic agents may produce a painful peripheral neuropathy, generally associated with distal sensory loss and weakness. Because most hematology patients are treated with chemotherapy protocols until shortly before they die, chemotherapy-induced peripheral neuropathy may be a significant problem. Even though part of the nerve damage might be reversible over time, most of these patients will not live to see the effects of nerve regeneration. Preexisting nerve damage,53 such as diabetic or alcoholic neuropathy or

485 disease-related peripheral neuropathy, may add to the risk of chemotherapy-induced neuropathy. Assessment relies mainly on patient report and clinical examination, because there is no technical method available for detecting and evaluating neuropathy at an early stage. Extrapolating from studies in noncancer patients with peripheral neuropathy is a common approach to treating patients with chemotherapyinduced peripheral neuropathy. However, caution should be exercised. A double-blind, placebo-controlled study in cancer patients with chemotherapy-induced peripheral neuropathy produced no improvement in pain in those treated with up to 100 mg/day of nortriptyline, whereas this is an effective treatment for patients without cancer suffering from peripheral neuropathy. These results suggest that there may be substantial differences in the underlying physiopathology of the two entities.54 Several chemotherapeutic agents have been identified as neurotoxic at the level of the CNS, the peripheral level, or a combination of the two.55 Oxaliplatin Oxaliplatin is a relatively new agent recently approved by the U.S. Food and Drug Administration for the treatment of colon cancer. It has been observed that this agent can produce dose-dependent peripheral neuropathy characterized by paresthesias and dysesthesias.56 A unique, frequent, acute sensory neuropathy triggered or aggravated by exposure to cold that resolves rapidly occurs in 80%– 85% of patients, whereas chronic symptoms are reported by 16%.57 The acute neurologic symptoms reflect a state of peripheral nerve hyperexcitability that is suggestive of a transient channelopathy.58 With cumulative doses of 1020 mg/m2 , peripheral neuropathies of grades 1, 2, and 3 have been observed in 48%, 31%, and 12% of patients, respectively.59 A long-term follow-up study reported persistent nerve conduction abnormalities a year after the last treatment, whereas the results from motor studies remained normal.60 This is an important finding, because the addition of bevacizumab to oxaliplatin in combination with infusional 5-fluorouracil/leucovorin (FOLFOX, FUFOX) for advanced colorectal cancer could conceivably prolong progression-free survival. However, that neurotoxicity rather than tumor progression could become the dominating treatment-limiting issue in first-line therapy for these patients. Cisplatin Cisplatin is often substituted with other, less toxic derivatives but is still very useful, particularly in head and neck cancer. Peripheral neuropathy occasionally results from

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cumulative doses of as little as 200 mg/m2 and is usual after 400 mg/m2 . The degree of neuropathy correlates directly with the cumulative dose of platinum and with each individual dose.61 The peripheral neuropathy starts with tingling, which occasionally is painful, in the toes and later in the fingers. It then spreads proximally to affect both legs and arms. The deep tendon reflexes disappear (ankle jerk first), and proprioceptive loss may be so severe that patients become unable to feed themselves and walk. Nerve conduction study findings are consistent with sensory axonopathy (decreased conduction velocities and diminished amplitude of sensory nerve potentials). The first neuropathic symptoms may not appear until cisplatin treatment is completed and may progress for several months before stabilizing. DRG neurons are probably the primary site of pathology. Pathologic examination of nerve roots reveals axonal loss with secondary demyelination. Axonal loss is observed in dorsal (sensory) but not ventral (motor) roots, with secondary degeneration of posterior columns. It has been suggested that a careful clinical evaluation combined with a detailed electrophysiological evaluation of the patient before the chemotherapy could predict the final neurological outcome of the cisplatin- or/and paclitaxel-based chemotherapy.62 Vincristine Vincristine is the most neurotoxic of the vinca alkaloids. Although it primarily affects the peripheral nervous system, it also may cause CNS toxicity. Almost all patients show a dose-limiting sensorimotor neuropathy that starts with tingling and paresthesias of the fingertips followed by the toes, and loss of ankle reflexes. Fine movements often are impaired. Motor weakness is typical at the dorsiflexion of the feet (unilateral or bilateral foot drop) and wrist extension. On occasion, motor weakness may develop months after the treatment has been completed. Infrequently, the neuropathy may involve the cranial nerves and the patient may develop ophthalmoplegia, vocal cord paralysis, and ptosis. Nerve conduction studies and biopsy findings, although rarely needed, are consistent with axonal neuropathy. It has been observed that the nutritional status, abnormal liver enzymes, and other chemotherapeutic agents (etoposide, teniposide, cyclosporine) may enhance toxicity. The sensory symptoms, weakness, and loss of reflexes are reversible, although recovery may take as long as several months after stopping chemotherapy. Paclitaxel Approximately 60% of patients receiving paclitaxel at doses of 250 mg/m2 develop hand and foot paresthesias.

Cumulative dosages greater than 1000 mg/m2 invariably are associated with gradual development of sensorimotor peripheral neuropathy that involves all sensory modalities. In most patients, the symptoms do not progress and may even resolve despite continued therapy, but in some patients, they may be dose limiting. Interestingly, itching may be a manifestation of neuropathy; it may sometimes produce proximal weakness of neuropathic rather than myopathic origin that may resolve or reappear with repeated treatments.63 Thalidomide The neuropathy produced by thalidomide depends on treatment duration and is seen most frequently with doses ranging from 25 to 1600 mg/day. The neuropathy is sensory axonal and in some cases has been reported to be nonreversible. In a more recent study, improvement was reported after treatment, suggesting that the site of the lesion is the axon rather than the DRG neuron itself.64 Summary With longer disease-free intervals because of advances in cancer therapy, quality of life has become increasingly important in selecting the right chemotherapeutic regimen for individual patients. At present, there is no specific treatment for toxic neuropathy, and in most cases the effects of neuropathic pain on quality of life are not reversible. Therefore, prevention or attenuation of toxic neuropathy remains a major goal. In addition, recent data suggest that a subset of patients, including those with a history of diabetes, those in whom neuropathy is present at the time of chemotherapy, and patients receiving high-dose regimens, are at higher risk for developing neuropathy. Because the development of neuropathy is often the dose-limiting factor, the prevention of this toxicity might allow the use of higher doses of chemotherapeutic agents and potentially improve their efficacy.65 Oxaliplatin in addition to FOLFOX has become a firstline treatment for colon cancer. Oxaliplatin can induce acute cold-triggered painful neuropathy (self-limiting) and cumulative chronic neuropathy, which are seen most frequently in patients who received ≥540 mg/m2 . It has been suggested that the neuropathy is induced by the liberation of the metabolite oxalate, which alters the normal functioning of neuronal voltage-gated sodium channels. The effect of calcium and magnesium, which are oxalate chelators, was studied in a double-blind placebo-controlled study in 161 patients. Ninety-six patients were infused with 1 g of calcium gluconate and magnesium sulfate before and after oxaliplatin infusion. Only 4% of patients withdrew because

neuropathic pain of neurotoxicity in the calcium/magnesium group, versus 31% in the control group. In this study, calcium and magnesium solutions reduced the severity of symptoms without affecting tumor response to chemotherapy.66,67 Because of its toxicity, cis-platinum has been replaced by carboplatin in most chemotherapy regimens, but it is still used for the treatment of head and neck cancer. Peripheral neuropathy secondary to cis-platinum is well documented. Once the neuropathy has developed, it cannot be reversed. Some degree of protection against the development of peripheral neuropathy induced by cis-platinum has been reported with an adrenocorticotropic (4-9) hormone analogue (ORG 2766), the radioprotective agent WR 2721, and nimodipine, which delayed development of neuropathy and increased tolerability of higher doses of vincristine or a combination of cisplatin and paclitaxel in a rat model. Phase II and III clinical trials have evaluated the effect of recombinant human NGF in patients with HIV and those with diabetic peripheral neuropathy. In addition, gangliosides, glutamic acid, isaxonine, prednisone, pyridoxine, folic acid, and ORG 2766 induced some improvement in vincristine-associated toxic peripheral neuropathy. However, none of these strategies is used routinely in clinical practice.13 Low levels of vitamin E were reported after two to four cycles of cisplatin, and a correlation with neuropathy was suggested.68 The neuroprotective effect of vitamin E on neuropathy induced by cisplatin, paclitaxel, or their combination was tested in a pilot randomized open-label controlled trial with blind assessment. The mean peripheral neuropathy scores were 3.4 ± 6.3 for the treatment group and 11.5 ± 10.6 for the control group (P = 0.026). These data suggest that vitamin E supplementation in cancer patients may have a neuroprotective effect.69 A recent report suggests a possible role for topiramate and venlafaxine in oxaliplatin-induced disabling, permanent neuropathy.70

Other neuropathic pain syndromes Complex regional pain syndrome Complex regional pain syndrome (CRPS) is a condition characterized by spontaneous pain, allodynia, hyperalgesia, edema, and trophic changes of the skin and nails with or without sympathetic involvement. This syndrome was initially named reflex sympathetic dystrophy (RSD) in reference to the sympathetically mediated responses that were observed in the affected body part. Later, a second syndrome with symptoms similar to those of RSD, but caused by nerve injury, was described and named causalgia. In an

487 effort to clarify the syndrome, a change in taxonomy was adopted in 1992 and it was named complex regional pain syndrome types I and II. CRPS type I (formerly known as RSD) is caused by injury to non-nerve tissue, whereas in CRPS II (causalgia), a clear history of nerve injury can be documented. This classification is not mechanistic and does not take into consideration the presence or absence of sympathetic features. Hence, CRPS types I and II may present with or without sympathetic involvement. This is in contrast to the old classification, in which sympathetic compromise was part of RSD. Although there are several reports of CRPS in cancer patients, this condition is frequently undiagnosed. Because of mixed presentations in this patient population, specific signs of CRPS may be unrecognized. As an example, patients with Pancoast syndrome who present with a red, swollen arm may be diagnosed with venous stasis and plexopathy without CRPS being considered as a differential diagnosis. The mechanical pressure of the tumor on the plexus can cause CRPS to develop in this subgroup of patients. Because CRPS can be triggered by trauma, surgery, or immobilization of a body part, cancer patients are at risk. As a result of the lack of correlation between the intensity of the pain and the triggering trauma (which on occasion cannot be found at all), it is usually misdiagnosed or undertreated. Surgery and trauma are the most common culprits. However, it is unclear why some patients develop this condition whereas others undergoing similar procedures do not. The clinical presentation is characterized by acute onset of pain that does not follow the distribution of a root or nerve. It is more common in the upper extremities than the lower ones and may involve the entire arm or only the hand. The affected area may not show visible changes initially, but a careful neurological examination may reveal hyperalgesia and allodynia. If these changes are not present, the diagnosis should be revised. These findings are not constant and do not define the syndrome. When abnormalities of the sympathetic nervous system are detected, the syndrome is said to have “sympathetically mediated pain.” The skin of the area involved may show changes in coloration that may alternate between redness and paleness. The temperature of the affected area also is unstable. The same area may present with a decrease in temperature at one visit, whereas on other occasions, it may demonstrate an increase in temperature. In cases for which the diagnosis is difficult to determine, a temperature probe is applied and small differences in temperature can be detected. The syndrome, for prognostic purposes, has been divided into four phases. In the early stages, only pain and mild changes in temperature are observed during the

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neurologic examination. In advanced disease, atrophy of the skin and nails, muscle atrophy due to disuse, and changes visualized on a three-phase bone scan become apparent. A three-phase bone scan has been advocated as a diagnostic tool. However, the third phase is positive in only 20%–30% of cases during the initial stages, so negative findings on the scan do not rule out the condition. Paraneoplastic syndromes Paraneoplastic syndromes may be defined as neurologic abnormalities not caused by the spread of cancer but are commonly described as the remote effects of cancer on the nervous system. They can affect any portion of the nervous system, with both central and/or peripheral components. Although the incidence of paraneoplastic syndromes is low, it is important for clinicians to recognize them because the neurologic symptoms may precede and signal the diagnosis of systemic cancer. They also should be differentiated from metastatic disease, metabolic or nutritional disorders, and cancer treatment–related side effects. It has been reported that most peripheral neuropathies in patients with lung cancer are likely related to weight loss and nutritional disturbances and are not truly paraneoplastic. Sensory neuronopathy may be present when the spinal cord and DRG are involved. Encephalomyelitis may present as the result of multiple levels of CNS and peripheral nervous system involvement. When peripheral nerves are involved, it may be manifested as a subacute or chronic sensorimotor peripheral neuropathy, mononeuritis multiplex, brachial neuritis, peripheral neuropathy with islet cell tumors, or peripheral neuropathy associated with paraproteinemia. Subacute sensory neuropathy is a rare syndrome that is not limited to patients with cancer; it also may affect patients with autoimmune diseases. Symptoms typically begin in midlife, without a gender preference. When the neurologic symptoms precede the diagnosis of cancer, the diagnosis usually turns out to be small cell lung cancer. Among these patients, the majority of those who test positive for anti-Hu antibodies are women. The initial symptoms include dysesthesias and pain in the lower extremities. The symptoms may progress over days or weeks, eventually affecting all four limbs, the trunk, and occasionally the face. Subacute sensory neuropathy compromises all sensory modalities in contrast to cis-platinum, which spares pinprick and temperature sensations. The pathology is significant for inflammatory infiltration of the DRG with neuronal loss that may progress into the peripheral nerves and posterior horns and columns of the spinal cord.

Subacute sensory motor neuropathy can cause a predominantly distal symmetric polyneuropathy, which is more pronounced in the lower extremities and may precede a diagnosis of cancer by 3–5 years. Characteristically, patients demonstrate weakness and sensory deficits in a gloveand-stocking distribution. The course of the disorder tends to progress more rapidly in patients with cancer than in patients with other diseases, such as diabetes. Pathology is significant for axonal degeneration with lymphocytic infiltration of peripheral nerves and spinal root demyelination. In general, treatment of paraneoplastic syndromes is disappointing, and patients may be left with severe neurologic deficits. Phantom pain Phantom pain refers to the pain experienced where an amputated body part used to be. In the case of an amputated lower extremity, the patient may complain of excruciating pain in a missing foot that may be exacerbated by the imaginary movement of the missing leg. That the pain exists at all may be very disturbing to patients, who may think that it is impossible to have such sensations and, as a result, may begin to question their own sanity. The entity, first described by soldiers wounded during the Civil War in the United States, is frequently encountered in cancer patients. Classically, it has been described after a limb amputation (e.g., Edwin sarcoma) but also may occur after other surgical treatments (mastectomy, eye removal secondary to an astrocytoma, anus removal). The incidence of phantom pain correlates with the intensity of pain present before the amputation, and for that reason, preemptive therapy has been proposed. The pain improves spontaneously, with only 2% of patients suffering from this condition 1 year after surgery. A sign of improvement is the feeling that the limb is becoming shorter. The patient has the sensation in the distal part of the extremity immediately adjacent to the stump. This symptom, called telescoping, is an excellent prognostic sign. In addition to phantom pain, patients may have other pain syndromes. The stump itself may be painful to touch, suggesting a neuropathic component. The pain may be accompanied by redness, a change in temperature, and muscle trophism, indicating the presence of sympathetically mediated pain. After amputation, the surgeon buries the free end of a transected nerve into neighboring soft tissue structures to avoid pressure and irritation. Nonetheless, neuromas may form and cause extreme pain. A neuroma is the normal evolution of a sectioned nerve, and it is characterized by anarchic regeneration of the end of the nerve, in a phenomenon that has been compared with Medusa’s

neuropathic pain head. Removal of the neuroma may be helpful in certain cases, but it may regenerate with the same or worse symptoms. The literature indicates that when there are more than three interventions, pain almost never improves and may worsen. The pain tends to be localized in a specific area that corresponds to the underlying neuroma, and it can be reproduced or aggravated by pressing on it. Phantom pain also may be accompanied by neuropathic pain in the area of the surgical incision. Pain resulting from an amputated limb is a good model that can be used to review the various strategies available for the treatment of neuropathic pain because of the simultaneous occurrence of several types of pain that may require specific individual attention. The phantom pain itself may be helped by a combination of adjuvant analgesics (e.g., anticonvulsants, antidepressants), opioids, and rehabilitation. The patient is encouraged to exercise the missing limb, resulting in better pain control, presumably as a result of normalization of the changes in plasticity at the level of the sensorimotor cortex that resulted from the amputation.71–76 Physical therapy of the amputated limb may be difficult for the patient because he/she cannot visualize the missing body part. To facilitate the therapy, the patient can use a box with mirrors inside that are placed so that the patient can visualize an image where the missing limb would be. The visualization of the limb allows the patient to perform motor exercises.77–81 The pain caused by the neuroma may improve with injections of local anesthetics to the site of the pain. Surgical exploration of the stump to release the free nerve ending from pressure or to bury it in the surrounding muscles to protect it from microtraumas may be helpful as well. Local application of topical lidocaine to the stump can improve local pain. A block with local anesthetics of the sympathetic structure that innervates the affected area (e.g., satellite ganglia for the upper extremity) may alleviate the component of sympathetically mediated pain, if present. In addition, if the pain is refractory to medications, a plexus infusion may allow temporary release. Spinal cord stimulation is a treatment option for phantom pain that is localized in a limb. Patients who achieve a degree of relief with opioids but experience severe side effects may benefit from a trial of intrathecal opioids and adjuvants (e.g., clonidine, baclofen). Post–cerebral infarct pain In addition to the common causes of stroke in the general population (longstanding hypertension, poorly controlled diabetes), cancer patients have unique risk factors.

489 Interestingly, hypercholesterolemia is less frequently seen in these patients than in the general population. It has been speculated that poor nutrition and cachexia may result in the reversal of previously formed cholesterol plaques. Whatever the mechanism might be, various studies have shown that patients with malignant melanoma or breast or lung cancer presented with less atherosclerotic lesions in the circle of Willis than patients with nonmalignant diseases. Cerebral infarct may involve arterial or venous territories (more commonly, the venous sinuses). Infarct in the arterial territory is more commonly embolic in nature, including bacterial or fungal endocarditis, nonbacterial thrombotic endocarditis, tumor, mucin, fat, bone marrow, and calcified valves. Disseminated intravascular coagulation occurs in as many as 75% of patients with disseminated disease, particularly leukemias, although it also may be seen in patients with breast or lung cancer. In autopsies, 1%–2% reveal brain involvement. Although many structures may be affected, the superior sagittal sinus is most frequently involved. Once the coagulation factors are dissipated, the infarct may become hemorrhagic. Hypercoagulability may be secondary to chemotherapy with l-asparaginase, with the mechanism apparently being depletion of antithrombin III by l-asparaginase. Although the classical description of post-stroke pain is pain that occurs in a stroke that involves the thalamus, virtually any stroke can produce chronic central pain. Of the patients who survive the event, 20% may experience pain in the area affected by the stroke. The pain does not follow a radicular or nerve distribution and may be extremely severe and refractory to treatment. Affected patients report classical symptoms of neuropathic pain, such as allodynia and hyperalgesia. Herpes zoster and postherpetic neuralgia Herpes zoster results from reactivation of the varicella zoster virus that remains dormant in DRG neurons after chickenpox infection in childhood. For unclear reasons, reactivation occurs in about 1% of immunocompetent individuals and 10% of immunocompromised patients, with an increased incidence with age. In 90% of cases, it resolves in days to weeks, but 10% of patients progress into a debilitating, chronic, painful condition known as PHN. The virus replicates in the DRG, causing an inflammatory response with swelling, hemorrhage, areas of necrosis, and neuronal loss. Subsequently, the virus travels centrifugally along the nerve (producing in its wake nerve inflammation and damage), to the skin, where it forms a self-limiting rash known

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as “shingles.” In 50% of immunocompromised patients, this cascade produces a generalized life-threatening viral dissemination involving the CNS. The most commonly affected areas are the thoracic dermatomes, preferentially T10. The ophthalmic branch of the trigeminal nerve is the most commonly affected cranial nerve, and on occasion, the virus invades the eye, producing keratitis and/or uveitis. Aggressive treatment is crucial to avoid subsequent scarring and compromised vision. In addition, involvement of cranial nerves III, IV, and VI with palsies occurs frequently. When shingles affect the ear, a condition known as Ramsay Hunt syndrome, they can cause facial paralysis, hearing loss, and vertigo. Inspection of the external auditory canal may reveal blisters in the tympanic membrane. Herpes zoster usually starts with a prodromal phase characterized by pain, paresthesias (numbness/tingling), and dysesthesias (unpleasant sensations) in the affected dermatomes in a “belt-like fashion” that does not cross the midline. A few days later, a maculopapular rash develops, which evolves into vesicles that usually scab within 10 days and heal in a month. Sometimes the prodrome has no cutaneous involvement (zoster sine herpete). When lesions do form, they are not contagious after the scab forms. Once resolved, the scarred areas are less sensitive than normal skin and often anesthetic. During active infection, the skin may exhibit marked superficial pain with light touch (allodynia) or an increased sensitivity to noxious stimulation (hyperesthesia). The normal progression is resolution of the vesicles accompanied by decreased pain. PHN is the most common complication of herpes zoster. This self-limiting condition is defined as pain persisting beyond 3 months after the resolution of the skin lesions. The symptoms may be very intense and disabling. Antiviral therapy in combination with amitriptyline early in the initial viral infection may reduce the incidence of progression into PHN.82 Symptoms tend to abate over time. Less than 25% of patients still experience pain 6 months after the herpes zoster eruption, and fewer than one in 20 has pain at 1 year. Patients may complain of a steady burning or aching pain with or without paroxysmal lancinating pain. Both may occur spontaneously and may be aggravated by even the lightest contact. It is not unusual for patients to report that they cannot tolerate contact with clothing or the bed sheets at night. Some have to stay away from fans or air conditioning; even the light breeze provoked by fast walking can cause significant discomfort. Lack of allodynia in the early stages of herpes zoster infection is a predictor of good recovery by 3 months.83

Physical activity, temperature change, and emotional upsets may exacerbate the pain. The patient’s quality of life may become severely affected, and depression may develop. The pain is caused by changes in the posterior horn of the spinal cord that lead to deafferentation and hypersensitivity. There is no role for antiviral therapy in treating PHN. For patients with a poor response to a pharmacologic approach, laminectomy and electrocoagulation of the dorsal root entry zone have been advocated. However, because this procedure is invasive and the pain may worsen as a result of additional deafferentation, it is not performed frequently. There is evidence that spinal cord stimulation may give some relief.

Management of neuropathic cancer pain Successful management of neuropathic cancer pain begins with a thorough evaluation of the pain complaint to establish an accurate diagnosis. It is particularly important to identify pain-producing lesions that may respond to antineoplastic treatment so that such treatment may be initiated in a timely manner. For example, urgent decompressive surgery or radiation may protect neurologic function and relieve pain in epidural spinal cord compression, and focal radiotherapy may be effective in radicular pain from leptomeningeal metastases. Patients whose neuropathic pain had responded to opioid treatment in the past but who later experience increased pain intensity, the change in pain characteristics must be comprehensively reassessed as the initial step in management. The goal is to determine whether specific contributing factors can be identified that could be amenable to primary therapeutic strategies such as chemotherapy and/or radiotherapy to address disease progression associated with loss of analgesic effectiveness. Other potential factors underlying the exacerbation of preexisting pain, such as cord compression, systemic or local infection, psychiatric disorders, and psychological distress, should be ruled out or addressed before nonspecific modification of the treatment strategy. Pharmacologic approaches Pharmacologic treatment represents the mainstay of neuropathic cancer pain management. Numerous medications have shown efficacy in the management of neuropathic pain. Many of these drugs are considered adjuvant analgesics; that is, the drugs were designed for indications other than pain but may be analgesic in certain circumstances. Few

neuropathic pain

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Table 26.3. Anticonvulsants used as adjuvant analgesics Drug

Daily dose

Dosing interval

Side effects

Mechanism of action

Evidence

Gabapentin

300–3600 (6000)

Sedation

Ca++ channel

CT

Carbamazepine

100–1600

Hyponatremia, neutropenia

Na+ channel

CT

Valproate

400–1200

At bedtime to four times daily Twice a day to four times a day Twice a day

Na+ channel

OLT

Phenytoin

100–300

Daily

Na+ channel

CT

Clonazepam Lamotrigine Topiramate Pregabalin

1–10 150–500 25–400 300–600

Twice a day Twice a day Twice a day Daily

Cl− conductance Na+ channel Na+ channel Ca++ channel

OLT CT CT CT

Oxcarbazepine

300–2400

Twice a day

Nausea, tremor, weight gain, hair loss, hepatic toxicity Ataxia, rush, sedation, neuropathy, gingival hyperplasia, hirsutism Sedation, addiction, tolerance Rush, Steven-Johnson syndrome Weight loss, renal calculi Sedation, attention and memory difficulties Dizziness, peripheral edema, weight gain, and somnolence

Na+ channel

OLT

Abbreviations: CT, controlled trials; OLT, open-label trials. Modified from Farrar and Portenoy.41

of these drugs have been evaluated specifically in cancer patients with neuropathic pain. Their potential usefulness is often extrapolated from studies in patients with chronic nonmalignant neuropathic pain. Anticonvulsants Originally, anticonvulsants (Table 26.3) were thought to be most effective in syndromes characterized by lancinating or paroxysmal neuropathic pain, such as trigeminal neuralgia. Recent data, however, support their usefulness in a broad variety of neuropathic pain syndromes, including PHN and peripheral diabetic neuropathy (PDN). Controlled studies show that as many as two thirds of patients obtain good pain relief.84 Gabapentin In two large controlled studies of patients with PDN and PHN, gabapentin was shown to be efficacious for the treatment of pain and its interference with sleep, mood, and quality of life.85,86 In an uncontrolled study of 22 cancer patients whose neuropathic pain was not completely controlled with opioids, the addition of gabapentin resulted in decreased pain in 20 patients.87 Gabapentin significantly reduced pain in 48% of patients with chemotherapyinduced peripheral neuropathy.88 Gabapentin is a chemical analogue of ␥ -aminobutyric acid (GABA) but does not act as a GABA-receptor agonist. It binds to a receptor site in the CNS, gabapentin-binding protein, and interacts with calcium channels in the CNS. It increases GABA synthesis and release, but its exact mechanism of action is still not fully understood. Gabapentin has an acceptable adverse effect profile, is not metabolized in the liver, and has no known

drug–drug interactions. The most common side effects are somnolence, dizziness, ataxia, and peripheral edema. Treatment usually starts with 100–300 mg/day, and dose titration continues until benefit occurs, side effects supervene, or the total daily dose is at least 2700–3600 mg/day. A slow titration of the dose is recommended in patients who are elderly, have renal impairment, or are receiving other CNSdepressant drugs. Some do not reach a maximal response until the dose is increased to 6000 mg/day or even higher. Dose adjustment is recommended in patients with renal impairment or those undergoing hemodialysis. The daily dose is usually administered in three equal parts, but if daytime sedation remains a problem, a single nighttime dose may be used for analgesia and sleep-related benefits. In patients taking antacids containing aluminium or magnesium, the administration of gabapentin should be separated by at least 2 hours. If required, the capsules can be opened and the contents mixed with water, fruit juice, and other beverages.89 Recent data suggest that gabapentin in combination with morphine produces more pain relief than each agent individually.90 Although this combination is used very commonly in clinical practice, the double-blind placebo-controlled three-arm study reported here provides the first evidence that supports this strategy. Pregabalin Pregabalin is a new anticonvulsant available in Canada and Europe that has been recently approved in the United States. Its mechanism of action is similar to that of gabapentin, but with more predictable pharmacokinetics. The dose ranges between 200 and 600 mg/day. A double-blind placebo-controlled study in patients with

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PDN showed significant pain improvement.91,92 Similar results were observed in the treatment of PHN, although the improvement was not significantly better than that achieved with traditional therapy. Withdrawal due to adverse events also was more frequent with pregabalin than with placebo.93 The most common adverse events were dizziness, peripheral edema, weight gain (not affecting diabetes control), and somnolence. A recent multicenter prospective study investigated the effect of a flexible-dose regimen of pregabalin on 55 patients with treatment-refractory neuropathic pain. Data showed a reduction of 24.6% in mean pain score over 28 days.94 In addition, patients reported significant improvement in sleep and psychological distress. Lamotrigine Lamotrigine, another new anticonvulsant, is effective for treating neuropathic pain and putatively acts by decreasing glutamate release through blocking presynaptic sodium channels.95,96 Several randomized studies suggest a role for lamotrigine in the treatment of nonmalignant neuropathic pain and trigeminal neuralgia.97,98 In a double-blind placebo-controlled study in 30 adult patients with central pain, it was shown that 200 mg/day of lamotrigine decreased pain by 50%.99 Various case studies have been described.100 Lamotrigine showed inconsistent effectiveness for painful diabetic neuropathy in two recent replicated randomized, double-blind, placebo-controlled trials conducted in 360 patients (per study).101 Patients were randomly assigned to receive 200, 300, or 400 mg/day or placebo during the 19-week trial period. Patients assigned to lamotrigine, 400 mg, reported greater mean reduction in pain intensity than the placebo group in only one of the two studies. Additionally, patients assigned to receive lamotrigine, 200 mg and 300 mg, did not differ from patients receiving placebo in either study. In both studies, the main reported side effects were headache and rash. However, the drug was generally well tolerated and safe. Another recent randomized, double-blind, placebocontrolled study102 investigated the effect of adding lamotrigine to an existing regimen of gabapentin, tricyclic antidepressant, and nonopioid analgesic for poorly controlled neuropathic pain. Results showed a nonsignificant difference between the treatment and placebo group. Although lamotrigine demonstrated a general pattern of safety and tolerability, it did not demonstrate efficacy as an adjunctive treatment of neuropathic pain. To investigate the efficacy of lamotrigine in the treatment of central pain due to multiple sclerosis, a randomized, double-blind, placebocontrolled, two-period, crossover pilot study was performed.103 Patients first underwent an 8-week double-blind lamotrigine titration period to a maximum of 400 mg/day,

followed by a 3-week maintenance period, then a 2-week tapering period. Between the two treatment periods, there was a 2-week washout period, at the end of which patients received the placebo. Results showed no significant difference between lamotrigine and placebo on outcome measures of quality of life and pain. Other anticonvulsants Oxcarbazepine, a metabolite of carbamazepine, has a similar spectrum of indications and better tolerability than the parent drug. Levetiracetam, topiramate, zonisamide, and tiagabine also demonstrate efficacy. Levetiracetam, gabapentin, and pregabalin have few drug–drug interactions. Carbamazepine, phenytoin, valproate, and clonazepam have been used for many years. Despite the high effectiveness of carbamazepine, its utility in the cancer population is limited by its potential to suppress bone marrow production, in as many as 7% of cases,104 and to alter the liver metabolism of other drugs. During the past few years, gabapentin has become the most commonly used first-line adjuvant analgesic to treat neuropathic pain. The onset of action varies, but a trial usually requires several weeks to allow for dose adjustment and determination of efficacy. Sequential trials of different agents may be needed to identify the most useful one. Clonazepam may be particularly useful if pain is associated with anxiety. Opioids The notion that neuropathic pain would not respond to opioid therapy was widely accepted and resulted in unnecessary suffering. Portenoy et al.105 reported that as many as 50% of patients with this condition may respond to this form of therapy. Since then, many studies have been published showing similar results. More recently, the importance of aggressive treatment for neuropathic pain with opioids has been addressed. Studies in amputees with phantom pain showed changes in the cortical representation of the missing limb. Indeed, the cortical representation of the amputated arm decreased while neighboring areas (mouth) took over that region. Flor and coworkers72 showed that the sensory cortical representation of the lips will extend into the missing limb’s cortical area and that this takeover correlates with increased pain. Of these patients, 50% responded to opioids and the reduction in pain correlated with reexpansion of the cortical representation of the missing limb. This study illustrates that aggressive opioid treatment of phantom pain (and perhaps other forms of neuropathic pain), can reverse plastic changes at the level of the sensory cortex. More studies are required to determine whether long-lasting

neuropathic pain phantom pain changes in plasticity are reversible. In the study by Flor, morphine was the opioid of choice; however, any opioid can be used for the treatment of neuropathic pain. The current recommendation by the World Health Organization106 – the so-called ladder approach – is an excellent strategy for the treatment of pain in this patient population, including patients with neuropathic pain. The recommendation is to start treatment with the least potent agent and switch to a more portent opioid if maximal dosing has been achieved and pain control is inadequate. All full opioid agonists (codeine, morphine, oxycodone, fentanyl, and methadone) have the potential to achieve a maximal therapeutic effect if there are no side effects and a gradual dose escalation can be accomplished. Methadone is an opioid that may produce an additional benefit compared with the classical mu agonists. In the United States, this agent is commercially available as a combination of the l- and d-enantiomers. The l-enantiomer produces analgesia through the activation of ␮-opioid receptors, whereas the d-enantiomer is a weak blocker of N-methyl-d-aspartate (NMDA) receptors. These receptors are activated by the naturally occurring excitatory amino acid glutamate and may be responsible for the development of allodynia and hyperalgesia, two cornerstone symptoms of neuropathic pain. In addition, Trujillo and Akil107 suggested a role for this excitatory neurotransmitter in the development of tolerance to opioids. Hence, methadone could be accomplishing two important functions at once: analgesia plus hyperalgesia blocking and prevention of tolerance. Because of methadone’s long-lasting effect and low cost, many pain specialists are beginning to use it as a first-line agent for the treatment of neuropathic pain. The recent reemergence of methadone as an analgesic justifies a more detailed discussion of its unusual properties. Although it was originally developed as an analgesic by the Germans during World War II, in the 1960s, it was introduced for the treatment of opioid addiction. Based on the work by Dole and Nyswander,108,109 which proposed that drug addicts had an endogenous deficiency of opioids and that opioid utilization was a way to supplement this deficiency, clinics were created to provide methadone to this patient population. In time, methadone became stigmatized and identified by patients and the general public as a drug for drug addicts and was largely eliminated from the pain armamentarium. When using methadone to treat pain, attention should be paid to the patient-to-patient half-life variability that may result in accumulation of the drug and toxicity. Additionally, methadone has been identified as a drug with potential

493 to prolong the QTc interval. This cardiac side effect was reported by Krantz and coworkers,110 who reported several cases of fatal torsades de pointes in intensive care unit patients receiving methadone. Some of the patients, however, had electrolyte abnormalities that could account for the tragic events. Most recently, Cruciani and coworkers111 studied more than 100 patients who had received a wide range of methadone dosages for pain treatment or maintenance (up to 1.5 g/day) and did not find a single case of torsades de pointes. Another study of intravenous (IV) methadone showed that the vehicle for this drug, rather the methadone itself, was responsible for the cardioelectrical abnormalities.112 For patients with cancer-related neuropathic pain and comorbidity of drug abuse who are currently enrolled in a methadone maintenance treatment program (MMTP), methadone can be prescribed for the treatment of pain in addition to using the maintenance dose. This strategy requires coordination with the patient’s counselor in the program. The patient continues going to the program and receives his or her dose on a daily or weekly basis, depending on the patient, so that the pain practitioner then prescribes methadone solely for the treatment of pain. The schedule includes additional prescribed methadone divided into three or four doses, which are separate from the patient’s daily morning maintenance dose. This additional amount of methadone may be titrated to pain and side effects, independently of the maintenance dose, which may remain constant. The adjustment of the maintenance program would be done by the MMTP clinic, using the usual criteria for the treatment of drug abuse. Several approaches have been described to facilitate the switch from morphine to methadone.113 In a recent publication, morphine was stopped and immediately substituted with methadone, using different methadone–morphine ratios based on the patients’ daily morphine doses: 1:4 (1 mg of oral methadone = 4 mg of oral morphine) for patients receiving less than 90 mg/day of morphine, 1:8 for patients receiving 90–300 mg/day, and 1:12 for patients receiving more than 300 mg/day.114 This changing equianalgesic ratio is based on the observation that the potency of methadone increases in patients with substantial prior opioid exposure. This observation may be explained by reversal of tolerance produced by the d-isomer. Antidepressants Although antidepressants are widely accepted as adjuvant drugs, there have been no randomized trials of these agents for cancer-related neuropathic pain. Most indications and recommendations for treatment have been extrapolated

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494 Table 26.4. Antidepressants used as adjuvant analgesics Drug

Daily dose

Dosing interval

Evidence

Tricyclic Antidepressants Tertiary Amines Amitryptiline 10–200 mg Daily CT Imipramine 10–200 mg Daily to twice a day CT doxepin 25–150 mg Daily to twice daily CT Secondary Amines Nortryptiline 20–80 mg Daily to twice a day CT Desipramine 10–300 mg Daily to twice a day CT Tetracyclic Antidepressant Maprotiline 25–225 mg Daily CT triazolopyridine derivatives Trazadone 50–200 Three times daily CR Selective Serotonin Reuptake Inhibitors Citalopram 20–80 mg Daily CT Fluoxetine 20–80 mg Daily CT Paroxetine 20–80 mg Daily CT Sertraline 50–250 mg Daily OLT Selective Serotonin/Norepinephrine Reuptake Inhibitors Duloxetine 60–120 mg Daily CT Venlafaxine XR 150–225 mg Daily CT Selective Norepineprine/Dopamine Reuptake Inhibitors Bupropion XR 75–150 mg Twice daily CT CT, controlled trials; OLT, open-label trials; CR, case report; XR, extended release.

from neuropathic pain in noncancer patients, such as those suffering from diabetes or PHN. Realistic goals should be discussed with patients, and they should be told that although their pain could improve, complete pain relief is unusual (Table 26.4). Tricyclics Tricyclic antidepressants have been found to be effective in the treatment of PHN and PDN independently of their antidepressant effects.115 Nortriptyline has been shown to be as effective as and better tolerated than amitriptyline in patients with PHN.116 In the treatment of PDN, desipramine seems comparable with amitriptyline. A recent crossover-design randomized controlled study of 25 patients with PDN compared amitriptyline with gabapentin, finding no difference in pain relief or adverse effects.117 However, clinical experience suggests a better tolerability of gabapentin, particularly in the elderly, in whom the anticholinergic side effects of the tricyclics are more pronounced. The most commonly used antidepressants are the selective serotonin reuptake inhibitors (SSRIs) because they are better tolerated by cancer patients than other antidepressants. Patients with metastatic disease and those undergoing cancer treatment may experience even more severe side

effects. Nonetheless, most of the data on chronic pain treatment are from studies with tricyclics used in patients with noncancer neuropathic pain, so if possible, these agents should be tried first. This group of medications may have severe side effects due to their anticholinergic properties. In a study of 15 patients with postmastectomy syndrome treated with amitriptyline, five of the eight women who had a good response did not want to continue receiving the drug because of adverse events (the order of importance being tiredness, dry mouth, and constipation).118 Urinary retention, confusion, and orthostatic hypotension are less common. Cardiotoxicity (e.g., conduction defects, arrhythmias) is very uncommon. Patients who have significant heart disease, including conduction disorders, arrhythmia, or heart failure, should not be treated with tricyclic antidepressants. Amitriptyline is the best studied and, on this basis, may be the best choice after a failed trial with gabapentin. Patients who are not able to tolerate the common side effects might be considered for a trial with a secondary amine tricyclic, such as nortriptyline or desipramine. The secondary amine tricyclic drugs are less anticholinergic and therefore better tolerated than the tertiary amines. They also are less likely to cause orthostatic hypotension, somnolence, and confusion. A trial with paroxetine or bupropion is appropriate for patients who cannot tolerate a secondary amine tricyclic drug or have contraindications to a tricyclic trial.119 To decrease the likelihood of side effects, tricyclics should be started with low initial doses. In the elderly and those predisposed to side effects such as hypotension, one might begin with 10 mg at night; in others, one might start with 25 mg at night. The dose should be increased every 2–3 days by the size of the starting dose. The optimal dose usually ranges from 50 to 150 mg. Dry mouth may be a good indicator that the drug is achieving a significant blood level. For higher doses, blood levels of the drug should be determined to avoid toxicity. Selective serotonin reuptake inhibitors Adverse effects are even less likely with the SSRIs (Table 26.2), but evidence of analgesic efficacy for these drugs is very limited. Another double-blind, placebo-controlled study showed that paroxetine, 30–70 mg/day, induces pain improvement in patients with PDN.120 The analgesic effect shown in both studies was independent of the antidepressive action. On the other hand SSRIs such us fluoxetine seem to be ineffective. To avoid side effects, the SSRI should be started at a low therapeutic dose, with the dose being increased after 1–2 weeks, based on the effect. Serotonin–norepinephrine reuptake inhibitors Several controlled studies suggest efficacy for drugs with a

neuropathic pain mixed mechanism of action (combined serotonin and norepinephrine reuptake inhibitors), such as venlafaxine, duloxetine, and bupropion (dopaminergic agonist). A doubleblind, placebo-controlled trial in diabetic patients with painful PDN showed a 50% improvement in those on extended-release (ER) bupropion at 150 mg administered twice daily.121 A double-blind, placebo-controlled randomized study in patients with PDN showed an improvement of about 50% in pain scores in patients taking duloxetine, 30–60 mg twice daily for 4 weeks.122 A multicenter, parallel, double-blind, randomized, placebo-controlled study123 investigated the effect of duloxetine, 60 mg once daily or 60 mg twice daily, on pain due to peripheral neuropathy in 348 patients. Both treatment groups reported significant improvement in 24-hour average pain score, with duloxetine being generally well tolerated. In another recent randomized, double-blind study,124 patients were randomly assigned to duloxetine, 60 mg once daily; duloxetine, 60 mg twice daily; or placebo, for 12 weeks. Results showed significant improvement in 24-hour average pain severity with duloxetine, 60 mg once daily and 60 mg twice daily, compared with placebo. Both doses were safely administered, with nausea, somnolence, dizziness, and fatigue being the most frequently reported side effects. A slightly higher rate of side effects was reported with duloxetine, 120 mg/ day. A double-blind, placebo-controlled study investigated the effect of venlafaxine ER on diabetic neuropathy.125 Patients were randomly assigned to receive venlafaxine ER, 75 mg/day; venlafaxine ER, 150–225 mg/day; or placebo, for 6 weeks, with doses being titrated during the first 3 weeks. At week 6, patients in the venlafaxine ER, 150– 225 mg/day, group reported significant improvement as measured by scores on visual analogue scales of pain intensity and pain relief compared with the other two groups. The most commonly reported adverse effects were nausea and somnolence. Failure to respond to one type of antidepressant does not predict a failure to respond to another. In the case of poor response to a particular agent, a rotation to another antidepressant of the same or different class should be attempted. If the reason for the rotation is intolerable side effects, particularly if observed at low doses, a rotation to a different class of antidepressant may be preferable. If there is no major benefit (e.g., pain reduction ⬎50%) despite reasonable doses and length of trial (4–6 weeks), or if the side effects are substantial despite gradual dose escalation, the antidepressant should be discontinued. Withdrawal symptoms and insomnia may occur following discontinuation of antidepressants, so the drug should be tapered over the course of at least 1 week. However, the antidepressant

495 should be continued if the patient shows signs of depression. There is a high comorbidity of depression in patients with chronic pain and cancer. There has been considerable speculation regarding the mechanism involved in the analgesic effect of antidepressants. An overview of the pathways involved in pain mechanisms and the interaction with serotonin and noradrenergic pathways may help clarify the issue. Primary afferent fibers (A␦- and C-fibers) synapse in the posterior horn of the spinal cord with the projection neurons that eventually convey pain information to the thalamus and from there to the sensory cortex. The neurotransmitters involved in this pathway are glutamate and substance P. As a response to noxious stimuli, these neurotransmitters are released and excite selective postsynaptic receptors, facilitating the transmission of pain signals. The synapse is modulated negatively by enkephalins that are released from interneurons localized at the same level. The enkephalins bind to both pre- and postsynaptic opioid receptors. This binding abrogates the release of glutamate and substance P by the primary afferent neuron and decreases the responsiveness of the postsynaptic neurons, respectively, hence decreasing pain information. It is noteworthy that interneurons are modulated by descending pathways with cell bodies localized in the periaqueductal gray area (brainstem). Normally, this pathway is inhibited by GABA (an inhibitory neurotransmitter), so enkephalins are not released and pain transmission occurs. However, as a response to pain, the descending pathway is disinhibited and enkephalins are released to the interphase. This release decreases the response to glutamate and substance P, which ultimately results in the transmission of less pain information. The descending pathway utilizes norepinephrine and serotonin as neurotransmitters. Because the antidepressants increase serotonin and/or norepinephrine levels, it has been postulated that the release of descending pathways by the antidepressant is the mechanism by which it has an analgesic effect independently of its antidepressant properties. Moreover, amitriptyline has been shown to increase the plasma concentration of morphine in cancer patients. Systemically administered local anesthetics The use of local anesthetics for nerve blocks is a common practice; however, IV infusion for the treatment of neuropathic pain is used less frequently. Intravenous lidocaine has been found to be useful for patients with neuropathic pain due to phantom limb pain, diabetic neuropathy, and herpes zoster, which are all conditions that may be found in cancer patients.126 In patients with pain crisis, it can be used to “break the cycle.” In some centers, IV trials with

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local anesthetics are used to identify responders, who are then placed on long-term therapy with equivalent oral formulations. The mechanism of action is unclear but seems to be related to stabilization of membranes through blockade of sodium channels with the subsequent interference of initiation and propagation of nerve fiber depolarization. Lidocaine is used most commonly for systemic infusion via the subcutaneous (SC) or IV route. The rapid onset of effect makes it useful in the treatment of patients with severe, rapidly progressing neuropathic pain. Baseline laboratory work that includes basic electrolytes, liver function tests, and an electrocardiogram should be done. With monitoring, 1–2 mg/kg of lidocaine is infused over 30 minutes in an IV line. Because a dose response can ensue, a prudent approach involves an initial low-dose infusion, which if unsuccessful, is followed by infusions at incrementally higher doses. The dose is repeated every 10 minutes up to a dose of 100 mg for the adult patient. The effect of a lidocaine infusion may last 3–21 days. For patients needing frequent IV lidocaine infusions, a continuous SC infusion of 1–2 mg/kg/hour of lidocaine may be considered. A plasma concentration of 2–5 ␮g/mL should be achieved to determine whether lidocaine is effective. Common side effects of lidocaine are neurologic (paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions) or cardiovascular (bradycardia, hypotension, and cardiac arrhythmias). Patients with a history of myocardial dysfunction or arrhythmia may be at increased risk of serious cardiac events and should undergo an appropriate cardiac evaluation before local anesthetic therapy is initiated. Given the increased risk of arrhythmias, tricyclic antidepressants should be stopped at least 48 hours before starting lidocaine or mexiletine. Verbal analogue scores are recorded before and after the trial is completed. Some clinicians advocate that a decrease of 50% or more in pain scores warrants a trial with an oral local anesthetic (mexiletine). The data are inconsistent, but a select group of patients can experience a significant improvement using this strategy. In a prospective study, pain relief following an IV lidocaine test correlated with the subsequent response to mexiletine.127 On the other hand, in a pilot study evaluating oral anesthetics for the treatment of cancer-related neuropathic pain, 90% of the patients did not benefit from the treatment and five of eight patients experienced intolerable nausea/gastrointestinal distress.128 The trial medication delivered by the oral route is started with a dose of 150 mg at bedtime, and if tolerated, the dose is increased to a threetimes-a-day schedule. Titration of the dose should be at 150-mg increments every 3–7 days, with a maximum

dose of 1200 mg/day. Mexiletine may have significant side effects, such as gastrointestinal distress/nausea, dry mouth, and CNS symptoms, including sleep disturbance, headaches, and drowsiness. Treatment usually involves the infusion over 30 minutes of a dose that ranges between 2 mg/kg and 5 mg/kg. A trial with an oral local anesthetic usually is considered after antidepressant and anticonvulsant drugs have been tried. IV or SC lidocaine may be useful in the treatment of severe, rapidly increasing neuropathic pain. Intraspinal therapy Opioids in combination with adjuvant therapy benefit most patients. However, for a small percentage of patients with severe, intractable neuropathic pain, intrathecal or epidural application of analgesic drugs can help. This strategy may also reduce the need for systemic opioids in patients who experience unacceptable side effects. Most patients undergoing these procedures still require a certain amount of systemic therapy as well.129 Neuropathic pain is poorly responsive to spinal opioids alone, but in combination with local anesthetics or ␣2 -adrenergic agonists (e.g., clonidine), they may be efficacious.130 In one study, the epidural infusion of bupivacaine 0.1%–0.5% in addition to morphine was very helpful. Sensory loss was observed only at bupivacaine concentrations above 0.25%, and motor weakness at concentrations over 0.35%. In an uncontrolled study in patients with severe refractory cancer pain, a constant intrathecal infusion of 0.5 mg/mL of morphine plus 4.75 mg/mL of bupivacaine resulted in good pain relief. Side effects including urinary retention, paresthesias, paresis, and gait impairment were observed in approximately one third of the patients, but these did not interfere with the trial. In addition, a controlled study in 85 cancer patients with refractory pain syndromes demonstrated adequate neuropathic relief in more than 50% of the patients treated with 30 ␮g/hour of epidural clonidine together with rescue epidural morphine. The most common side effects are hypotension and bradycardia, and patients should be monitored thoroughly during the first treatment days. Baclofen has demonstrated powerful antinociceptive effects in experimental animal models at doses that produce little or no motor-blocking effects but has rarely been used as a spinal analgesic agent in patients without spasticity. So far, three studies have shown it to be effective in patients with peripheral nociceptive or neuropathic pain mechanisms. In clinical and animal studies, combinations of baclofen and morphine or clonidine have demonstrated greater efficacy than each drug alone.131

neuropathic pain

497

Table 26.5. Other oral adjuvant analgesics Drug

Daily dose

SISTEMIC DRUGS Local anaesthetics Mexiletine 150–900 mg/d Lidocaine IV infusion NMDA antagonists Ketamine 1.5 mg/kg Mamentine 10–20 mg Corticosteroids Prednisone 10–20 mg/d Dexamethasone 2–4 mg/d GABA agonist Baclofen 30–200 mg/d Benzodiazepines Clonidine 1–10 mg/d Alprazolam 0.75–1.5 mg/d Diazepam 5-20 mg/d ␣2 adrenergic agonists Clonidine Intrathecal/topical Tizanidine 2–12 mg

Dosing interval

Evidence

Three times a day In patient/outpatient

CT

Three times a day Two times daily

OLT CT (inconclusive)

Daily to twice a day Daily to twice a day

CR CR

Three times a day

CT

Twice a day Three times a day Twice a day

OLT OLT CR

Twice to three times daily

CT OLT

TOPICAL Clonidine 0.005% (CT), Lidocaine patch/gel 5% (CT), capseisine (CT), doxepine (CT), aspirin (CT). Others: NSAID’s, Ketamine, various Antidepressants, various Anticonvulsants, lidocaine/ prilocarpine cream (EMLA) CT, controlled trials; OLT, open-label trials; CR, case report.

PHN may be very resistant to treatment. In a doubleblind placebo-controlled study of 277 patients, Kotani et al.132 showed significant improvement in pain symptoms in intractable PHN with the administration of intrathecal methylprednisolone.132 Adjuvants and nonopioid analgesics A description of adjuvants and nonopioid analgesics is given in Table 26.5. ␣ 2 -Adrenergic agonists ␣2 -Adrenergic agonists activate the autoreceptors localized in the presynapses of noradrenergic neurons, decreasing the release of endogenous norepinephrine. Clonidine, the prototype of this family, has been used to treat hypertension for many years and has been used successfully to treat nonmalignant neuropathic pain. The severity of its side effects and its limited benefit make clonidine a second-line agent, which is used for refractory neuropathic pain only after other agents have failed. It can be administered orally, transdermally, or intraspinally. The intraspinal route of administration is particularly useful in patients who are only partially responsive to opioids. Tizanidine is a more selective ␣2 -adrenergic receptor agonist than clonidine and causes less hypotension. Current

data support its use in myofascial pain syndrome as an antispasmodic and also in the prophylaxis of chronic daily headache. However, some positive reports for its use in treating neuropathic pain justify a trial after other adjuvants have failed. N-methyl-D-aspartate receptor antagonists Excitatory amino acids play a fundamental role in pain transmission at the level of the spinal cord. Noxious stimuli activate A␦and C-fibers of pseudo-bipolar DRG neurons that project their axons to the posterior horn of the spinal cord. There they synapse with projection neurons that are localized in laminae I and II. The neurotransmitters involved in this pathway are glutamate and substance P. Substance P is a peptide, which is inactivated rapidly. At this point, there are no stable antagonists that can be used successfully in clinical practice. On the other hand, glutamate is an excitatory amino acid that can be blocked with several stable drugs that are currently in use in clinical practice for other indications, including ketamine (anesthesia), dextromethorphan (antitussive) and memantine (advanced Alzheimer’s disease). For this reason, responses mediated by glutamate have received more attention than those mediated by substance P. Once in the biophase, the two neurotransmitters,

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glutamate and substance P, activate projection neurons by binding selectively to postsynaptic receptors. The receptor activated by glutamate has been named after the NMDA ligand that also binds to it with high affinity. Under physiologic conditions, the response to painful stimuli is mediated by the normal release of glutamate at the level of primary afferent neurons in the posterior horn of the spinal cord. Excitatory amino acids have been implicated in the development of abnormal responses that occur in neuropathic pain syndromes and also in the development of tolerance to opioids. Preclinical studies have established that NMDA receptors are involved in the sensitization of central neurons following injury and in the development of the “wind-up” phenomenon, a change in the response of central neurons. Trujillo and Akil107 , in preclinical studies, suggested that hyperalgesia (one of the abnormal sensory findings in neuropathic pain) and the development of tolerance to opioids can be ameliorated by blocking the NMDA receptors. Shortly afterward, clinical trials were conducted to determine a possible role for dextromethorphan and ketamine, two NMDA receptor antagonists widely used in clinical practice, in the clinical setting. Although the affinity of dextromethorphan for the NMDA receptors is weak, it was found to be safe and well tolerated when used as an antitussive. Pierce and coworkers133 studied the analgesic efficacy of dextromethorphan in diabetic neuralgia and PHN, two widely used models for neuropathic pain. The design was a double-blind placebo-controlled crossover study. A decrease in pain was observed in patients with diabetic neuropathy, whereas patients with PHN did not experience improvement. Patients were allowed to titrate the dose to obtain pain relief or relief from side effects. The doses required to produce pain relief were too high, and most patients experienced side effects, resulting in a very limited clinical tool. Clinical studies with ketamine also were performed and showed moderate benefit as well (see later). Preclinical studies by Pierce and coworkers133 suggested that pretreatment with dextromethorphan might prevent the development of tolerance to morphine in mice. They assayed several combinations of the two compounds, with an optimal ratio of about 1:1. Based on their data, several clinical trials were conducted in patients with neuropathic pain using the same ratio of dextromethorphan to morphine (1:1), suggesting a role for this treatment modality. Ketamine is an NMDA receptor antagonist used extensively in anesthesia because of its dissociative properties. Because of its toxicity and side effects, it is considered a third-line drug for the treatment of neuropathic pain. When combined with opioids, it can be very effective. Indeed, the addition of oral ketamine significantly reduced pain scores

in seven of nine cancer patients with severe neuropathic pain who were treated with opioids, sodium valproate, amitriptyline, or a combination of these.134 Following administration of an anesthetic dosage of ketamine over 5 days, complete remission was observed in all 20 patients with refractory CRPS enrolled in an open-label study.135 To evaluate the effects of ketamine on cognitive and emotional functioning, nine patients with refractory CRPS received a neuropsychological evaluation before and 6 weeks after ketamine infusion therapy.136 Patients reported marked a reduction in both acute and overall pain. With the exception of a mild decline in motor strength, performance on cognitive domains remained stable. Effects of treatment on mood and personality were inconclusive. A recent prospective study137 investigated the side effects of the drug in a group of 32 patients with diabetic polyneuropathy and PHN after infusion of 10 mg of ketamine in 100 mL of normal saline, and after 3 months of 30 mg of oral ketamine five times a day. Patients reported dizziness, drowsiness, and dry mouth (after oral therapy). Over the 3-month study period, 15.6% of patients withdrew because of failure of therapy and 12.5% withdrew because of severity of side effects. Ketamine may be used as an oral formulation or by IV or SC infusion. Oral ketamine may be added to the existing drug regime in a dose of 0.5 mg/kg three times a day. Continuous IV or SC infusion should be started at a dose of 2.5–5 mg/kg/24 hours and may be increased gradually by 50–100 mg/24 hours up to 500 mg/24 hours. Concomitant administration of antipsychotics or diazepam may reduce the risk of psychomimetic effects, such as derealization, visual or auditory hallucinations, nightmares, and delirium, which may have a significant impact on patients’ quality of life. Ketamine is contraindicated in patients with intracranial hypertension or seizures. There is some evidence that oral ketamine has a more favorable side effect profile than parenteral ketamine, with drowsiness being the most common side effect to which patients may develop tolerance over a 3-week period. ␥-Aminobutyric acid agonists Baclofen is a muscle relaxant that binds to GABAB postsynaptic receptors, inducing increased K+ conductance and reduced neuronal excitability. It has been shown to be effective in the treatment of trigeminal neuralgia and may be a useful drug for neuropathic pain in the medically ill.138 In addition to its direct effectiveness for neuropathic pain, baclofen decreases muscle spasms and the pain associated with it. The benzodiazepines may have a similar effect through a different mechanism of action. When started at low doses (2.5–5 mg three times daily), the most common side effects

neuropathic pain of drowsiness, dizziness, and gastrointestinal distress are usually well tolerated. The dose then should be increased, if tolerated and necessary, by 5–10 mg every other day. Baclofen cannot be discontinued abruptly after prolonged use, as hallucinations, manic psychotic episodes, or seizures may occur. Baclofen may be especially useful for patients with paroxysmal neuropathic pain. Benzodiazepines A survey of cancer patients with mixed types of neuropathic pain suggested that alprazolam might have analgesic effects.139 Pain may result in the development of muscle spasms, which in turn may cause more pain. The centrally mediated muscle relaxant effect of the benzodiazepines may contribute to a decrease in pain. Whether this group of pharmacologic agents has a direct analgesic effect may not be entirely clear. However, patients with cancer pain commonly experience anxiety and muscle spasms, phenomena that may exacerbate the intensity of pain and respond well to other benzodiazepines, such as diazepam. Changes in mental status may occur during dose titration and must be monitored closely. Dosing should be started at the lowest possible dose. Modulators of bone metabolism Bisphosphonates reduce bone reabsorption by inhibiting osteoclastic activity.140 They have been shown to have analgesic properties in various disorders, but their mechanism of action remains unclear. Pamidronate, the most extensively studied of the bisphosphonates, has been shown to have an analgesic effect in bone metastasis in patients with breast cancer or multiple myeloma. In addition, it has been shown to decrease the number of pathological fractures, the incidence of cord compression, and the need for radiation and hypercalcemia. Although in general pamidronate is well tolerated, it may cause a flu-like syndrome and hypocalcemia. Recently, more potent analogues have been introduced. Zoledronic acid, an analogue threefold more potent than pamidronate, has been shown to reduce pain in lung cancer, multiple myeloma,141 and breast and prostate cancer. In a long-term follow-up study of 122 patients with prostate cancer skeletal-related events, the side effects were similar to those experienced with pamidronate. Zoledronic acid can be infused safely at a dose of 4 mg every 3 weeks. In contrast to pamidronate, the dose does not need to be adjusted for renal failure. Fatigue, nausea, and arthralgia are the most frequently observed side effects. Clodronate is another agent of the same family that can be administered by mouth at a dose of 1600 mg/day.142 The drug is not available in the United States, and the analgesic effect in prostate cancer and multiple myeloma is not

499 conclusive. However, clodronate was effective in the treatment of skeletal complications from prostate cancer. There was an objective response in 91.4% of treated patients, with a marked improvement in the subjective visual pain scale evaluation as well as on Karnofsky’s index, with low side effects. Etidronate, like clodronate, triggers apoptosis by generating a toxic analogue of adenosine triphosphate, which then targets the mitochondria. Its inhibition suppresses protein geranylgeranylation, which is essential for the basic cellular processes required for osteoclastic bone resorption. Calcitonin Data on the analgesic effect of calcitonin are inconclusive. A double-blind placebo-controlled study in patients with CRPS type I found no positive effects.143 However, positive results in patients with neuropathic pain in diverse diseases including cancer justify a trial with the intranasal formulation. The initial dose should be 200 IU, alternating nostrils to avoid epistaxis. The dose may be increased if no effects are observed, but the maximum dose has not been well established. Although calcitonin has also been administered via the SC and IV routes, the intranasal route of administration is more convenient. Anti-inflammatory drugs Corticosteroids Patients with cancer may present with diverse pain syndromes that may be benefited by the use of corticosteroids.144,145 Patients with metastatic disease to the spine may present with symptoms suggestive of spinal cord compression. In this situation, IV dexamethasone, 20–100 mg followed by 60–90 mg/day in three divided doses, is the drug of choice. This presentation is a medical emergency, and steroids should be initiated before confirmatory ancillary studies are done. In addition, immediate consultation with radiation oncology should be requested. Steroids may be continued at this dose level until radiation is instituted (when applicable), after which the dose of corticosteroids is tapered gradually. Compression of nerve roots by metastatic breast or prostate cancer to the vertebral bodies also may result in neuropathic pain. This syndrome also may benefit from radiation therapy or nerve blocks. Lymphoma-related neuropathy has a significant inflammatory and mass effect component and may benefit from corticosteroids as well. Doses can range from 5 to 10 mg of prednisone or from 1 to 2 mg of dexamethasone once or twice daily. Initiation of treatment with adjuvant analgesics such as gabapentin is recommended. Once therapeutic gabapentin levels are reached, corticosteroids may be tapered off.

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Neuroleptics Olanzapine, a new-generation neuroleptic, has been shown to improve pain and decrease the use of opioids in cancer patients. In a case series, olanzapine improved cognitive function and decreased anxiety.146 However, because of its potential severe side effects, including tardive dyskinesia and neuroleptic malignant syndrome, the recommendation is to use neuroleptics only in the presence of delirium or psychosis. Cannabinoids Animal studies suggest that cannabinoids may be useful analgesics for neuropathic pain.147,148 CB1 acts on pathways that partly overlap those affected by opioids such as morphine, but also acts through pharmacologically distinct mechanisms. There is evidence that oral ⌬ 9 tetrahydrocannabinol (THC) and other cannabinoids can improve appetite, reduce nausea and vomiting, and alleviate moderate neuropathic pain in patients with cancer. CB1 is distributed widely throughout the CNS and peripheral nervous system, reaching high concentrations in periaqueductal gray matter.149 Because of the similarities in the physical distribution of their receptors, cannabinoids and opioids may have additive or synergistic analgesic effects. Studies of analgesia in humans with experimentally induced pain have shown mixed results;150 however, similar to the analgesic effects of opioids,107 better analgesic results have been observed in clinical studies of cannabinoids in patients with severe, persistent cancer pain resistant to traditional analgesics. These double-blind placebocontrolled trials showed that cannabinoids had analgesic effects equal to those of codeine and also improved mood, well-being, and appetite. In the setting of chronic pain, a series of well-designed studies using THC, cannabidiol, both agents, or placebo provides good evidence of the efficacy of cannabinoids and suggests that they may have a role in managing neuropathic pain but have less efficacy in treating nociceptive pain. A study of a cannabinoid analogue in a few patients demonstrated a substantial analgesic effect for chronic pain, with fewer psychotropic effects.151 In this 7-day placebo-controlled trial, the cannabinoid analogue significantly reduced pain 3 hours after use, and the benefit lasted 6 hours. Water-soluble cannabinoids such as ⌬ 8 THC-11-oic acid have a wider range of medication formulations and drug-delivery methods than THC but need to be studied in adequately powered clinical studies to assess their analgesic and other therapeutic effects. A recent British randomized, double-blind, placebo-controlled trial152 randomly assigned 63 patients to receive Sativex, administrated on a self-titrating regimen, and 62 patients to receive

placebo. Patients suffered from peripheral neuropathic pain with allodynia. Results showed a significant reduction in pain intensity scores, sleep, dynamic allodynia, punctuate allodynia, pain disability, and patient’s Global Impression of Change. The most commonly reported side effects were sedation and gastrointestinal effects. Topical analgesics Topical lidocaine Topical lidocaine may be applied as a gel, cream, or patch. The lidocaine patch has become very popular because it is easy to apply and has a low profile of side effects. Lidocaine systemic absorption is minimal, with no systemic side effects for up to three patches at a time (although monitoring for toxicity at initiation of treatment is recommended). Application of more than three patches may be useful for some patients, but this approach should be accompanied by initial monitoring for local anesthetic toxicity. An adequate trial may require several weeks of observation. The most frequently reported adverse event is mild to moderate skin redness, rash, or irritation at the patch. Because lidocaine has a local mode of action, it should be applied directly to the area where the pain is felt. Although to avoid tachyphylaxis (acute tolerance) the patch should not be kept on for more than 12 hours at a time, limited data suggest that it is safe to use lidocaine around the clock. The 12-hour period should be customized to the patient’s specific problem. For example, if the pain is localized to the foot, it probably would be better to use the patch during the night, so it stays in place.153 The patch may be used in combination with other drugs that may be helpful in the treatment of neuropathic pain. For example, one study154 showed that the simultaneous use of lidocaine patches and oral gabapentin was more effective than either agent used individually. Capsaicin Capsaicin is a peptide that depletes substance P, which, along with glutamate, is the most important neurotransmitter of pain in small primary afferent neurons in the posterior horn of the spinal cord. Capsaicin is applied locally in a 0.05% formula (starting dose) to the affected area. The application must be done carefully, and the mucosa should be avoided. The patient or his or her caregiver must be warned to use disposable gloves, because capsaicin can inadvertently cause painful irritation of the conjunctiva. Immediately after the first application, capsaicin may cause a severe burning sensation limited to the area of application, which may result in abandonment of the treatment. Simultaneous application of 5% lidocaine may decrease the intensity of the initial burning. Despite this side effect, a recent study in cancer patients with surgical

neuropathic pain neuropathic pain (e.g., postmastectomy syndrome) found that capsaicin significantly decreased pain and was preferred by 60% of the patients.155 If results are not seen in a week, it is unlikely that further treatment will result in pain relief.

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r.a. cruciani, e.a. strada, and h. knotkova in new users of antiepileptics. Neurology 64:1134–8, 2005. Vinik AI, Tuchman M, Safirstein B, et al. Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain 128:168–79, 2007. Silver M, Blum D, Grainger J, et al. Double blind, placebocontrolled trial of lamotrigine in combination with other medication for neuropathic pain. J Pain Symptom Manage 34:446– 54, 2007. Breuer B, Pappagallo M, Knotkova H, et al. A randomized, double-blind, placebo-controlled, two-period, crossover, pilot trial of lamotrigine in patients with central pain due to multiple sclerosis. Clin Ther 29:2022–30, 2007. Sobotka JL, Alexander B, Cook BL. A review of carbamazepine’s hematologic reactions and monitoring recommendations. DICP 24:1214–19, 1990. Portenoy RK, Khan E, Layman M, et al. Chronic morphine therapy for cancer pain: plasma and cerebrospinal fluid morphine and morphine-6-glucuronide concentrations. Neurology 41:1457–61, 1991. Jadad AR. The WHO anelgesic ladder for cancer pain management: stepping up the quality of its evaluation. JAMA 274, 1870–73, 1995. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85–7, 1991. Dole VP. Implications of methadone maintenance for theories of narcotic addiction. JAMA 260:3025–9, 1988. Nyswander M, Dole VP. The present status of methadone blockade treatment. Am J Psychiatry 123:1441–2, 1967. Krantz MJ, Kutinsky IB, Robertson AD, et al. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 23:802–5, 2003. Cruciani RA, Sekine R, Homel P, et al. Measurements of QTc in patients receiving chronic methadone therapy. J Pain Symptom Manage 29:385–91, 2005. Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation associated with intravenous methadone. Pain 105:499–506, 2003. Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects. Cancer 86:1856–66, 1999. Mercadante S, Cacuccio A, Fulfaro F, et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol 19:2898– 904, 2001. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:1250–6, 1992. Watson CP, Vernich L, Chipman M, et al. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 51:1166, 1998. Morello CM, Lechband SG, Stoner CP, et al. Randomized double blind study comparing the efficacy of gabapentin with amitriptyline in diabetic peripheral neuropathy pain. Arch Intern Med 59:1931–7, 1999.

118. Kalso E, Tasmuth T, Neuvonen P. Amitriptyline effectively relieves neuropathic pain following treatment of breast cancer. Pain 64:293–302, 1996. 119. Ansari A. The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature. Harv Rev Psychiatry 7:257–77, 2000. 120. Sindrup SH, Grodum E, Gram LF, et al. Concentrationresponse relationship in paroxetine treatment of diabetic neuropathy symptoms: a patient-blinded dose-escalation study. Ther Drug Monit 13:408–14, 1991. 121. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 57:1583–8, 2001. 122. Goldstein DJ, Lu Y, Detke MJ, et al. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 116:109–18, 2005. 123. Raskin J, Pritchett YL, Wang F, et al. A double blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 6:346–56, 2005. 124. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 67:1411–20, 2006. 125. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo controlled study. Pain 110:697– 706, 2004. 126. Mao J, Chen LL. Systemic lidocaine for neuropathic pain relief. Pain 87:7–17, 2000. 127. Galer BS, Harle J, Rowbotham MC. Response to intravenous lidocaine infusion predicts subsequent response to oral mexiletine: a prospective study. J Pain Symptom Manage 12:161–7, 1996. 128. Chong SF, Bretscher ME, Mailliard JA, et al. Pilot study evaluating local anesthetics administered systemically for treatment of pain in patients with advanced cancer. J Pain Symptom Manage 13:112–17, 1997. 129. Bennett G, Serafini M, Burchiel K, et al. Evidence-based review of the literature on intrathecal delivery of pain medication. J Pain Symptom Manage 20:S12–36, 2000. 130. Du Pen SL, Kharash ED, Williams A, et al. Chronic epidural bupivacaine-opioid infusion in intractable cancer pain. Pain 49:293–300, 1992. 131. Slonimski M, Abram SE, Zuniga RE. Intrathecal baclofen in pain management. Reg Anesth Pain Med 29:269–76, 2004. 132. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 343:1514–19, 2000. 133. Pierce TL, Tiong GK, Olley JE. Morphine and methadone dependence in the rat: withdrawal and brain metenkephalin levels. Pharmacol Biochem Behav 42:91–6, 1992. 134. Kannan TR, Saxena A, Bhatnagar S, et al. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. J Pain Symptom Manage 23:60–5, 2002. 135. Kiefer RT, Rohr P, Ploppa A, et al. Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex

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regional pain syndrome: an open label phase II study. Pain Med 9:1173–201, 2008. Koffler SP, Hampstead BM, Irani F, et al. The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome. Arch Clin Neuropsychol 22:719–29, 2007. Cvrcek P. Side effects of ketamine in the long-term treatment of neuropathic pain. Pain Med 9:253–7, 2008. Fromm GH. Baclofen as an adjuvant analgesic. J Pain Symptom Manage 9:500–9, 1994. Fernandez F, Adams F, Holmes VF. Analgesic effect of alprazolam in patients with chronic, organic pain of malignant origin. J Clin Psychopharmacol 7:167–9, 1987. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev CD003474, 2005. Terpos E, Dimopoulos MA. Myeloma bone disease: pathophysiology and management. Ann Oncol 16:1223–31, 2005. Reszka AA, Rodan GA. Mechanism of action of bisphosphonates. Curr Osteoporos Rep 1:45–52, 2003. Kovcin V, Jeli´c S, Babovi´c N, Tomasevi´c Z. A pilot study to assess the efficacy of salmon calcitonin in the relief of neuropathic pain caused by extraskeletal metastases. Support Care Cancer 2:71–3, 1994. Vecht CJ, Haaxma-Reiche H, van Putten WL, et al. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology 39:1255–7, 1989. Watanabe S, Bruera E. Corticosteroids as adjuvant analgesics. J Pain Symptom Manage 9:442–5, 1994. Khojainova N, Santiago-Palma J, Kornick C, et al. Olanzapine in the management of cancer pain. J Pain Symptom Manage 23:346–50, 2002.

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147. Hohmann AG. Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives. Chem Phys Lipids 121:173–90, 2002. 148. Goya P, Jagerovic N, Hernandez-Folgado L, et al. Cannabinoids and neuropathic pain. Mini Rev Med Chem 3:765–72, 2003. 149. Cravatt BF, Lichtman AH. The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol 61:149– 60, 2004. 150. Hoffman AG. Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives. Chem Phys Lipids 121:173–90, 2002. 151. Karst M, Salim K, Burstein S. Analgesic affect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 290:1757–62, 2003. 152. Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterized by allodynia: a randomized, double-blind, placebo-controlled clinical trial. Pain 133:210–20, 2007. 153. Galer BS, Rowbotham MC, Perander J, et al. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain 80:533–8, 1999. 154. White WT, Patel N, Drass M, et al. Lidocaine patch 5% with systemic analgesics such as gabapentin: a rational polypharmacy approach for the treatment of chronic pain. Pain Med. (4):321–30, 2003. 155. Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebocontrolled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 15:2974–80, 1997.

27

Breakthrough pain sebastiano mercadante University of Palermo

Introduction Patients with cancer pain often present with fluctuations in pain intensity. Previous surveys have found that this phenomenon, commonly reported as breakthrough pain (BTP),1 is highly prevalent among patients with cancer pain and predicts more severe pain, pain-related distress, and functional impairment, and relatively poor quality of life.2 In several surveys, 50%–90% of cancer patients with pain reported that they experienced intermittent flares of their pain, although each survey used different definitions and methodology.1–8 BTP has not always been given due consideration in reports on pain in cancer patients, and imprecision in the nomenclature may account for the different meanings of the term.9 These figures have been confirmed in a large international survey assessing the prevalence of BTP, which showed a prevalence of about 65%, although a referral bias may limit generalizability of the data.10 BTP may be associated with other conditions of chronic pain.11 In a noncancer population with chronic pain, 70%–75% of patients with adequate basal pain control experienced severe to excruciating BTP.12,13 In a terminal noncancer hospice population, 63% of patients had BTP.14 Similar to BTP in adults, BTP in children is relatively frequent, although less recognized. In a recent small institutional study with a cross-sectional design, about 60% of children with controlled background pain of different origins had episodes of BTP.15

Characteristics The pioneer study of BTP defined it as a transitory increase in pain intensity from a baseline pain of moderate intensity in patients on regularly administered analgesic treatment.1 This definition suggests a high intensity of pain over a limited period, that is, a transient episode of uncontrolled

506

pain. The term breakthrough pain does not have any equivalent in other languages in Europe, especially in Latin countries, where patients and untrained physicians may have a misconception regarding the definition of BTP. To increase the relevance of this type of pain in the clinical setting, broader and less burdensome terms, such as episodic or transient pain, have been adopted in some European countries for establishing a common language among researchers.9

Classification Patients with BTP and their treatment frequently have been described as a common group. The therapeutic approach, however, may change considerably according to the phenomenology and pathophysiology of the BTP. Different forms of intermittent pain flares should be distinguished to identify clinical situations typically dependent on the temporal pattern. The most striking distinction can be made between movement-related pain and non–movementrelated pain. Three principal categories of BTP have been identified: 1) spontaneous pain with no evident precipitating event; 2) incident pain with an evident precipitating cause or event, such as activity; and 3) end-of-dose failure, which is associated with therapeutic holes due to a reduction in blood analgesic levels of medications provided at regular intervals. The last category does not exactly correspond to the definition of BTP. However, it occurs clinically and requires rescue medications while the basal analgesic regimen is adjusted (Table 27.1). Another way to classify BTP is based on the presence of volitional or precipitant factors, which have been identified in more than 50% of patients. Therefore, for each category, different subtypes also can be identified.

breakthrough pain Table 27.1. Principal categories of BTP Volitional–predictable: incident pain due to movement or other maneuvers Nonvolitional–unpredictable: typical BTP of unknown origin, with different mechanisms End-of-dose failure or insufficient background analgesia

Predictable events A well-understood subtype of BTP is incident pain, which is caused by movement and is commonly associated with bone metastases or fractures. Continuous pain may be absent or moderate on resting but may be exacerbated by different movements or positions.16 Patients tend to prevent pain by limiting their movements, depending on the site of the painful bone metastases.9 As a consequence, autonomy and quality of life are highly compromised by this status. Incident pain usually has a sudden onset, reaching peak intensity within a few minutes. Because the onset is quite predictable and may be considered volitional, these episodes are associated with functional impairment on measures of mood and anxiety and on scales of pain interference with function.2 This type of BTP limits the functional activity of patients, and freedom from pain in motion is particularly difficult to achieve. Other pains are considered volitional rather than induced by a specific movement, such as pain induced by swallowing or chewing in patients with mucositis. Mucositis renders patients unable to take oral medication or to swallow, leading to a decrease in food and fluid intake. Similarly, complex and probably mixed visceral mechanisms, which generally are considered nonvolitional, may be induced by voluntary maneuvers. For example, tenesmus of the colon or bladder may be induced by attempts at defecation or micturition. Touching hyperesthetic skin areas in patients with ulcers or neural lesions may precipitate a pain crisis of different duration. On the other hand, the same paroxysmal event also may occur without evident stimulation (spontaneous allodynia), with variable duration. Thus, different pain mechanisms may produce similar temporal and severe baseline pain in uncontrolled situations. Thus, BTP may be an expression of opioid underdosing, regardless of time intervals of administration. End-of-dose failure is a phenomenon typically observed when the analgesic duration of a certain opioid is not enough to cover the interval between doses, which occurs because the global dosage is too low or the interval between doses is too long. Although the latter cause, expressing a status of inappropriate analgesia, does not fit the typical definition of BTP, from a

507 clinical perspective, it still represents a clinical problem to be addressed as BTP. Assessment Patients often receive basal medication for pain that is otherwise considered acceptable. Assessment of BTP in these patients is particularly difficult, and currently there is no independently validated tool to assess episodic pain. It is recommended that these patients undergo a comprehensive pain assessment including frequency and duration of each episode, intensity, precipitating factors, and previous and current pain treatments for baseline (persistent) pain as well as their effectiveness. Pain assessment also should include the inferred pathophysiology and origins of the pain syndrome. The patient’s involvement in pain assessment is of paramount importance. In their education about cancer pain, patients can learn how to use a pain diary and how to talk to members of their health care team so they receive better pain relief. Thus, good patient–provider communication ensures that the patient’s cooperation will contribute to the successful management of BTP, particularly with regard to identifying the quality of pain and the alleviating or precipitating factors. Although highly variable, BTP typically is rapid in onset, moderate to severe in intensity, and relatively short in duration. A significant association has been found between BTP and psychological distress.2 Recent data have confirmed the association between BTP and higher ratings on the worst and average pain scales, and higher interference with function. Although BTP seems to be more frequent in advanced stages of disease, in a multivariate model, only pain caused by vertebral metastases and plexopathies predicted BTP,10 confirming previous studies reporting bone pain on movement as the most important predictor of poor pain relief.17,18 The characteristics of this kind of pain suggest that it must be assessed with instruments aimed at measuring pain intensity over short periods. One key agreement is to assess BTP as a pattern distinct from baseline pain, and it would be clinically helpful to have pain scales with cutoff points able to identify episodes for which a rescue medication is needed. Although the traditional measures of pain intensity, such as visual analogue scales, numerical rating scales, and verbal rating scales, most likely are suitable for this purpose, measurements should be performed frequently, at the onset and then at intervals, until the episode vanishes spontaneously or after a specific treatment, or even when it occurs again. The use of analgesics, the relationship between the occurrence of the episode and the administration of drugs,

508 and the onset of the effect should be recorded. Onset and peak intensity, location, quality and predictability, factors that precipitated the pain, and factors that provided relief once it occurred – or prevented it – also should recorded. Another question to resolve is whether the episode represents an acute worsening of chronic pain or is an entirely distinct phenomenon.9 The Brief Pain Inventory is a useful tool for evaluating the degree to which pain interferes with function and quality of life. It is helpful in eliciting information on episodic pain, and includes several questions on pain intensity that allow one to differentiate between average pain and worst pain, possibly as an indicator of episodic pain intensity.10 The assessment of incident pain due to bone metastases is particularly difficult, as patients maintain pain control by avoiding particular movements that may trigger their pain. In some cases, pain may be elicited carefully to assess the real impact of pain induced by movement. End-of-dose failure also may be anticipated, especially when patients and caregivers keep diaries that associate time of pain with time of the last dose of scheduled medication. Spontaneous BTP is more challenging to predict. This type of pain often is neuropathic, with short pain flares, or visceral in origin, such as gastrointestinal cramps, and is quite disabling and difficult to treat. Because there are different subtypes of BTP, a different therapeutic approach is required for each. For example, patients with nerve injuries may need preemptive therapy to prevent BTP episodes, and other patients may be administered drugs as needed.

Treatment Patients or their caregivers may help alleviate an episode of BTP by changing position, applying heat or cold, massaging the painful area, or using relaxation techniques. These measures also may be used provide relief while the patient waits for medication to take effect. An appropriate balance between basal analgesia and medications as needed, according to the individual needs of the patient, is of paramount importance in the prevention and management of BTP.18 Optimization of the basal treatment It is essential to optimize the basal analgesia by titrating the opioid dosage to obtain the best balance between analgesia and adverse effects. This balance also may be achieved by using different sequences of opioids and combining analgesics and adjuvants as necessary. Careful titration may improve the basal analgesia while limiting the adverse

s. mercadante effects. If BTP occurs because the dose of around-theclock (ATC) medication is insufficient (end-of-dose failure), increasing the dose of ATC medication, or decreasing the interval between doses, may provide a benefit, depending on the opioid preparation.19 There are several reasons to optimize the basal analgesia of opioid and nonopioid drugs, particularly in the presence of frequent and intense episodes of BTP. In some cases, there is no medication with an onset quick enough to alleviate an acute temporal pattern of pain firing. For example, patients with neuropathic pain may have exacerbations lasting a few seconds or minutes. Pain may develop too fast after initiating a volitional movement, such as walking, coughing, sitting, or standing, or after an involuntary movement in bed. On the other hand, patients with movementrelated pain due to bone metastases often are receiving basal medication for their pain, which is otherwise considered acceptable, but are confined to bed, with limited mobility. Could BTP be a consequence of an inappropriate but apparently effective opioid regimen? It has been suggested that spinal cord sensitization may be the common denominator in BTP. Although the mechanisms of spontaneous ongoing pain and intermittent flares of pain may be difficult to separate, there are experimental lines of evidence that suggest that peripheral and/or central sensitization (hyperexcitability) may play a major role in many cases of BTP. Mechanical stimuli (e.g., microfractures) change in chemical environments, and release of tumor growth factors may initiate sensitization both peripherally and centrally. Recent experimental studies in animals have shown that metastatic bone pain may have some similarities to neuropathic pain in terms of opioid responsiveness. In a model of bone cancer pain, injection of cancer cells was coincident with the development of mechanical allodynia and a reduction in paw withdrawal threshold,20 and the doses of morphine required to block bone cancer pain–related behaviors were 10 times those required to block peak inflammatory pain behaviors of comparable magnitude.21 This means that similar pain intensities induced by different stimuli (cancer cells injected in bone or inflammatory stimulus), may have different sensitivities to opioids. From a pathophysiological point of view, bone pain elicited by movement corresponds to mechanical allodynia (pain induced by a non-noxious stimulus, such as movement), which means a state of hypersensitivity, requiring opioid doses higher than those sufficient to control basal pain to be suppressed or reduced. Patients presenting with a relevant incident component responded to further opioid dose increases despite having

breakthrough pain

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pain peaks

Well controlled pain a pain peaks

Uncontrolled pain

c

b

Fig. 27.1. A: Typical BTP pattern requiring rescue doses. B: Uncontrolled basal pain requiring both optimization of basal analgesia and rescue doses during titration. C: Changes in pain intensity of both basal analgesia and BTP, obtainable after optimization of therapy.

pain that was controlled at rest, and had improvement in their physical activity. Opioid titration with intravenous morphine (IV-MO) resulted in a significant decrease in pain intensity on movement in patients with incident pain.22 The response to an analgesic trial was a better prognostic factor, even in patients with an incident pain mechanism.18 Increasing the pain threshold is likely to prevent most pain on movement, or render it more acceptable. Careful dose titration may improve the basal analgesia while limiting the adverse effects. Therefore, a further opioid dose escalation may prevent or reduce the intensity of these flares, even though the pain at rest seems to be controlled (Fig. 27.1). However, an increase in dose also may result in unacceptable toxicity, mostly sedation, during the period between incident pain episodes. An increase in opioid dose – on average, from 248 mg to 496 mg over 6 days – resulted in better pain control, although methylphenidate was used to assist opioid titration in patients with incident pain.23 In these studies, most patients could increase their opioid doses without reporting significant toxicity, which means there is more space in the therapeutic window for patients who have their basal pain controlled. Optimization of basal opioid therapy should be attempted in cancer patients who have bone metastases presenting as movement-induced pain and who apparently have well-controlled pain at rest but probably have hypersensitivity to an innocuous stimulus, such as movement, requiring higher preemptive doses of basal opioid medication to reduce the occurrence of increased pain input.24 The possibility of improving opioid adverse effects by switching opioids has never been tested in this context.

Nonopioids to improve basal analgesia and limit the occurrence of BTP events The intermittent use of a nonsteroidal anti-inflammatory drug (NSAID) may be effective in some BTPs, such as headache and incident pain associated with bone metastases. These drugs have proven very useful in improving basal analgesia, possibly preventing or limiting the occurrence of BTP.16 Other adjuvant drugs, including antitussives, myolitic agents, and laxatives, may be useful in reducing the frequency of recognized precipitating events. Because of their anti-inflammatory properties, steroids may have beneficial effects in reducing metastatic bone pain, but controlled studies specifically addressing BTP are lacking. Radiotherapy, radionuclides, and bisphosphonates have been reported to reduce pain and the occurrence of fracture as well as the development of new osteolytic lesions and, as a consequence, improve the quality of life,25–27 but the need to measure the analgesic effect emerged only recently.28 Prospective observational studies found a reduction in intensity of pain at rest and in movement-related pain after treatment with up to six infusions of zoledronate, 4 mg every 28 days, or with infusion of a single 1.0-mCi/kg dose of samarium.29,30 These treatments should be considered unique preemptive analgesic treatments, although the real effectiveness is difficult to demonstrate – that is, whether the effects are additive, synergic, or opioid sparing, or whether a specific population may benefit. Swallowing-induced burning pain associated with oral mucositis may be treated preemptively with locally applied substances other than morphine, including ketamine or local anesthetics, and could similarly be used for touchinginduced pain associated with skin ulcers.31–33 Episodes of neuropathic pain with a lancinating character may be alleviated by the regular use of adjuvants such as antidepressants and anticonvulsants, although studies of these drugs in this context are lacking.34 Three studies with different designs have shown some benefit from the use of gabapentin in neuropathic cancer pain, although no study specifically assessed the entity of BTP in such conditions.35–37 Some topical drugs, including capsaicin or a cream of eutectic mixture of local anesthestics (EMLA), may reduce the input from peripheral nerve lesions in neuropathic pain syndromes with lancinating characteristics.34 The desensitizing effect of ketamine also may be useful in relieving dysesthesias and hyperalgesia associated with neuropathic pain, typically presenting with paroxysms. Ketamine has been found to be effective in relieving neuropathic pain in patients receiving opioids.38 However, specific studies

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510 of BTP in the presence of a prevalent neuropathic pain mechanism may be helpful in clarifying the exact role of anticonvulsants. The role of nonopioids administered with opioids to provide basal analgesia with the aim of reducing the number and intensity of BTP episodes should be better assessed in future studies with appropriate designs. Intrathecal delivery of a combination of opioids and local anesthetics Opioid titration, eventually supported by switching opioids to further improve the opioid response during escalation to the maximum tolerated dose, may fail to improve both basal analgesia and BTP on movement in patients with bone metastases. In these conditions, patients are confined to bed, limiting even minimal physical activity or movement. Incident pain is the most frequent indication for initiating intrathecal therapy with opioids and local anesthetics.39

O - MO IV - MO TM fentanyl 0

30

60

90

120 minutes

Fig. 27.2. Peaks of plasma concentration after oral morphine (O-MO), IVMO, and transmucosal fentanyl (TM fentanyl). ☺ = time for meaningful pain relief.

Considering the incidence of BTP, a prescription for an effective rescue drug with the appropriate dosage is mandatory for each patient. Opioids are used commonly and have been the subject of several studies in the past decade. There also are some complex interventions in selected patients. Depending on the setting, patient characteristics, and compliance, there are different modalities for delivering opioids for the management of BTP. Approaches differ in timing, setting, and costs.

chosen. A shorter onset of effect is commonly obtainable only with parenteral administration of opioid analgesics (Fig. 27.2). IV-MO has been found to be highly effective and safe, as only a low intensity of opioid-induced adverse effects was observed, even when large doses were administered.41 Although IV-MO is feasible in acute units, it is not favored in other centers, and at-home injections are not easily manageable. The subcutaneous route is commonly preferred. A recent confirmatory study of a large sample of patients confirmed that nurse-administered IV-MO for the management of BTP in doses proportional to the basal opioid regimen, even those given to older patients or those that were relatively large, did not result in life-threatening adverse effects and were effective in most cases.42

Oral and parenteral opioids The main treatment strategy suggested for managing pain flares is supplemental doses of oral opioids in addition to continuous analgesic medication. Current dosing guidelines for BTP generally recommend that the effective dose of BTP medication be a percentage of the patient’s total daily opioid dose.40 These recommendations, which are based entirely on anecdotal experience, favor the selection of a short-acting opioid at a dose proportionate to the total daily dose. However, an oral dose form may take longer to relieve pain, with peak concentrations achieved within 30–45 minutes (Fig. 27.2). On the other hand, the slow analgesic peaks achieved with oral opioids may be useful in other circumstances; for example, they may be administered 15–30 minutes before physical activity in patients with predictable incident pain, or during the opioid titration phase. Because pain relief is usually required urgently, routes of administration designed to deliver drugs rapidly often are

New generations of noninvasive fast-delivery systems Transmucosal administration of lipophilic substances has gained a growing popularity in the past years because of its rapid effect, clinically observable 10–15 minutes after drug administration (Fig. 27.2). New delivery systems for fentanyl are or will be available, including inhalatory delivery systems, nasal sprays, sublingual tablets, and effervescent buccal tablets. These routes have the advantage of bypassing the first-pass effect of the liver, providing prompt availability. Studies of oral transmucosal fentanyl citrate (OTFC) have shown that this approach produces a faster onset of relief and a greater degree of pain relief than oral morphine at 15, 30, and 60 minutes.43–46 No relationship between the effective OTFC dose and a fixed-schedule opioid regimen was observed, regardless of the opioid used, suggesting the need to titrate the dose of OTFC. Similar findings were reported recently with buccal tablets of fentanyl in a study with a similar design.47 This observation contradicted the anecdotal assumption that the effective dose needed is a

Treatment of BTP events

breakthrough pain percentage of the opioid daily dose. The reasons for these findings are not clearly explained. Some issues gathered by these previous studies should be pointed out. As 66% of the episodes treated with placebo did not require an additional dose of medication, the episodes recorded were possibly short-lived or not too severe, and/or spontaneously resolved. This also may explain why minimal doses of oral morphine equivalents (about 20 mg) were effective in patients taking a mean basal dose of 100 ␮g/hour of fentanyl (about 240 mg/day of oral morphine dose equivalents). Eligible patients were defined as those with basal pain that was no worse than moderate occurring no more than four times per day. However, patients reporting pain intensity 4.7–4.8 times that of basal pain (with some at the highest extremes) cannot be universally considered as having well-controlled pain, especially if matched with a pain intensity of breakthrough events (6.8 on average, with some patients at the lowest extremes). No distinction was made between incident pain, dependent on activity, and other mechanisms that may have a different temporal pattern. Finally, almost no adverse effects were reported with usual breakthrough medication in comparison with OTFC, doses of which were titrated in patients apparently responsive to their usual medication, suggesting that most patients probably were undertreated with basal as well as “as-needed” medication. The problem of opioid dosing as rescue medication The choice of opioid dose to be prescribed as needed remains controversial. The need to titrate opioid doses for BTP may make the use of OTFC difficult in daily practice, particularly in at-home patients or outpatients. Moreover, using different doses of OTFC for treating each episode may be time consuming and exceed the duration of BTP, which may subside spontaneously, as evidenced by patients treated successfully with placebo. Patients may be reluctant to try different doses so may avoid using OTFC, preferring instead the traditional oral dosing of morphine. OTFC, in doses proportional to the basal opioid regimen, has been found to be quite effective and above all, safe; however, the dose titration may be considered laborious by some patients, reducing their compliance with the treatment.48 This observation contrasts with almost all studies of OTFC, although some data could be interpreted in another way. For example, many patients on higher doses of original medication require larger doses of OTFC, and in successful patients, the regular rescue dose is a moderate predictor of the effective OTFC dose. In one controlled study of OTFC, a relationship between the OTFC dose and the fixed-schedule opioid was found, and the regular rescue dose was a moderate

511 predictor of the effective OTFC dose. However, only 19% of the variability of the final dose of OTFC was explained by basal doses of opioids, according to the low R-square value of the model used.43 Finally, recent observations from data pooled from trials of OTFC showed a statistically significant relationship between the breakthrough dose and the ATC dose, despite a relevant interindividual variability in patients’ dose requirements for BTP.49 It is likely that patients receiving high doses of opioids as the basal analgesic regimen are not candidates for titration with minimal doses of opioids, as they are opioid tolerant, and the process would be time consuming. Thus, a reliable compromise between the different opinions might be to start with relatively higher doses of opioids in highly tolerant patients, until more information is available to settle the question. The use of nonopioid drugs for BTP episodes Rescue doses of particular formulations of NSAIDs (fastrelease, sublingual, or parenteral) may be useful in controlling BTP when adverse effects occur with opioids administered as needed.16 Although the specific usefulness of NSAIDs in bony pain has not been assessed appropriately, a relevant response may be observed occasionally in individual patients. Nitrous oxide has properties that might enable prompt control of BTP. It is an analgesic, anxiolytic, and psychosedative agent with a rapid onset of action. Nitrous oxide delivered as a 50%–50% mixture of nitrous oxide and oxygen by a patient-controlled mechanism was used safely and effectively in advanced-cancer patients with BTP due to bone metastases. Environmental exposure to caregivers was minimal.50 In a subsequent work, however, the beneficial effects of nitrous oxide were not confirmed.51 Nitrous oxide should not be used in the presence of bowel distention. Predictable BTPs, such as those occurring with dressing changes, may be prevented with light sedation using midazolam or ketamine. Ketamine has been given in subhypnotic doses for severe colic in malignant bowel obstruction, for BTP, to prevent incident pain evoked by a change in body position, to facilitate hygienic procedures, in the transportation of patients, and to perform certain short but painful procedures. Ketamine appears to be a very effective and safe agent that should be recommended for terminally ill patients.52 The sublingual and intranasal mucosa has high permeability and extensive vascularity, facilitating rapid systemic absorption of lipophilic drugs such as ketamine. Ketamine has the advantage of not being dependent on the level of opioid tolerance. This treatment recently received a favorable report from a controlled crossover

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512 study using ketamine in patients with cancer and noncancer pain who were receiving opioids chronically. Intranasal ketamine administered in a 10-mg spray every 90 seconds for a total of five sprays provided statistically significant pain relief within 10 minutes of dosing and lasting for up to 60 minutes; only one patient reported no relief after treatment with ketamine. No patient in the ketamine group required his/her usual rescue medication to treat the BTP episode, whereas 35% of patients in the placebo group did. Intranasal ketamine was relatively well tolerated, with no serious adverse events.53 Ketamine also has been used for treating BTP in difficult situations, with highly opioidtolerant patients receiving a combination of intrathecal opioids and local anesthetics.54 Although the availability remains variable, a significant effect is demonstrated using mucosal absorption methods. Thus, using drugs other than opioids, it is possible to overcome the problem of highly tolerant patients who are poorly responsive to systemic opioids, maintaining relatively low doses of drugs for a certain period, although the development of tolerance or a reduction of effect over time cannot excluded and should be assessed in future studies. Moreover, ketamine has been labeled a difficult drug to manage because of its well-known excitatory effects, and its use requires adequate experience. In patients in a palliative intensive care unit who were largely tolerant to opioids and were receiving intrathecal therapy in which even high doses of IV-MO were unsuccessful for BTP, boluses of intrathecal local anesthetics equivalent to the hourly opioid dose were safe and effective.54

Future developments Data on BTP are principally based on cross-sectional studies. Because of the dynamicity of cancer, pain components, including BTP, may vary over time. Thus, changes in the time of occurrence and incidence of BTP are likely and should be assessed in appropriate longitudinal studies overlapping the natural history of disease. BTP remains underdiagnosed because health care professionals do not have the necessary knowledge to adequately manage patients with this type of pain. Even when BTP medicine is prescribed, patients tend not to take it for various reasons.55 Thus, much effort should be dedicated to educating both patients and professionals. New delivery systems and more options are available, or will be available in the next few years, to provide a rapid onset of analgesia (i.e., within a few minutes) for treating BTP episodes. However, efforts should be made to develop preemptive treatments to limit the frequency and intensity

of BTP events. For example, bisphosphonates are promising agents, although specific studies with appropriate designs are lacking. Similarly, the new generation of antihyperalgesic drugs should be tested in this context. The extent to which basal analgesia is improved by titrating the basal opioid regimen, or even by switching opioids or adding specific adjuvant drugs, should be explored further. References 1. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 41:273–81, 1990. 2. Portenoy RK, Payne D, Jacobson P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 81:129– 34, 1999. 3. Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain 101:55–64, 2003. 4. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. J Pain Symptom Manage 20:87–92, 2000. 5. Fine PG, Busch MA. Characterization of breakthrough pain by hospice patients and their caregivers. J Pain Symptom Manage 16:179–83, 1998. 6. G´omez-Batiste X, Madrid F, Moreno F, et al. Breakthrough cancer pain: prevalence and characteristics in patients in Catalonia, Spain. J Pain Symptom Manage 24:45–52, 2002. 7. Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: a survey of hospice patients on admission. Palliat Med 15:9–18, 2001. 8. Petzke F, Radbruch L, Zech D, et al. Temporal presentation of chronic cancer pain: transitory pains on admission to a multidisciplinary pain clinic. J Pain Symptom Manage 17:391–401, 1999. 9. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain. Cancer 94:832–9, 2002. 10. Caraceni A, Martini C, Zecca E, et al. Working Group of an IASP Task Force on Cancer Pain. Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med 18:177–83, 2004. 11. Svendsen K, Andersen S, Arnason S, et al. Breakthrough pain in malignant and non-malignant diseases: a review of prevalence, characteristics and mechanisms. Eur J Pain 9:195–206, 2005. 12. Hojsted J, Nielsen PR, Eriksen J, et al. Breakthrough pain in opioid-treated chronic non-malignant pain patients referred to a multidisciplinary pain centre: a preliminary study. Acta Anaesthesiol Scand 50:1290–6, 2006. 13. Portenoy RK, Bennett DS, Rauck R, et al. Prevalence and characteristics of breakthrough pain in opioid-treated patients with chronic noncancer pain. J Pain 7:583–91, 2006. 14. Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Palliat Med 15:243–6, 2001.

breakthrough pain 15. Friedrichsdorf SJ, Finney D, Bergin M, et al. Breakthrough pain in children with cancer. J Pain Symptom Manage 34:209–16, 2007. 16. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 69:1–18, 1997. 17. Banning A, Sjogren P, Henriksen H. Treatment outcome in a multidisciplinary cancer pain clinic. Pain 47:129–34, 1991. 18. Mercadante S, Maddaloni S, Roccella S, Salvaggio L. Predictive factors in advanced cancer pain treated only by analgesics. Pain 50:151–5, 1992. 19. Mercadante S, Arcuri E. Breakthrough pain in cancer patients: pathophysiology and treatment. Cancer Treat Rev 24:425–32, 1998. 20. Medhurst SJ, Walker K, Bowes M. A rat model of bone cancer pain. Pain 96:129–40, 2002. 21. Luger NM, Sabino M, Schwei MJ, et al. Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs. inflammatory pain. Pain 99:397– 406, 2002. 22. Mercadante S, Villari P, Ferrera P, et al. Rapid titration with intravenous morphine for severe cancer pain and immediate oral conversion. Cancer 95:203–8, 2002. 23. Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate in patients with incident pain receiving regular opiates. A preliminary report. Pain 50:75–7, 1992. 24. Mercadante S, Villari P, Ferrera P, Casuccio A. Optimization of opioid therapy for preventing incident pain associated with bone metastases. J Pain Symptom Manage 28:505–10, 2004. 25. Wardley A, Davidson N, Barrett-Lee P, et al. Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer 92:1869–76, 2005. 26. Smith H, Navani A, Fishman SM. Radiopharmaceuticals for palliation of painful osseous metastases. Am J Hosp Palliat Care 21:303–13, 2004. 27. Rey P, Vecino A, Rubiales AS, Lopez-Lara F. Criteria of pain response to radiotherapy in advanced cancer patients. J Pain Symptom Manage 25:197, 2003. 28. Mercadante S, Villari P, Ferrera P, Dabbene M. Pamidronate in incident pain due to bone metastases. J Pain Symptom Manage 22:630–1, 2001. 29. Ripamonti C, Fagnoni E, Campa T, et al. Incident pain and analgesic consumption decrease after samarium infusion: a pilot study. Support Care Cancer 15:339–42, 2007. 30. Ripamonti C, Fagnoni E, Campa T, et al. Decreases in pain at rest and movement-related pain during zoledronic acid treatment in patients with bone metastases due to breast or prostate cancer: a pilot study. Support Care Cancer 15:1177–84, 2007. 31. Cerchietti LC, Navigante AH, Korte MW, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitisrelated pain: a pilot study. Pain 105:265–73, 2003. 32. Slatkin NE, Rhiner M. Topical ketamine in the treatment of mucositis pain. Pain Med 4:298–303, 2003.

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33. Zeppetella G, Paul J, Ribeiro MD. Analgesic efficacy of morphine applied topically to painful ulcers. J Pain Symptom Manage 25:555–8, 2003. 34. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 83:389–400, 1999. 35. Caraceni A, Zecca E, Bonezzi C, et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol 22:2909– 17, 2004. 36. Ross JR, Goller K, Hardy J, et al. Gabapentin is effective in the treatment of cancer-related neuropathic pain: a prospective, open-label study. J Palliat Med 8:1118–26, 2005. 37. Keskinbora K, Pekel AF, Aydinli I. Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: a randomized open trial. J Pain Symptom Manage 34:183–9, 2007. 38. Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage 20:246–52, 2000. 39. Mercadante S, Intravaia G, Villari P, et al. Intrathecal treatment in cancer patients unresponsive to multiple trials of systemic opioids. Clin J Pain 23:793–8, 2007. 40. Hanks GW, De Conno F, Cherny N, et al.; Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 84:587–93, 2001. 41. Mercadante S, Villari P, Ferrera P, et al. Safety and effectiveness of intravenous morphine for episodic-breakthrough pain, using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage 27:352–9, 2004. 42. Mercadante S, Intravaia G, Villari P, et al. Intravenous morphine for episodic-breakthrough pain in an acute palliative care unit: a confirmatory study. J Pain Symptom Manage 35:307–13, 2008. 43. Christie J, Simmonds M, Patt R, et al. Dose-titration multicenter study of transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 16:3238–45, 1998. 44. Coluzzi P, Schwartzberg L, Conroy J, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulphate immediate release (MSIR). Pain 91:123–30, 2001. 45. Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain 79:303– 12, 1999. 46. Farrar J, Cleary J, Rauck R, et al. Oral transmucosal fentanyl citrate: a randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst 90:611–16, 1998. 47. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain 22:805–11, 2006.

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48. Mercadante S, Villari P, Ferrera P, et al. Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Br J Cancer 96:1828– 33, 2007. 49. Hagen NA, Fisher K, Victorino C, Farrar JT. A titration strategy is needed to manage breakthrough cancer pain effectively: observations from data pooled from three clinical trials. J Palliat Med 10:47–55, 2007. 50. Keating HJ 3rd, Kundrat M. Patient-controlled analgesia with nitrous oxide in cancer pain. J Pain Symptom Manage 11:126– 30, 1996. 51. Enting RH, Oldenmenger WH, Van Der Rijt CC, et al. Nitrous oxide is not beneficial for breakthrough cancer pain. Palliat Med 16:257–9, 2002.

s. mercadante 52. Kotlinska-Lemieszek A, Luczak J. Subanesthetic ketamine: an essential adjuvant for intractable cancer pain. J Pain Symptom Manage 28:100–2, 2004. 53. Carr D, Goudas L, Denman W, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, doubleblind, placebo-controlled, crossover study. Pain 108:17–27, 2004. 54. Mercadante S, Arcuri E, Ferrera P, et al. Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain. J Pain Symptom Manage 30:485–91, 2005. 55. Davies A, Vriens J, Kennett A, McTaggart M. An observational study of oncology patients’ utilization of breakthrough pain medication. J Pain Symptom Manage 35:406–11, 2008.

28

Bone pain badi el osta and eduardo d. bruera The University of Texas M. D. Anderson Cancer Center

Introduction

Arrest of the metastatic cell in the bone marrow

The skeleton is one of the most common sites of tumor metastases. Metastatic cancer invades bone in 60%–84% cases.1 Up to 80% of all bone metastases are related to cancer of the breast, prostate, lung, thyroid, and kidney. Multiple myeloma also is commonly associated with skeletal disease. Approximately 70% of patients with bone metastases develop pain.2,3 In addition to pain, metastatic bone disease results in immobility, frequent hospital admissions, pathological fractures, metabolic complications such as hypercalcemia, neurological abnormalities, and bone marrow infiltration and suppression. These devastating symptoms may have a prolonged effect and also have major psychosocial implications. Detection of bone metastases may be the first indicator that cancer has not been cured; bone is the first site of recurrence in up to 40% of women with breast cancer. Patients suffering from bone metastases secondary to breast cancer survive an average of 34 months, with a range of 1–90 months.4 This chapter primarily discusses pain associated with bone metastases. It also addresses some of the recent developments in the prevention and management of osteolysis.

Primary tumors, such as lung or breast cancer, grow and invade adjacent normal tissues. As part of their growth, these tumors penetrate the blood and lymphatic vessels and cells are carried to different areas. Although the likelihood of a certain tumor invading bone as compared with other organs may be associated with the anatomic location of the tumor – for example, colon cancers drain into the portal system, making them more likely to metastasize to the liver – metastatic sites cannot be predicted from anatomic considerations alone. A number of animal and human tumor models show clear preference for metastases to one or two specific organs, which might be explained by organ tropism.5 Although tumor cells disseminate to all organs, they may adhere to the endothelial surface of the bone marrow in some patients, probably because of the presence of organ-specific endothelial determinants, such as glycoproteins, or the presence of local growth factors, cytokines, or hormones in the bone or bone marrow.5–8

Pathophysiology of bone pain The invasion of bone by tumor is well understood; however, the mechanisms of nociception are not well known. The three main mechanisms by which the skeleton is affected by cancer are primary bone cancer, direct invasion from adjacent primary tumors, and bone metastases. The last is by far the most common mechanism; primary tumors of bone are much less frequent. Fig. 28.1 summarizes the four sequential steps in the development of a painful bone metastasis.

Extravasation and growth in the interstitium Once the tumor cell has been arrested in the bone marrow, it proceeds to extravasate and grow in the interstitium before direct bone destruction. This local growth is conditioned by mechanical processes, local enzymes, growth factors, and host response. Although the invasive behavior of cancer in soft tissues can be explained largely on a purely mechanical basis, this mechanical theory cannot explain the invasion or destruction of calcified tissue. Therefore, in addition to the simple increased tumor size due to cell division, a number of products of malignant cells directly or indirectly cause resorption of bone, allowing tumor cells to grow into the reabsorbed space. Prostaglandins and cytokines, mainly in

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Arrest of metastatic cell in bone marrow

local growth

mechanical processes local enzymes growth factors host response

Extravasation and growth in interstitium

osteolysis

prostaglandins cytokines local host factors (tissue collagen, inflammatory response)

Invasion and growth in bone

Nociception Fig. 28.1. Steps in the development of a painful bone metastasis.

breast or renal cancer, probably play a major role in osteolysis. In some cases, specific factors capable of stimulating the osteoclast have been described. Finally, the local host environment affects the ability of tumor cells to invade. Tissues rich in collagen resist invasion because they act as a strong mechanical barrier. On the other hand, the inflammatory response of the host might aid tumor cell invasion by providing leukocytes with a large content of proteolytic enzymes, which can destroy host tissues.9 Invasion and growth in the bone Because the process of bone metastasis almost always starts in the bone marrow, bones more frequently involved are those with a high proportion of red marrow, such as the axial skeleton.10 Bone metastases are usually multiple at the time of diagnosis, with the exception of renal carcinoma or neuroblastoma, in which up to 10% of patients may have a single site of bone involvement.5–8 Metastatic cancer growth in the bone results in a combination of bone destruction and bone formation. In patients with radiographic appearance of lytic skeletal metastases, bone destruction predominates,

resulting in the net loss of bone. In patients with blastic metastases, excessive amounts of bone formation develop with less bone destruction. Whereas lytic metastases tend to be highly cellular, sclerotic metastases are relatively acellular and contain large islands of intramembranous new bone formation in the fibrous stroma (e.g., metastatic prostatic carcinoma). Whereas the initial process of bone destruction is mediated by osteoclasts, during the late stages of the metastatic process, the osteoclasts disappear but osteolysis continues. This is probably the result of tumor growth action.6 Osteosclerosis is mediated by osteoblasts, possibly stimulated by factors derived from the bone stroma. Nociception The mechanisms for the invasion and growth of metastatic cancer in bone and the production of nociception have been better understood in recent years. Between one fourth and one third of fully developed bone metastases will not cause any pain.3,6 Honore and colleagues11 developed a model of cancer pain by injecting murine osteolytic sarcoma cells into the intramedullary space of the murine femur. Aiming

bone pain to determine a characteristic neurochemical set for each mechanism of pain, they compared neurochemical changes that occur in the spinal cord and the primary afferent neurons in C3H/HeJ mice with cancer pain with those occurring in C3H/HeJ mice with pain due to inflammation, neuropathy, and nerve transaction. The neurochemical changes detected in the model of bone cancer were the increase in dynorphin-immunoreactive (dynorphin-IR) neurons in laminae III-VI of the dorsal horn and the increase in glial fibrillary acidic protein (GFAP) throughout the gray matter. Although these two changes were common between cancer and inflammation for dynorphin-IR and cancer and neuropathy for GFAP-IR, the increase in these two markers were the most pronounced in the cancer model (50%– 75% and 150%, respectively). Whether these neurochemical changes are incidental markers or involved in the generation and the maintenance of each type of pain remains to be determined. However, a variety of factors may play a role in the bone cancer pain state through tumor-induced tissue destruction and nociceptor activation:12 pro-hyperalgesic factors secreted by the cancer cells, such as prostaglandins and endothelins; tumor necrosis factor and interleukin-1 produced by the macrophages in the tumor mass; bone growth factors; compression of sensory neurons that innervate the marrow; tumor-induced proliferation and hypertrophy of osteoclasts; an acidic microenvironment, resulting from bone resorption and apoptosis; and mechanical stress. These factors are thought to change as the cancer progresses, making treatments for cancer bone pain different at each stage of the cancer.13 Mach and colleagues14 examined the innervation of the normal mouse femur by using immunohistochemistry with antigen retrieval, confocal microscopy, and threedimensional image reconstruction. They showed that the femur was remarkably rich and heterogeneously innervated by sensory and sympathetic fibers throughout the periosteum, the mineralized bone, and the bone marrow. The periosteum was the most densely innervated and the mineralized bone was the least. When factoring the total volume of each tissue, the bone marrow had the greatest number of sensory and sympathetic nerve fibers and the periosteum had the least. The fact that the bone marrow has abundant innervation may explain the absence of radiological findings and the presence of bone pain earlier in the disease. These fibers may mediate the initial pain, as they are the first fibers to become excited by the bone disease occurring in the intramedullary space. In another study, Honore and colleagues15 studied the effect of osteoprotegerin (OPG) as a possible treatment for bone cancer pain. Using the same murine model described

517 ealier,1 they found that treatment with OPG abolishes cancer-induced bone destruction and reduces cancerinduced skeletal pain and neurochemical changes in the spinal cord, without any observable side effect. The authors suggested that the effect of OPG is mediated through the inhibition of action of OPG ligand on osteoclasts, leading to the inhibition of osteoclast activity. Whether treatment with OPG can show a similar effect in humans with bone cancer pain remains to be determined.

Clinical features Autopsy studies suggest that the skeleton is the third most common site of cancer metastases, surpassed only by the lungs and liver. Pathological fractures have been reported to occur in 8%–30% of patients with bone metastases. Among patients treated surgically for bone metastases, the main source is breast, accounting for approximately 50% of total cases. Proximal parts of long bones generally are involved before the distal parts, and the bones that are fractured more often are the femur (50%), humerus (15%), or both.6 Other tumors capable of causing pathological fractures are kidney (10%), lung (10%), and thyroid (5%). Cord compression occurs in approximately 5% of patients. The most common primaries associated with this complication are breast (20%–30%) and lung (15%). Metastases from the prostate account for a fairly small percentage of the operative cases, partly because they most often occur in the lumbar spine, where they are not likely to cause spinal cord compression, and partly because they tend to be osteoblastic, with a relatively low incidence of fracture.16 Hypercalcemia occurs in approximately 10% of patients with malignancy and even more commonly in those with metastatic bone disease.17 When present, hypercalcemia causes significant cognitive impairment that makes the assessment and management of the pain syndrome more difficult. The diagnosis of bone metastases is usually very simple, even in patients with unknown primary tumor. Bone scans are highly sensitive for the detection of bone metastases but are relatively nonspecific.18 The false-negative rate for bone scans is approximately 8%, whereas the false-positive rate may be as high as 40%–50% when only a few positive lesions are observed. Therefore, abnormal observations in the bone scan should be confirmed radiologically.6,18 Radiography is specific but quite insensitive. At least 50% of the bone in the beam axis of the x-ray must be destroyed before lesions involving the medulla can be seen radiographically. In contrast, lesions that involve the cortex are detected when they are much smaller.2,3

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518 Table 28.1. Bone pain syndromes r Continuous bone pain r Incident pain r Mixed bone and neuropathic pain r Mixed bone and visceral pain

CT or magnetic resonance images give additional information, especially for lesions on the spine, when the possibility of spinal cord involvement is suspected, or in the case of direct involvement by tumors of the head and neck or intrathoracic malignancies.18 Another dimension to skeletal complications of malignancy exists in women who have been treated for breast cancer. This group has an increased risk of osteoporosis due to premature menopause induced by chemotherapy,19 and some chemotherapeutic agents are known to adversely affect bone formation.20 This increased risk of skeletal complications exists even in the absence of metastatic disease. Women with treated breast cancer without evidence of metastatic disease have been shown to have a risk of vertebral fracture five times higher than normal, and the risk was found to be 20 times higher in women with soft-tissue metastases without evidence of bone metastases.21

Pain syndromes Table 28.1 summarizes the most frequent syndromes associated with bone involvement by cancer.

perform the pain-causing maneuver (e.g., moving, standing, walking). Bone metastases are the most frequent cause of incident pain. Recent data suggest that episodes of incident pain occur in almost two thirds of patients with cancer pain, with a frequency range from just a few to several hundred per day, suggesting that incident pain is a serious management problem.22,24,25 It responds less well to opioids,22 because movement-related pain is repetitive and unpredictable, and doses of opioids required to control it may produce unacceptable side effects when the patient is at rest.26,27 Mixed bone and neuropathic pain In addition to either continuous or incident somatic bone pain, patients with mixed bone and neuropathic pain present evidence of involvement of areas of the central or peripheral nervous system. Most frequently, these patients present evidence of neuropathic pain due to involvement of the spinal cord, nerve routes, or peripheral nerves. The typical “burning” or “tingling” nature of the pain, the radiation following nerve distribution, and the presence of sensory or motor deficits are indicators of mixed bone/neuropathic pain syndromes. Pain related to spinal cord compression from collapse of a vertebral body typically is exacerbated by coughing, sneezing, and straining and becomes worse on straight leg raising. The location of the tumor frequently facilitates the diagnosis.24 Mixed bone and visceral pain

Continuous bone pain Continuous pain is the most frequent presentation of bone pain. Pain is usually well localized to one or more specific bone areas and can be pinpointed by the patient with relative ease. It usually has a gradual onset over a period of weeks or months, becoming progressively more severe in intensity. It may be dull in character and/or have a deep, boring sensation that aches or burns and may be accompanied by episodes of stabbing discomfort.22,23 Pain usually increases with pressure on the area of involvement, which may account for it worsening at night when the patient is lying down. Because of the higher prevalence of axial skeletal metastases, this pain is more likely to involve the pelvis, rib cage, or lumbar, dorsal, or cervical spine. Incident pain Patients with incident pain have mild or no pain while resting and mobile but suffer severe exacerbation when they

Patients with mixed bone and visceral pain present with metastatic locations in bone as well as in different intraabdominal or intrathoracic organs. In our experience, the most frequent associations are the presence of metastatic bone pain with intra-abdominal tumor or liver metastases. The diagnosis of visceral pain is usually relatively easy to make, and some patients may require specific analgesic techniques aimed at controlling the visceral component; therefore, inadequate diagnosis of the pain syndrome will have prognostic and therapeutic implications.24

Treatment Table 28.2 summarizes some of the available treatment modalities for bone pain. Time to pain relief and other beneficial effects vary with different types of treatment. This may influence the choice of treatment in an individual patient; for example, if life expectancy is very short, it may not be appropriate to commence treatment with

bone pain

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Table 28.2. Treatment modalities for bone pain

Table 28.4. Opioids for bone pain

r Opioid analgesics r NSAIDs r Corticosteroids r Bisphosphonates r Radiation therapy r Radioisotopes r Orthopedic surgery r Vertebroplasty or kyphoplasty r Hormonal therapy or chemotherapy r Other treatments

r Regular administration r Consider adjuvants (bisphosphonates, NSAIDs, corticosteroids) r Prevent side effects (nausea, constipation, sedation) r Less effective for incidental/neuropathic bone pain

osteolysis and/or fractures. In the following paragraphs, we discuss the role of some of these interventions. Opioid analgesics

bisphosphonates, radiotherapy, or radioisotopes. Table 28.3 shows expected time to first pain relief with various modalities of treatment. A recent study looking at risks of complications from bone metastases in breast cancer found that patients with metastatic disease confined to the skeleton are most likely to develop pathological fractures, to require radiotherapy to painful osseous deposits, and to develop spinal cord compression.28 This is the result, at least in part, of the increased survival in this group compared with those who have both osseous and extraosseous metastases. Median survival for patients with bone and liver metastases was 5.5 months. In a placebo-controlled study in 382 patients with bone metastases from breast cancer treated with intravenous (IV) pamidronate, statistically significant reductions in the need for radiotherapy and surgery to bone and in the occurrence of nonvertebral fractures were seen after 6, 9, and 12 months of treatment.29 By identifying patients most at risk of skeletal complications and looking at time to benefit from specific treatments, studies such as these may help improve cost–benefit analysis by helping to target those most likely to benefit from a particular treatment approach. Patients with bone involvement frequently require multimodal therapy consisting of the management of the primary cancer, analgesics, and/or measures to prevent further Table 28.3. Time to expected first improvement in pain with various treatments

Treatment

Approximate time to first relief

Bisphosphonates Calcitonin External beam radiotherapy Hemibody radiation Radioisotopes Hormonal treatments Vertebroplasty or kyphoplasty

1 week 1–7 days 2–3 weeks 2–3 days 1–3 weeks 2–8 weeks Immediate

Bone pain usually responds well to opioids,30,31 and they remain the mainstay treatment for symptom control of isolated bone involvement areas and for diffuse bone pain.32 Table 28.4 summarizes the general principles of opioid use for bone pain. A regular around-the-clock dosing of an opioid is advised, as most patients experience continuous pain. In addition, a breakthrough or rescue dose should be prescribed for breakthrough pain on an as-needed basis. The dose can then be titrated to achieve adequate pain control. A majority of patients likely will require a strong opioid agonist, such as morphine, hydromorphone, oxycodone, fentanyl, or methadone. At the same time, measures to prevent common side effects, such as constipation and nausea, should be implemented. In addition, knowledge of common neuropsychiatric side effects, such as opioid-induced delirium, hallucinations, myoclonus, and excessive sedation, as well as their management strategies, is essential.33 With regard to route of administration, the oral route is preferred, although on occasion, an alternative route is required. The subcutaneous route has been shown to be as effective as the IV route and more convenient. Other options include rectal and transdermal formulations. With regard to incident pain, titration of opioids may prove difficult, and these individuals may require shortacting breakthrough or rescue doses of analgesics to provide relief of pain that breaks through the chronic daily pain.22,34 Patients usually are advised to take these breakthrough or rescue doses before an activity that may elicit pain. Unfortunately, most patients with incidental pain find limited benefit from currently available breakthrough analgesics, because the duration of pain is shorter than the latency for analgesia.35 Newer, highly liposoluble opioids, such as transmucosal fentanyl, might prove particularly useful in the management of incidental bone pain.36,37 In cases in which severe sedation arises as a symptom of dose-limiting opioid toxicity during the intervals between incident pain, the addition of a psychostimulant may be considered; this may allow patients to tolerate a higher dose

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520 of opioids because of reduced sedation, thereby improving analgesia.35 Nonsteroidal anti-inflammatory drugs Although nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended by the World Health Organization as the first-line approach for the management of mild to moderate cancer pain,38 strong methodologically sound studies have yet to establish evidence-based support in favor of NSAIDs in cancer pain.39 Moreover, the use of NSAIDs carries the risk of the development of adverse reactions, particularly gastrointestinal, renal, and hematological effects. NSAIDs may cause renal insufficiency by impairing intrarenal blood flow via inhibition of prostacyclin, a renovasodilator. Thus, renal impairment may result in opioid metabolite accumulation, giving rise to various neuropsychiatric toxicities.40,41 Corticosteroids Corticosteroids appear to be effective in reducing bone pain from a variety of solid tumors. Apart from their adjuvant analgesic properties, corticosteroids have various other potential benefits for patients with advanced disease, including improvement in appetite, decrease in nausea, and improvement in the sensation of well-being.43 The ideal type of corticosteroid and optimal dose have not been well established; dose recommendations are based mainly on uncontrolled anecdotal reports and clinical experience. Recommended corticosteroids and doses are 4–8 mg of dexamethasone orally or subcutaneously two to three times per day, 20–40 mg of prednisone orally two to three times per day, or 16–32 mg of methylprednisolone orally two to three time per day.44 Dexamethasone appears to be preferred because of its ease of administration on a twice-daily basis and its minimal to absent mineralocorticoid effects. If effectiveness is demonstrated, the corticosteroid dose should be tapered gradually to the lowest possible effective dose or, if possible, be discontinued so as to avoid long-term adverse effects.42 Corticosteroids also have been found to be beneficial in the treatment of spinal cord compression and should be initiated early when spinal cord compression is suspected.45 In patients with relatively long expected survival, maintenance therapy with corticosteroids should be weighed carefully against the potential side effects, including immunosuppression, avascular necrosis, edema, hyperglycemia, proximal myopathy, and neuropsychiatric side effects.46 With regard to the latter, delirium has been found to be more common than mood disorders in cancer patients

making use of dexamethasone.47 As steroid myopathy may contribute further to decreased ambulation and immobility, this side effect, in particular, should be observed more closely. If it arises, consideration may be given to discontinuing the corticosteroid, which often results in complete reversibility of the problem.48 Another option for those who are benefiting from the use of a corticosteroid is to change to a nonfluorinated steroid such as methylprednisolone or prednisone.49 Bisphosphonates Patients with metastatic bone disease experience frequently severe bone pain.50–52 This type of pain is commonly treated with opioids and NSAIDs. First- and second-generation bisphosphonates (e.g., clodronate and pamidronate) have been shown to reduce bone pain arising from metastatic breast cancer and myeloma53–55 but do not lead to a statistically significant reduction in pain after 1–2 years of treatment.55 Bisphosphonates are analogues of pyrophosphate, a natural inhibitor of the formation of calcium phosphate crystals. Following systemic administration, these drugs have a complex effect on the function and differentiation of osteoclasts. Evidence is emerging that bisphosphonates may have direct antitumor effects in addition to their effect on osteoclasts.56,57 In vitro, they inhibit breast and prostate tumor cell invasion58 and also inhibit the proteolytic activity of matrix metalloproteinase in tumor cells. The mechanism for this appears to involve the chelation of zinc by the phosphonate group.56 In addition, bisphosphonates may have an apoptotic effect on macrophages and tumor cells.57 There are many bisphosphonates, all of which are capable of treating disorders of bone resorption, such as osteolytic metastases and osteoporosis; however, traditionally, some have been researched and used for treatment of certain conditions more than others. Clodronate and pamidronate have been studied most extensively in malignant disease, particularly in multiple myeloma and breast cancer. Studies also have been conducted in other solid tumors, including lung, gastrointestinal, and prostatic cancer.2 Table 28.5

Table 28.5. Clinical effects of bisphosphonates Level of evidence Analgesia Prevention of osteolysis Prevention of bone metastasis Improved survival

I I II II

bone pain summarizes some of the clinical effects of these drugs. Bisphosphonates currently are used for three main indications in the treatment of metastatic bone disease: to treat bone pain, to prevent skeletal complications, and to treat hypercalcemia. A recent review of phase III trials of a number of bisphosphonates in the treatment of painful metastatic bone disease reported strong evidence from numerous double-blind crossover trials demonstrating analgesic effects for these drugs.59 Therefore, bisphosphonates are a valuable analgesic treatment for most patients with painful metastatic bone disease. Clodronate probably has a shorter duration of analgesic effects as compared with pamidronate. However, one of its main advantages is that it can be delivered in relatively small volumes subcutaneously, with excellent local tolerance.60,61 Subcutaneous administration may be particularly useful for patients in rural areas, at home, or in continuing care facilities, or for those in whom IV access has become difficult because of poor veins.59 A recent systematic review addressed the role of bisphosphonates in the prevention of osteolysis.62 The author identified 18 randomized controlled trials providing level 1 evidence for the use of bisphosphonates to reduce both skeletal events and pain in multiple myeloma and breast cancer. Long-term follow-up (24 months) results from two prospective, multicenter, randomized, doubleblind, placebo-controlled trials were published recently. Pamidronate as a supplement to antineoplastic therapy in breast cancer patients with skeletal metastases was shown in long-term follow-up to be superior to antineoplastic therapy alone in palliating symptoms and preventing nonvertebral pathological fractures, hypercalcemia, and skeletal complications such as the need for surgery or radiotherapy. It also was found to delay the median time to first skeletal complication from 7 months in the placebo group to 12.7 months in the pamidronate group.63 Studies of oral clodronate in breast cancer patients have shown it to be effective in reducing the rate of morbid skeletal events,64 to significantly lengthen the time to first skeletal event,65 and to reduce the number of new skeletal metastases.66–69 Conflicting evidence exists regarding clodronate and its effect on nonosseous metastases. Three recent studies looked at oral clodronate, 1600 mg daily, in women with breast cancer. Diel et al.,67 who conducted a randomized controlled trial of oral clodronate over 2 years in women with breast cancer who had tumor cells detected in their bone marrow, found a significantly lower incidence of both osseous and visceral metastases in the treated group. At a median of 53 months, the prophylactic effect on bone metastases was still seen but was weakened, and the effect

521 on visceral metastases was no longer seen.68 The analysis of a larger multicenter placebo-controlled double-blind study of all women with primary breast cancer demonstrated a significant reduction in the incidence of bone metastases but no statistical difference in the number of visceral metastases in the treated group.69 A randomized controlled study in Finland of node-positive breast cancer patients indicated no significant difference between those who were treated with oral clodronate and controls in the incidence of bony metastases, increase in the number of visceral metastases, or deterioration in overall survival.70 Among these three studies, there were methodological differences in the groups, which may partly explain the dramatically different findings. Diel et al.67 studied patients with tumor cells in their bone marrow (patients with distant metastases were excluded), and it is possible that this group may benefit most from prophylaxis. The multicenter study was by far the largest and the only placebo-controlled study of the three. Clodronate has been studied extensively and used for many years, and there is no previous evidence that clodronate can adversely affect metastatic disease or survival in cancer patients. Further studies are required to clarify this issue. Bisphosphonates have poor intestinal absorption (⬍5%) and a short half-life. When taken orally, they must be taken with water at least 2 hours before and 2 hours after ingestion of food. They localize very selectively to bone and are retained very well there. They are generally well tolerated. The more common side effects are nausea, vomiting, fever, and elevation of serum creatinine. Nausea and vomiting are more common in first-generation bisphosphonates (etidronate and clodronate) and less common in newer drugs such as pamidronate and ibandronate. Hypocalcemia may occur with intravenous administration of bisphosphonates for bone pain, especially in patients who are normocalcemic before treatment.71,72 Esophageal erosions and ulceration are a rare but potentially very serious complication of oral bisphosphonate administration, and for this reason it is recommended that tablets be taken with about 200 mL of water when the patient is upright and that the patient remain upright for at least 30 minutes afterward. Caution is advised in patients with upper gastrointestinal problems, and bisphosphonates are contraindicated in those with achalasia or strictures, which cause delayed esophageal emptying. Patients should be advised to discontinue the drug and seek medical advice if esophageal symptoms develop. Newer bisphosphonates include alendronate, ibandronate, risedronate, and zoledronate. There is preliminary evidence that some of the newer bisphosphonates retain their effects on hypercalcemia and pain while requiring

522 much lower dosages. Ibandronate and zoledronate have been used in the treatment of hypercalcemia of malignancy; the effective doses for IV use appear to be as low as 2– 4 mg and 1–2 mg, respectively.73 Zoledronate in doses of 4– 8 mg has been shown to be superior to pamidronate, 80 mg, in reducing cancer hypercalcemia.74 Oral risedronate, 5 mg daily, has been shown to actually increase bone mass.75 An intermittent regime of oral risedronate, 30 mg/day for 2 of 12 weeks, gave similar results.76 There is recent evidence that oral ibandronate has potent effects on reducing the rate of bone resorption in patients with metastatic bone disease.77 Ibandronate is a third-generation bisphosphonate that is under evaluation for the treatment of metastatic bone disease. Body and colleagues78 conducted a multicenter, randomized, double-blind trial of patients with metastatic bone pain from breast cancer. They assessed the impact of intravenous ibandronate on bone pain. They found that patients receiving ibandronate, 6 mg IV every 3–4 weeks for 2 years, had highly significant reductions from baseline in pain scores compared with placebo (P ⬍ 0.001). In the light of Body’s study, Mancini and colleagues79 conducted an open-label pilot study to investigate the effect of short-term high doses of IV ibandronate on pain relief in patients with severe opioid-resistant metastatic bone pain. They used ibandronate, 4 mg IV in a 2-hour daily infusion for 4 consecutive days, as an adjuvant therapy to the patients’ opioid therapy. Pain was assessed using a visual analogue scale from 0 (no pain) to 10 (maximum pain). The authors concluded that ibandronate seemed to have a significant analgesic effect in patients with opioid-resistant metastatic bone pain during the 6-week period of the study (difference in pain scores: P ⬍ 0.001 at day 7 and P ⬍ 0.05 at day 42) as well as a positive effect on quality of life and performance status (P ⬍ 0.05). The adjuvant therapy was well tolerated, with no evidence of renal or gastrointestinal side effects. There is a lack of direct comparative evidence among different bisphosphonates in metastatic bone disease. At present, intravenous pamidronate is the only bisphosphonate approved for use in bone metastases in the United States. The idea of oral or even transdermal administration is appealing, especially for the newer, more potent bisphosphonates. Compared with the IV route for the treatment of bone metastases, the effects of oral administration have been marginal, and there have not been many well-designed placebo-controlled studies of oral bisphosphonates.80 Further trials with the specific end points of effects on bone pain and skeletal complications in patients with metastatic

b. el osta and e.d. bruera osseous disease are needed to accurately assess the effectiveness of oral bisphosphonates. The new bisphosphonates offer possible advantages in terms of side effects, administration routes, and regimes, but more research is required to assess their clinical benefits. The American Society of Clinical Oncology (ASCO) Bisphosphonates Expert Panel recently issued guidelines on the role of bisphosphonates in breast cancer based on currently available information.81 The following summarizes the panel’s findings and guidelines: r Bisphosphonates have not had an impact on overall survival in breast cancer. r Benefits have been reduction in skeletal complications (pathologic fractures, radiation, spinal cord compression, hypercalcemia, and surgery for fracture or impending fracture). r IV pamidronate, 90 mg over 1–2 hours every 3–4 weeks, is recommended in patients who have evidence of lytic destruction of bone on plain radiographs and who are concurrently receiving systemic hormonal therapy or chemotherapy. r Starting bisphosphonates in women with an abnormal bone scan and an abnormal CT or MRI scan showing bone destruction and localized pain but normal plain radiographs is considered reasonable. r Bisphosphonates are not recommended in patients with an asymptomatic abnormal bone scan and normal radiographs. r IV pamidronate is recommended in women with pain caused by osteolytic metastases to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy. r Oral bisphosphonates may be used for prevention of osteoporosis in premenopausal women with treatmentinduced menopause. r Use of bisphosphonates is not currently recommended in patients without evidence of bony metastases, including patients with extraskeletal metastases and those with high risk for future bony metastases.

The expert panel advised that future research is warranted to identify clinical predictors of when to start and stop therapy, to integrate their use with other treatments for bone metastases, to identify their role in the adjuvant setting in preventing bone metastases, and to better determine their cost–benefit consequences. Many areas in which the use of bisphosphonates is not currently recommended are a result of lack of evidence rather than proven lack of effect. There are many questions

bone pain related to bisphosphonate use, which need to be answered with further research: r Do bisphosphonates have a real preventive effect on the formation of new skeletal or visceral metastases? If so, in which group should we use them for prophylaxis? r Do bisphosphonates have an antitumor effect in humans? r Are the newer bisphosphonates more clinically effective or safer in the treatment of painful metastatic bone disease? r Is oral or transdermal administration of newer bisphosphonates as effective as the IV route? If so, are intermittent oral regimes as beneficial as a regular daily dose?

If direct antitumor effects of bisphosphonates are confirmed in vivo, bisphosphonates may have a role not only in helping to manage and prevent complications of preexisting painful skeletal metastases, but also in preventing new metastases by modifying the natural history of cancer in some patients. Osteonecrosis of the jaw Bisphosphonates have been proven to be very useful in conditions with excessive bone resorption.82 In cancer, bisphosphonate therapy has been used in metastatic bone disease, hypercalcemia, and multiple myeloma. Many published reports have suggested a relationship between bisphosphonate therapy, most commonly administered intravenously, and the development of necrotic bone lesions called osteonecrosis of the jaw (ONJ).83–85 The most common presentation of this entity is exposed bone pain of the maxilla and/or mandible after a dental extraction or trauma. The main mechanisms of ONJ development in patients receiving bisphosphonates are reduced blood supply by inhibiting angiogenesis, decreased bone turnover by inhibiting osteoclast activity, and bacterial superinfection by oral flora. Bamias and colleagues85 reported a prevalence of ONJ of 6.7% after treatment of 252 cancer patients with bisphosphonates. In a retrospective study presented at the 2006 ASCO meeting, Hoff and colleagues found an ONJ frequency of 1.2% (16/1998) in breast cancer and 3.1% in multiple myeloma (14/1448). Despite this low prevalence, clinicians have to be vigilant and encourage the reporting of ONJ because of its potentially high impact on patients’ quality of life. Among the risk factors Hoff and colleagues identified for ONJ are higher doses of IV bisphosphonates, longer treatment duration, dental extractions, and periodontal disease.

523 Van den Wyngaert and colleagues84 identified 225 cases of ONJ reported in 22 retrospective chart reviews available in the literature. Their main objective was to determine whether this association is a true causal relationship rather than a coincidence. The bisphosphonates used, mostly pamidronate and zoledronic acid, belong to the potent nitrogen-containing bisphosphonate class. The duration of therapy at the time of OJN diagnosis was presented for 60 patients (26.7%) and ranged from 1 to 94 months, without a clear time dependency. The most common symptom of OJN at presentation was pain (81.7%), followed by purulent discharge (8.7%), oroantral fistula (6.1%), swelling (2.6%), and fever (0.9%); 69.3% of patients had a dental extraction preceding the diagnosis of ONJ, 74.5% were on chemotherapy, 38.2% received corticosteroids, and only 4.4% received radiotherapy to the jaw. Unfortunately, ONJ has been refractory to the treatments focusing primarily on local irrigation and long-term antibiotic therapy. Kademani and colleagues85 reported two cases in which surgical salvage was performed successfully for ONJ. In their opinion, primary tension-free closure of the wound site, with or without local pedicle flaps, ensures a sufficient blood supply and adequate protection for effective bone healing to occur and therefore to treat ONJ. However, more data are needed, and patients should be selected carefully for such therapy by experienced surgeons. In view of the difficulty of ONJ treatment, a thorough dental screening for patients likely to need bisphosphonates is warranted to identify existing infections, compromised teeth, and ill-fitting dentures. However, if dental extractions are necessary during or after IV bisphosphonate therapy, Kademani and colleagues85 believe that surgical salvage holds promise as a preventive option when performed by experienced surgeons. Calcitonin Salmon calcitonin is used in the management of benign bone pain in Paget’s disease and osteoporosis. A number of studies have shown it to be useful in metastatic bone pain.86–88 Some studies have shown benefit occurring within a few days of initiation of subcutaneous calcitonin,86,89 and even as early as 12 hours.88 Calcitonin is cheaper than bisphosphonates and comes in subcutaneous and nasal preparations; however, it has a more troublesome side effect profile and appears to be less potent than bisphosphonates, which generally have superseded its use. Because of its rapid onset of action, it may have an advantage in individual patients with severe acute bone pain or in those with a very short prognosis.

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524

The Bone Pain Trial Working Party study randomly assigned 761 patients to receive a single fraction of 8 Gy or a multifraction schedule of either 20 Gy in five fractions or 30 Gy in 10 fractions. Patients were followed up for 12 months. Overall survival was the same in both groups, with 44% of patients alive at the end of the 12-month study period. No statistical difference was observed between the groups in time to first improvement of pain, time to complete pain relief, time to first increase in pain, or in class of analgesics used. In both groups, 78% experienced pain relief, with complete pain relief in 57% of the singlefraction group and 58% of the multifraction group (difference in proportions, –1%; 95% CI, –9% to 6%). Retreatment was twice as common in the single-fraction group, which was thought to reflect a greater willingness to retreat with radiotherapy after a single fraction rather then a greater need. No significant difference was seen in the incidence of nausea, vomiting, pathological fracture, or spinal cord compression.93 The Dutch Bone Metastasis Study randomly assigned 1171 patients to receive 8 Gy in a single fraction or 4 Gy in six fractions. Median survival was 7 months; the overall pain response rate was 71%, with a complete response rate of 35%. There were no significant differences in these parameters between the two groups. The two treatment schedules were thought to be equivalent in terms of palliation rate. No significant differences were found in time to response, mean pain scores, time to progression of pain to original level, side effects (nausea, vomiting, tiredness, itching, and painful skin), percentage of patients using pain medication (including strong opioids), or quality of life. The incidence of spinal cord compression was similar, although significantly more patients in the single-fraction group than

Radiotherapy External beam radiation directed at the site of pain is well established and the treatment of choice for local bone pain due to metastatic disease.90 Pain relief usually occurs in 2–4 weeks. It is not suitable in patients who have multiple painful metastatic sites; in these patients, hemibody widefield irradiation may be useful. The upper body or lower body may be irradiated (usually in a single fraction of 6 Gy for the upper body and 8 Gy for the lower), and pain relief often occurs within 1–2 days, which is considerably earlier than in those who have external beam radiotherapy to a local lesion. In one series, 73% of those treated with a single dose of hemibody irradiation experienced pain relief.91 The side effect profile is more troublesome than that of external beam radiation, the majority of patients develop a period of bone marrow suppression, and there is a risk of potentially fatal radiation pneumonitis in those who have upper hemibody irradiation. The other radiation treatment modality that is useful for patients with bone pain from multiple metastatic sites is administration of bone-seeking radioisotopes. There is some evidence that radiotherapy to individual bony sites in brief courses for pain relief offers a significant cost advantage over narcotic analgesics.92 Traditionally, radiation has been administered in multiple fractions over several days and weeks, although current evidence indicates that single fractions are as effective as multiple fractions when pain relief is the goal.93–95 Two recent large prospective randomized trials compared single-fraction and multiple-fraction radiotherapy for local metastatic skeletal pain.93,94 Their findings are summarized in Table 28.6.

Table 28.6. Summary of two large trials comparing single-fraction and multifraction radiotherapy BPTWP (n = 761)

Overall response rate (%) Complete response rate (%) Retreatment rate (%) Survival, time to response, class of analgesics Nausea, vomiting Spinal cord compression Pathological fracture rate

DBMS (n = 1171)

Single fraction

Multiple fraction

Single fraction

Multiple fraction

78 57 23a

78 58 10a

72 37 25b

69 33 7b

No significant difference No significant difference No significant difference No significant difference

No significant difference No significant difference No significant difference 4% for single fraction vs. 2% for multifraction (P ⬍ 0.05)

P ⬍ 0.001. P ⬍ 0.0001. Abbreviations: BPTWP, Bone Pain Trial Working Party; DBMS, Dutch Bone Metastasis Group. a

b

bone pain

525

the multifraction group experienced pathological fractures (4% vs. 2%). There were significantly more retreatments in the single-fraction group (25%) than in the multifraction group (7%). Retreatment appeared to depend on preceding pain score (P ⬍ 0.0001); the higher the original pain score, the higher the chance of retreatment. Retreatments were done at a lower pain score and earlier in the single-fraction group, indicating that doctors were more willing to re-treat this group. There was no indication that treatment effects depend on tumor type or localization of bone metastases. The equality of single-fraction and multifraction treatment also was seen in long-term survivors.94 The authors pointed out that there may be a group of patients in whom singlefraction treatment is not the best approach and indicated that further analysis of their data is needed to look at this area. A smaller prospective nonrandomized study in 205 patients with a variety of primary tumors found that aggressive protracted radiotherapy offered advantages in patients in whom the expected life span was not short.96 When patient convenience and the economic benefit are taken into account, single-fraction radiotherapy has many advantages and is preferable to multifraction radiotherapy for the majority of patients with uncomplicated metastatic bone pain. Radioisotopes/radiopharmaceuticals Bone-seeking radioisotopes are administered parenterally and, unlike external beam radiotherapy, all bony metastatic sites are targeted at once. Table 28.7 compares various radioisotopes. Bone-seeking radioisotopes such as strontium-89 (89 SR) have been found to be effective in randomized controlled trials.97,98 The disadvantages of strontium therapy include potential for severe hematological toxicity, delay in pain relief, and high cost. There is substantial evidence that samarium-153ethylenediaminetetramethylene phosphonic acid (153 SmEDTMP) has a therapeutic benefit comparable with that of 89 SR,99,100 and it is now licensed for use in the United States. Rhenium-186-1,1-hydroxyethylidene diphosphonate (186 Re-HEDP) is not yet licensed for use in the United

States, and clinical experience with this agent is limited. A recent open clinical trial in 60 patients looked at the shortand long-term effects of treatment of painful bony metastases. 186 Re-HEDP was found to give pain relief to patients with a variety of tumors; 80% of individuals treated had prompt relief of pain (clinically evident pain relief the first week), 31% experienced complete relief, 34% had partial relief, and 14% had minimal relief. It was effective against advanced and relatively early stages of metastatic disease. Transient World Health Organization grade 1–2 hematological toxicity was seen with complete recovery. The duration of pain relief lasted from 3 weeks to 12 months and correlated positively with the degree of response. There was also an indication that 186 Re-HEDP may slow the progression of metastatic bone disease.101 Further research is required to look at this potential effect. Radioisotopes should show selective uptake in metastases rather than normal bone, and they should be cleared quickly from normal bone and soft tissues. Generally, radioisotopes may be considered in patients with refractory multifocal pain caused by metastatic disease. Eligible patients should have a life expectancy greater than 3 months, sufficient bone marrow reserve, and no further chemotherapy planned. Absolute platelet count less than 60, 000×106 , a recent rapid fall in platelet count, and a white cell count less than 2.5×106 are contraindications to the use of radioisotopes because of the risk of further bone marrow suppression following treatment. Patients with advanced prostate cancer may have subclinical disseminated intravascular coagulation; therefore, it is advisable to screen these patients with blood tests before initiating therapy.102 The slow onset of effect makes this modality inappropriate as a single therapy for patients with severe cancer pain. Clinical experience in the setting of palliative care in hospice does not seem to mirror the positive effects reported in the literature. Although radioisotope/radiopharmaceutical therapy may be well tolerated in the short term, data concerning long-term toxicity are very limited. At present, there is insufficient evidence to support the use of radiopharmaceutical therapy in patients with multiple painless skeletal metastases or in prostate cancer patients with a rising

Table 28.7. Comparison of radioisotopes Radioisotope (hematological toxicity) 89

Status

Sr (moderate) Licensed Sm-EDTMP (mild/moderate) Licensed 186 Re-HEDP (mild/moderate) Clinical trials 153

Half-life (days)

Response rate (%)

Time to response (days)

Duration of effect (months)

50.5 1.95 3.8

60–80 70–75 60–75

10–20 5–10 5–10

2–12 2–6 1–4

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526 prostate-specific antigen level as evidence of treatment failure but with no bone scan evidence of metastases.102 However, trials are underway in this area. Radioisotopes are a very expensive treatment option when compared, for example, with bisphosphonates, so they must prove themselves to be cost-effective. There also are ongoing trials to compare radiopharmaceuticals with bisphosphonates and to determine whether cisplatin as a radiosensitizer can improve the effectiveness of radiopharmaceuticals. Orthopedic surgery The possible direct consequences of not managing bone metastases adequately are fracture, pain, and neurological deficits. Pathologic fractures of bone generally will not heal by themselves because of excessive osteoclastic activity in the area of metastasis; this situation is complicated further by the fact that patients often are undernourished and their overall physical condition is compromised by their primary disease. Current techniques for surgical management of pathological fractures are extremely effective in alleviating pain and allowing patients to resume mobility, often without the need for external support. Table 28.8 outlines the percentages of patients getting good or excellent pain relief from various procedures. Improvement in pain and mobility significantly improves the quality of these patients’ remaining months or years. Long-term survival after the first pathological fracture from malignancy has more than tripled for patients with most cancers in the past 25 years. Surgical techniques for stabilizing pathological or impending fractures must be individualized according to the area of involvement, the particular qualities of the bone involved, and the potential for involvement of adjacent soft tissue structures.103 Many factors must be taken into account when considering a patient’s suitability for surgery. Fitness for surgery, the degree of pain or functional loss, the potential benefits to be gained, and the potential risks of surgery need to be considered. An expected survival of only weeks to

Table 28.8. Percentage of patients experiencing good or excellent pain relief with various orthopedic procedures for metastatic bone disease95

Procedure

Patients with pain relief (%)

Internal fixation of long bone fracture Acetabular joint reconstruction Decompression and stabilization of vertebra

96 84 88

months is not necessarily a contraindication to surgery.10 Even for bedridden terminally ill patients, orthopedic procedures may improve some degree of function and ease the nursing care of the patient. In many cases, particularly those involving pathological fractures of the hips and lower extremities, surgery offers the only definitive therapy to control pain and improve mobility. Quality of life is much better without the fear of fracture or pain, and surgery should be considered even if life expectancy is short. Orthopedic surgical interventions are useful in three main areas: 1. Prevention and treatment of long bone fractures 2. Reconstruction of major joints 3. Reconstruction/stabilization of the spine with or without decompression Prophylactic stabilization or fixation is recommended in cases in which there is a high risk of pathological fracture. It is much easier to treat an impending fracture than a complete fracture of a long bone. Lesions in long bones that involve at least 50% of the cortex have at least a 50% chance of fracture if not reinforced.104 Fracture is more imminent if the lesion is purely lytic and exceeds 5 cm in length; purely blastic lesions have a much lower risk of fracture and rarely require prophylactic fixation.10 Pain on weightbearing may be a warning of impending fracture. Upper- and lower-limb long bone fractures, such as those of the femoral shaft, tibia, humerus, radius, and ulna, require intramedullary rods, which act as load-sharing devices, distributing stresses along the bone in a graduated fashion. Plate-and-screw fixation is not suitable for these bones, as it results in excessive stress being applied to the area of bone where it is fixated; if the bone in this area is weakened by a metastatic lesion, another pathological fracture likely will develop. Because it is not a main structural member, the fibula generally does not require an intramedullary rod. Fixation devices for lower-extremity long bones, such as the femur, must be able to withstand weightbearing stresses; those used in the upper limbs often are subjected to forces inherent in lifting and pulling in addition to heavy compressive forces, particularly in patients who require crutches or other devices to assist them in walking. The efficacy of subsequent irradiation is improved by debulking as much tumor tissue as possible by curettage at the time of surgery. Defects may be filled with methylmethacrylate. Occasionally, it is necessary to replace an entire joint or one component of a joint. Proximal femoral lesions involving the head, neck, and/or intertrochanteric regions

bone pain may require replacement prostheses. Prostheses also are required for lesions in the proximal humerus affecting the articular cartilage or for fractures that occur through the anatomic neck of the humerus. In the knee, if there is destruction of articular cartilage, which prevents painless articulation, a total knee replacement is indicated. Most spinal metastases can be managed conservatively. Surgical intervention is required in patients who present with progressive neurological compromise or spinal instability. Stability of the spine can be assessed using the Kostuik classification system. The vertebrae are divided into six columns: right and left anterior and posterior vertebral body columns and right and left posterior columns, which include the pedicles. These are best assessed on the axial view of a CT scan. Destruction of two columns is considered stable, whereas destruction of three or more is considered unstable, making fracture likely. If the spine is stable and the patient’s pain is the result of bone destruction alone or compression from tumor alone, external beam irradiation often will be effective. If the tumor is not radiosensitive or if there is compression due to tumor and debris such as bone, disk, or ligamentous material, a surgical approach may be required. Mechanical instability, neural compression caused by tumor growth, and progressive neurological deficit during or after radiotherapy are indications for surgery to decompress and stabilize the spinal column. Techniques for vertebral stabilization have improved and include anterior and posterior approaches and endoscopic techniques. Most vertebral lesions that require decompression and stabilization originate in the vertebral body and are best managed by an anterior approach; decompression and stability can be achieved satisfactorily this way. This approach is superior to a posterior approach in terms of improvement in neurological function.105 Less frequently, tumor destruction posteriorly (e.g., of pedicles) necessitates the use of a posterior in addition to an anterior approach. Percutaneous vertebroplasty (methylmethacrylate cement injection) is another technique that has been used for spinal stabilization, but its use seems to be limited in patients with vertebral compression fractures related to malignancy.106 External beam irradiation, given to almost all patients after surgery, helps achieve pain control and inhibits local disease progression. It may be commenced 2 weeks after surgery if the wound is healed and there is no other local complication. Rehabilitation is very important in patients who have had surgery for a pathological fracture. In patients with more advanced cancer, rehabilitation aims to relieve discomfort and improve quality of life by reducing physical

527 dependence. This differs from rehabilitation in other areas, in which the goals are the return of the individual to a higher level of functioning, such as a return to work. The need and motivation for rehabilitation are great in terminally ill patients.107 Cancer patients who have had surgical treatment of a fracture are particularly in need of rehabilitation and, if possible, mobilization, to improve their level of functioning and prevent muscle wasting caused by immobility. Physical therapy is especially important in patients with paraplegia, to help them gain control and independence and to help prevent complications such as pressure sores and phlebitis. Vertebroplasty and kyphoplasty Vertebroplasty and kyphoplasty are two new minimally invasive techniques used to treat painful vertebral compression fractures (VCFs).108 These procedures require a clinician trained in spine anatomy and fluoroscopic imaging. A French group first introduced vertebroplasty in 1987 for the treatment of painful hemangiomas.109 Later, the use of this technique was expanded to the management of back pain caused by metastatic, traumatic, or osteoporotic fractures.110–112 Vertebroplasty consists of injecting bone cement, generally polymethyl methacrylate (PMMA), percutaneously into a vertebral body. Kyphoplasty consists of creating a cavity in the vertebral body by a sequence of inflating and deflating a balloon placed percutaneously before the cement injection. This technique may restore vertebral body height and reduce the kyphotic angulation associated with the compression fracture before cement injection. These procedures should be performed in a sterile operating suite where fluoroscopic imaging of the spine is feasible. Patients undergo these procedures under general anesthesia or monitored anesthetic care. Before these procedures, patients should be off anticoagulants, have a normal coagulation profile, and have a platelet count ⬎100,000. Sepsis and active infections are contraindications. To decrease risks, a waiting period of 2 weeks is recommended after treatment of an infection.108 Ideal candidates for either of these procedures have activity-related pain corresponding to the level of the compression fracture. A complete neurological examination and recent imaging studies are mandatory. On MRI, a recent VCF will show an increase in T2 signal and asymptomatic cord compression, which is a relative contraindication. A bone scan is helpful in showing multilevel fractures. CT reveals more detail of posterior cortical fractures. A plain spine radiograph delineates

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528 the pedicle anatomy, which is helpful in planning the procedure. Like any intervention, these two techniques are not devoid of complications that must be made clear to the patient when obtaining the informed consent. These complications include lack of pain relief; osteomyelitis; fracture of the vertebra or pedicle; extravasation of the cement into the spinal canal or neural foramen, or anteriorly into the paraspinous veins; paralysis or nerve root damage; and venous embolism. Also, the need for open surgery should be discussed with the patient. More studies are needed to determine the short- and long-term safety of these procedures.113–115 In a retrospective review, Fourney et al.116 evaluated the outcomes of 56 patients (21 with myeloma) with 97 cancer-related VCFs. Sixty-five levels were treated with vertebroplasty and 32 with kyphoplasty. Eighty-four percent of patients had pain relief post procedure during a mean follow-up of 4.5 months. PMMA leak was found in 9.2% of vertebroplasty cases, compared with 0% in the kyphoplasty group. The authors concluded that kyphoplasty and vertebroplasty are safe and effective for treating cancer-related VCFs. In another retrospective review, Wang et al.117 looked at 43 levels treated with vertebroplasty and 24 treated with kyphoplasty and concluded that these two procedures are safe and effective for treating myeloma-related VCFs. Pain score decreased from 7 to 2 at 1-year follow up. Asymptomatic PMMA leakage was observed in 4% of cases. Despite the lack of randomized clinical trials to prove the safety, outcomes, and cost-effectiveness of these techniques in bone pain, vertebroplasty and kyphoplasty remain promising in the treatment of painful VCFs related to cancer.108 Hormonal therapy and chemotherapy Antineoplastic interventions are of great importance in the management of metastatic bone pain. In some cases, such as prostate and breast cancer, simple hormonal interventions are capable of achieving pain relief in 60%–80% of patients, with minimal cost and toxicity. It is important to remember that even in the most successful cases of pain improvement with hormonal therapy and/or chemotherapy, analgesia occurs in a minimum of 2–8 weeks. Therefore, a plan for appropriate analgesic therapy needs to be in place for at least this period. Medical oncologists must manage pain effectively with the previously mentioned techniques while antineoplastic interventions are being considered and administered.

Other treatments Anesthetic techniques such as nerve blocks and intraspinal infusion of opioids or local anesthetics may be effective in patients who have not improved with other treatments. The main limitations of these interventions are their high cost and the need for specialized services for their maintenance. Neurosurgical procedures such as percutaneous cordotomy may be very useful for unilateral pain syndromes below the waist. With these techniques, analgesia has been reported to be prompt and to occur in the great majority of patients.

Future research The pathophysiology of bone pain is not well understood. The potential role of different tumor, endothelial, and host humoral factors needs to be adequately established. Increasing our knowledge of the role of different factors in the production of nociception at the bone level will make it possible to develop specific analgesic techniques in the future. Bone pain syndromes have not been appropriately characterized. A better definition of the clinical presentation of different bone pain syndromes will allow researchers and clinicians to better express the characteristics of patient populations and to evaluate therapeutic techniques. The role of bisphosphonates needs to be better clarified. However, the currently available agents and those under development are among the most promising developments for the management of bone pain in recent years. Finally, the role of more traditional interventions, such as chemotherapy, hormonal therapy, and even radiation therapy, must be better characterized in clinical trials that provide for adequate blinding. It is hoped that these trials will better illustrate the real potential of these agents in cancerrelated bone pain. References 1. Galasko CSB. Skeletal metastases. Clin Orthoped 210:18–30, 1986. 2. Pereira J. Management of bone pain. In: Portenoy R, Bruera E, eds. Topics in palliative care, vol. 3. New York, Oxford: Oxford University Press, 1998, pp 79–116. 3. Lote K, Walloe A, Bjersand A. Bone metastases: prognosis diagnosis and treatment. Acta Radiol Oncol 25:227–32, 1986. 4. Koenders PG, Beex LV, Kloppenborg PWC, et al. Human breast cancer: survival from metastases. Breast Cancer Res Treat 21:173–80, 1992. 5. Liotta LA, Stetler-Stevenson WGD. Principles and practice of oncology. Philadelphia: Lippincott, 1989, pp 98–115.

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SECTION X

SYSTEMS OF CARE

29

Integrating cancer pain management into hospice practice and institution-based palliative care programs sandra p. gomez a,b and paul w. bwalker b a

Memorial Hermann The Woodlands Hospital and The University of Texas M. D. Anderson Cancer Center

Introduction Institution-based palliative care continues to change rapidly thanks to the commitment of research in the field of palliative medicine. Home hospice care in the United States, however, still struggles to incorporate evidence-based medicine into its medical practice. Multiple reasons exist, including lack of physician leadership due to busy private practices, minimal available full-time opportunities for physicians in hospice care, poor support from hospices in the training and retention of qualified physicians, and a lack of teaching of hospice nursing staff by their team physicians. We have observed that two main factors affect the care of patients in home hospice today: tradition and economics. Many hospice treatments and guidelines exist because no one has had the time or interest in updating them or because some treatments exceed the allotted budget. With the support of the American Academy of Hospice and Palliative Medicine, however, there is a revival of interest in changing the involvement that physicians have in the care of the dying. Physicians dedicated to the field of hospice care are becoming board certified in hospice and palliative medicine, updating their knowledge, participating in research, developing into excellent teachers, and becoming physician champions for the field. This is the catalyst that will help the modern hospice movement incorporate evidence-based medicine and best clinical practice into this vital and final phase of the continuum of palliative care. This chapter is written to support physicians in the evolution of hospice care by addressing common problems faced in the care of patients in the home setting. This chapter also provides guidelines for physicians to discuss with their nursing staff in developing or updating treatment plans in their own community settings. For many years, home hospice nurses have been

the backbone of hospice, and it is time to increase physician support by continuing to help them through education and mentorship. This chapter outlines common skills that are important in the care and evaluation of patients dying at home. A review of pain assessment of the nonverbal patient will help the reader understand the needs of this special population. Routes of medication administration common in the hospice setting are reviewed, with a focus on subcutaneous medication administration, a route of medication delivery that is still new for many in the field. Common psychosocial problems, such as difficulties with medication diversion, depression in the dying, and the difficulties in understanding suffering at the end of life, are addressed. All these issues affect pain management in this unique population. This chapter was composed primarily by using a review of the literature, input from multiple hospice medical directors from different parts of the United States, and suggestions of topics for discussion from interdisciplinary teams.

Understanding hospice services in the United States The Study to Understand Prognosis and Preferences for Outcomes and Risks of Treatments (SUPPORT) showed that many patients die prolonged and painful deaths.1 It has been suggested that advances in medical technology have propelled the medical community to see a “good” death as one involving the fight against the disease. This has partly contributed to the emergence of the modern hospice movement.1 Hospice is a model designed for providing care to patients at the end of life. The Medicare hospice benefit requires that patients admitted into hospice care have a prognosis

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536 of 6 months or less if the disease follows its normal course. Several private insurance companies provide a hospice benefit that requires a prognosis of 12 months or less. A randomized trial showed significant improvements in quality of life when cancer care and hospice care were combined.2 Many patients and families still think of hospice as a “place you go to die.” Hospice is not a place but a philosophy of care centered on the emotional, physical, spiritual, and social needs of the patient. Care is managed by an interdisciplinary team (IDT). The 24-hour custodial care is provided by the family or other caregivers. The family and caregiver have access to the hospice team 24 hours a day, 7 days a week (24/7). The IDT is composed of registered nurses, social workers, chaplains, and physicians; other disciplines that assist in the care of the patient include home health aids, volunteers, bereavement counselors, pharmacists, advance practice nurses, and licensed practical nurses. When a patient’s condition requires it, the care also may involve dietitians and physical, speech, and occupational therapists contracted by the hospice. Frequency of nursing visits and home health aid services is determined by the IDT and may vary depending on the staffing ratios of the hospice and the needs of the patient. There are four levels of care that hospice must provide: 1. Routine home care. Care is provided in the patient’s home setting, which may include a nursing home, assisted living facility, or personal care home. 2. General inpatient care. The patient is admitted to a hospice-contracted facility for management of distressing symptoms related to the terminal diagnosis that are not manageable in the patient’s home setting. This care also may be provided in a hospice inpatient unit. Patients must meet certain criteria to be admitted, and there is a limit to the number of days they can stay. 3. Respite care. The patient is admitted to a hospicecontracted facility that is able to provide 24/7 registered nurse supervision for a limited number of days. This time is used so the family or caregiver can rest. This level of care is not appropriate to handle medical emergencies. 4. Continuous care. The patient is provided one-on-one nursing care for a minimum of 8 hours in a 24-hour period, but it may include around-the-clock nursing care for a limited amount of time. There are certain criteria that must be met to qualify for this service. Hospice patients can transition between the levels of care during their admission to hospice as their condition follows

the course of the disease. Admission to a general inpatient setting allows access to more resources, such as intravenous (IV) or subcutaneous medications, laboratory tests, and diagnostics, which at times may be needed to maximize the patient’s comfort. As patients continue to decline as a result of their terminal condition, families or caregivers may find themselves in an exhausting situation. This may lead to a breakdown in their coping skills, resulting in a situation known as “family breakdown.” In this situation, the family or caregiver is no longer able to care for the patient, either physically or emotionally. It is not unusual to admit hospice patients to a general inpatient level of care if the patient’s condition is deteriorating because of the family’s inability to cope with the situation. Respite care also may be used for this purpose. During this transition, the social worker on the team assesses the need for permanent placement in another facility and determines whether the home environment is safe for the patient to return. Hospice provides durable medical equipment required for the care of the patient, which may include multiple items from hospital beds to ventilators. Medications related to the terminal condition are covered by the hospice and are delivered directly to the patient’s home. In addition, once a patient dies, the family and caregivers are offered 13 months of bereavement services. The cost of bereavement services is covered by the hospice for 13 months, even though there is no further collection of fees from Medicare or other payors after the patient’s death. Medicare reimbursement for hospice services is based on a per diem, all-inclusive rate that must cover all services related to the terminal illness; the rates for 2009 are displayed in Table 29.1. Despite adjustments for inflation, the fees have not kept up with the cost of cutting-edge palliative treatments, and most experts agree that it is difficult to meet the needs of a dying patient on a capitated fee.3 It is because of this reimbursement model that patients often are Table 29.1. Level of care and Medicare reimbursement for 2009 Level of care

Reimbursement

Routine home care Continuous care

$140.15/day Full rate of 24 hour: $817.26 Hourly rate: $34.06 $152.41/day $622.66/day

Inpatient respite care General inpatient care

Data from the Department of Health and Human Services, Centers for Medicare and Medicaid Services, available at www.cms .hhs.gov/Hospice/downloads/hospicerates09.pdf. Accessed July 10, 2009.

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made to choose between palliation from oral chemotherapies, radiation, costly antiemetics, or blood transfusions and hospice care, even if their disease carries a prognosis of less than 6 months. These palliative treatments are difficult for a hospice to cover when its reimbursement is capped at about $140/day to cover all services related to the terminal diagnosis.

infusion company. Eileen was able to return home, where she died 6 weeks later under the care of hospice, which was able to coordinate her complex symptom management. Cases like Eileen’s are rare but illustrate the coordination between hospices and payor sources to improve care and maximize choices for patients and families. Another example of this type of coordination and utilization of open-access hospice involves patients who are currently on ventilators in an inpatient setting whose wish, or family’s wish, is to be extubated at home. Some hospices work with hospitals or other inpatient facilities to transport patients home, where they are extubated under the care of hospice. Hospice’s main focus remains providing care in the home, and it relies on the primary medical team’s duty to discontinue unnecessary monitoring or treatments before the patient’s discharge. A palliative care referral before a hospice referral may assist the primary medical team in determining the needs of the patient and clarifying the goals of care from curative to palliative.

The case of Eileen Eileen was only 52 and suffered from an aggressive ovarian cancer. She was given a prognosis of a few weeks by her oncologist and was now dependent on total parenteral nutrition (TPN) because of an inoperable bowel obstruction. Her care was complicated by issues of nausea, pain, and multiple pressure ulcers. These issues made her care too complicated to manage by the local home health agency because she lived in a rural setting 45 miles from the nearest community hospital. Her family traveled 4 hours each day to visit her at the large cancer center where she was currently admitted. Her final wish was to return home to be with her family and countless pets until the time of her death. Hospice was discussed, but because of her request to remain on TPN, she found herself having to choose between going home without TPN or remaining in the hospital for her final days. This caused great distress for her and her family. It is because of cases like Eileen’s that some larger hospices and a few private insurance companies are trying to bridge the gap between ongoing medical treatment and hospice by promoting open-access hospice programs. Openaccess programs promote the continuation of any treatment deemed palliative by the medical team during the course of the terminal illness. These treatments may include palliative chemotherapy, radiation therapy, and total parenteral nutrition. In these cases, the hospice continues to provide these treatments with the coordination of the hospice’s medical director and the primary medical team. These treatments continue until the patient wishes to discontinue them or they are deemed no longer palliative or beneficial by the medical team. Open-access hospice helps bridge the gap, but it is restricted to larger hospices, which can better negotiate pricing or spread the cost of expensive treatments across many patients. Most experts agree that an average daily census above 400 should be the minimum requirement for open access.3 In Eileen’s case, her private insurance included an openaccess hospice benefit and in coordination with a large hospice provider, arranged for the TPN to be provided by an

Barriers to referring patients to hospice There are multiple barriers to the referral of patients to hospice care, as well as many myths among the general population, including: 1. Difficulties in prognostication. Many physicians find it difficult to predict when the 6 months remaining in a patient’s life begin. Studies have shown that most physicians overestimate prognosis and that familiarity with the patient breeds optimism.4–6 2. Fear that choosing hospice is “giving up.” Often physicians and patients have the misconception that accepting hospice services is giving up on hope or “throwing in the towel.” There is the misconception that a patient is no longer able to return to the hospital for palliation of symptoms or that they are not able to see their treating physician. Hospice services can provide for return to the hospital if a patient’s disease requires admission for palliation of symptoms or if there is an acute medical problem that is not related to the terminal diagnosis and the patient wishes to be evaluated at the hospital. In addition, arrangements can be made with the treating physician so that he or she can continue as the attending physician. 3. Fear that hospice practices euthanasia. The hospice team does not perform euthanasia. Hospice philosophy centers on providing compassionate care for patients at the

538 end of life and allowing for the natural course of their terminal illness. Hospice does not act to precipitate death.

s.p. gomez and p.w. walker Table 29.2. Pain intensity rating scale No pain 0 1 2 3 5 6 7 8 9 10 Worst pain imaginable

Hospice statistics in cancer patients The National Hospice and Palliative Care Organization’s 2006 report shows that more than 1.2 million patients received hospice care in the United States in 2005. The average length of stay in hospice was 59 days, but the median length of stay, a more accurate gauge in understanding the experience of the typical patient, was only 26 days. It was reported that about one third of patients died within 7 days of referral to hospice. Cancer diagnoses accounted for 46% of hospice admissions, and more than 75% of patients receiving hospice care died at a place they called home (e.g., private home, nursing home, or other residential facility).7 Referral to hospice care is late in the disease process, and patients often do not benefit fully from hospice care because of a short stay. There are some data indicating that for certain terminally ill patients, such as those suffering from lung or pancreatic cancer, hospice care is associated with longer survival rates.8 One of the main services hospice provides is expert symptom management, and of all the symptoms managed, the most common is pain. Pain management is done in coordination with the attending physician under the guidance of the hospice medical director. The registered nurse assigned to the patient reports the patient’s assessment to the physician managing the case and receives orders on the treatment plan. The following sections provide a review of pain assessment and management in home hospice care.

Pain assessment in hospice care Less than 50 years ago, some medical textbooks discussed the need for patients to experience pain and suffering. It was believed that at the end of life, this suffering would relate to the agony that Christ endured and thus prepare one for redemption.9 In the new millennium, however, special attention has been placed on pain and symptom management for the chronically ill and those at the end of life. Evaluation of pain in the hospice patient Evaluation of pain in the hospice patient is similar to that in patients who are not terminal or not enrolled in hospice care, with some exceptions that are discussed later in this chapter.

Physicians, hospice staff, families, and caregivers, should be familiar with the tools that exist for the proper diagnosis, assessment, documentation, and follow-up of pain. Many of these tools are discussed in other chapters of this book, and the reader is encouraged to review this information. In the hospice setting, the most common tool used is the numerical pain intensity rating scale. Hospice patients are instructed to rate the intensity of their pain on a scale of 0 (indicating no pain) to 10 (worst pain imaginable). A sample of this scale is shown in Table 29.2. This is a good tool to teach families and caregivers, as they can obtain this information from the patient and communicate it to the hospice staff. Parameters should be given to the patient and caregiver so that pain is not allowed to go untreated, thereby eventually becoming intolerable and out of control. Because the care under hospice is provided by the family or caregiver and hospice staff is not constantly present in the home setting, there are some practical steps that can be taken to maintain pain at an acceptable level. In collaboration with hospice nurses, physicians, social workers, and chaplains, our team developed the Hospice Rule of 3s. The Hospice Rule of 3s Rule of 3s for the patient When your pain intensity on the rating scale is over 3, take a breakthrough dose of medication. If more than three doses of breakthrough medication are taken in 24 hours, contact the hospice staff. If your pain medication has been adjusted more than three times and your pain is not relieved, request a physician visit. Rule of 3s for the family When the patient’s reported pain level is over 3, administer a dose of breakthrough medication. If more than three doses of breakthrough pain medication are given in 24 hours, contact the hospice staff. If the pain medication has been adjusted more than three times without relief, request a physician visit. Rule of 3s for the nursing staff When the patient requires more than three breakthrough doses of pain medication in 24 hours, an evaluation for an extended-release preparation should be done and a nursing visit is indicated. If patient’s breakthrough medication has to be reordered more than three times in a month, an evaluation for an

integrating cancer pain management extended-release preparation or titration of the current extended-release preparation is in order. If the nurse has had to use three different medications in the hospice’s guidelines for pain management without relief of the patient’s symptoms, the nurse should meet with the physician and discuss the need for a physician visit. The goal of the assessment of pain is to maximize quality of life. Unfortunately, there is a perception among some health care providers that symptom relief in hospice, especially the use of opioids and sedatives, could cause patients to die sooner than they would otherwise. This places additional stress on the medical team, whose mission is to alleviate suffering but not precipitate death. Family members also may experience extreme anxiety over the fear of causing the patient’s death by administering opioids. This dilemma often leads to the undermedication of patients, the most vulnerable of whom are those unable to communicate.

Barriers to the treatment of pain As in any other field, there are multiple barriers we must face in dealing with pain management. Following are some examples of situations that are of particular importance in hospice care. Preservation of cognition Finding the balance between proper analgesia and preservation of mental awareness is something that has been shown to be very important to patients at the end of life. In one study, 92% of patients agreed that being mentally aware at the end of life was very important. In contrast, only 65% of physicians agreed that this was very important at the end of life.10 Additionally, patients indicated that freedom from pain is the most important consideration at the end of life when asked to rank several attributes, as seen in Table 29.3. Thus, the hospice has the responsibility of trying to maintain mental awareness but not at the cost of adequate pain management. Hospice staff must be properly trained in the evaluation of other illnesses that can mimic pain. The most common example is delirium. A delirious person can exhibit symptoms that may lead one to believe that pain in not under control (e.g., moaning and groaning, agitation). This may result in an increase of opioids, leading to increased sedation. Delirium also can mimic anxiety, and the use of benzodiazepines in this setting is discouraged. Benzodiazepine treatment for the anxiety or distress caused by pain should be administered carefully, and the

539 Table 29.3. Factors considered important at the end of life, according to patients, family members, and physicians

Attributes

Bereaved Patient family members Physicians

Freedom from pain At peace with God Presence of family Mentally aware Treatment choices followed Finances in order Feel life was meaningful Resolve conflicts Die at home

1 2 3 4 5

1 2 3 5 4

1 3 2 7 5

6 7 8 9

7 6 8 9

8 4 6 9

Note: 1 = the most important attribute and highest rank score; 9 = least important. Friedman tests were significant at P ⬍ 0.001, suggesting that rankings by each group were different than would be expected by chance alone. Adapted from table 5 in Steinhauser et al.10

patient should be assessed continuously for sedation related to medications. Lack of physician visits In this age of busy practices, long hours, and decreasing reimbursement rates, it has become more challenging for physicians to offer home visits. In the hospice setting, physician visits are available through the hospice medical director or associate medical director. The Medicare Hospice Conditions of Participation do not mandate that routine visits be made, but hospices are required to provide physician services within 24 hours when a change of condition is observed that requires medical diagnosis, treatment, and evaluation of prognosis.11 This includes pain management, and a physician is required to make a visit when an appropriate diagnosis and evaluation cannot be made over the phone. Physician visits are an important factor in providing excellent medical care to our most vulnerable patients, and the hospice should make an effort to set a system in place that allows for visits not just on an as-needed basis, but also in a scheduled manner that will optimize patient care and satisfaction. Fears of addiction Very often there is a concern about addiction in the minds of patients and families, but it is rarely verbalized. The physician and the hospice team must make it a priority to educate the patient, caregiver, and family on the differences among addiction, tolerance, physical dependence,

540 and pseudo-addiction. One should suspect these fears when families, caregivers, or patients appear resistant to taking or administering pain medication for the relief of symptoms. This fear can be alleviated if the hospice team takes the time to educate the patient and family on why a particular analgesic has been chosen. A conversation can be initiated making a statement such as, “Often patients and families worry when we start these types of medications because they worry about addiction. Is this something that concerns you or that you have questions about?” Hearing the concerns of our patients and families will help us address any misconceptions they have about opioids and any other medications prescribed. Cultural and psychosocial issues It is important to remember that patients of different cultural backgrounds may respond differently to the idea of being prescribed pain medications. Some patients, because of religious or spiritual issues, may see it as a violation of their belief that it is wrong to ingest a substance that has the potential to affect their mental status. Patients of different generations may have certain preferences with regard to their pain management. For example, when a patient in his late 70s who fought in World War II was asked why he did not want to take morphine, he replied, “Honey, my generation defeated Hitler. That was pain. This cancer has nothing on me compared to that. I’m OK without this morphine.” We addressed this patient’s pain by offering to listen about his experiences during the war. Support of the patient undergoing emotional pain is described later in this chapter. Fears of overmedication It is imperative for the physician to monitor the competence of the hospice staff in evaluating signs and symptoms of pain. Nursing staff need the physician’s support and the teaching that can come from visiting the patient together as a team. When the wrong diagnosis is made, sedatives or opioids are ordered, creating a vicious cycle that prolongs the myth that all hospice patients are overmedicated to relieve symptoms. Teaching family members about the purpose of the medications, the onset of action, and the duration of the analgesic effect can help them understand why certain medications cause the effects they see. Giving the caregiver and patient guidelines on how much sedation they should expect from the treatment can help them anticipate side effects and become aware of signs that the treatment may need adjustment.

s.p. gomez and p.w. walker The case of Lea Lea, a Philippine woman in her 40s dying from a bowel obstruction caused by inoperable metastatic colon cancer, was receiving pain management at home with subcutaneous hydromorphone via a patient-controlled analgesia pump. She had three children ranging in age from 8–11 years and a devoted husband, who was working from home to spend as much time as possible with her. Lea’s main worry had always been overmedication and “feeling too sleepy from the pain killer,” and thus she rarely gave herself a bolus of hydromorphone. Most of our time during home visits was devoted to her “sleepy feelings” and her concern regarding not being mentally aware to visit with her family. Lea received many letters and notes of encouragement from her church. She would take some of the prayers parishioners had written on small pieces of paper and place them on her abdomen, which resembled that of a woman in her 36th week of gestation. Lea would carefully wrap the pieces of paper around her swollen abdomen with a pink silk sheet. She would tell me, “The pain is not too bad, and besides, it’s good to have it so I can stay awake.” With gentle persuasion and teaching she allowed the initiation of a basal rate of hydromorphone. To her surprise, she was more awake during the day because now she could rest more during the night. The hospice staff was thoroughly educated on the signs and symptoms of delirium so as to minimize the risk of sedation by not making the proper assessment in case she experienced agitation or moaning and groaning. Whenever possible, the nurse on the case was present during the home visits by the physician. It was very important to keep the lines of communication with the hospice nursing staff open, as the preservation of cognition was the one thing this patient desired, even more than adequate pain management.

Administration of medications to the imminently dying patient During the dying process, many patients may be able to swallow only very small amounts of fluid placed in their mouth. The oral cavity of the dying patient may become so dry that there is not enough saliva to dissolve even a sublingual tablet. Many families, because of personal preference or cultural or religious practices, find it unacceptable to administer medications rectally. This presents a special challenge to hospice staff, who must continue to help families and caregivers administer medications to preserve the patient’s comfort. Many experienced nurses have developed compassionate and effective methods of administering easily dissolvable

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opioid preparations when liquid preparations are not readily available. These include:

environment, this short stay will provide a transition to another place where the patient can receive care. Discussion with the IDT. The suspicion or findings of medication diversion should be discussed by the team, with particular emphasis on the evaluation by the team’s social worker. These concerns and findings should be documented in the medical record. The team should decide on a plan of action and document it in the care plan. The plan should include an assessment by the social worker and address any issues requiring reporting to state or local agencies. The attending physician should be informed of the team’s plan, and his or her input should be requested and documented. Hospice administration notification. The hospice administration team should be alerted of the concerns or findings of the investigation. Drug diversion issues that cannot be resolved may lead to the patient’s discharge from the program, with appropriate follow-up or transfer of care to another hospice provider. Pharmacy notification. The pharmacy should be given guidelines on dispensing pain medications that are based on the care plan. These guidelines may include the quantity of medication dispensed, frequency of refills, staff authorized to order refills, and documentation of calls made for refills. There should be a hospice contact person to whom the pharmacist can report any violations in the care plan. Notification of after-hours staff. Communication with after-hours staff and on-call teams, including other physicians on the team, is imperative so they can be aware of the concerns and plan of action. Identification of team members allowed to provide refills. Appointing two clinical staff members to be responsible for requesting and ordering refills when needed minimizes the risk of unauthorized refills. These two individuals usually are the nurse assigned to the patient and the nurse manager. Lock boxes. These provide a safe place for storing medications in the home setting. They are inexpensive and can be provided by the hospice. Many patients may try to find a “safe hiding” place to avoid having a lock box. One patient in our hospice’s care refused a lock box, claiming that she could keep her bottles under her pillow and away from any “curious hands.” Unfortunately, she also took a sleep aid at night and was completely unaware when the curious hands were able to slip unnoticed under the pillow during her deep sleep. When lock boxes are given, two keys are provided, one to the patient or responsible caregiver and one to the hospice.

1. Preparing a paste of medication. Taking the required dose of opioid in a tablet form that is safe to crush (do not use extended-release tablets) and easily dissolvable in water, the nurse or caregiver crushes the medication with a spoon and adds a small amount of water, making a paste. Using gloves, the nurse or caregiver rubs the paste inside the patient’s cheek, where it will continue to dissolve and travel down to the stomach. 2. Preparing a liquid solution with tablets. Using the previously described technique, the caregiver or nurse adds additional water to the mixture to prepare a liquid solution that can be administered to the patient using a syringe. This technique should be used only if the patient can swallow small amounts of liquid. 3. Subcutaneous administration. This method of medication delivery is still unknown to many practitioners caring for dying patients. A detailed review of this technique and the medications used is presented later in this chapter.

4.

5.

6.

Diversion of medications in the home setting Medication diversion is a problem that hospice staff must deal with at times. Because of the high price of prescription pain medications on the street, hospice patients may fall victim to the abuse of caregivers or family members who are either selling the medication or using it themselves. This problem must be dealt with by the IDT, hospice administrator, and pharmacy. All efforts should be made to treat the patient’s pain, but at the same time steps must be taken to minimize the risk of drug diversion. When drug diversion is suspected, a potential plan of action may include the following steps: 1. A log of medication administration. This will help clarify how much medication the patient requires. The log must document the reason the pain medication was administered. 2. Assessment of the patient’s need for the quantity of pain medication. A good physical examination by the nurse or physician is recommended to assess the need for pain medication. This assessment should include an interview with the caregiver or family. 3. Inpatient admission. The suspicion of medication diversion is an acceptable criterion for admission to an inpatient facility such as a hospital or inpatient hospice unit for a short stay to evaluate the patient’s pain and medication needs. If the patient is in an unsafe

7.

8.

9.

542 10. Family meeting. A meeting must be scheduled and attended by members of the IDT, a responsible caregiver, and the parties suspected of the diversion, if they agree to meet with the team. The goals of the meeting are to address the concerns of the team, initiate the care plan, identify a responsible caregiver, consider inpatient admission, and discuss the consequences if the agreed-on care plan is not followed. 11. Changes in the clinical staff. It is not unusual for issues such as these to cause a great deal of frustration for the clinical team. Often, the nurse caring for the patient feels manipulated or frustrated. Nurse managers and hospice medical directors should support their staff and, as an option, be able to appoint members of other clinical teams to help manage the case. 12. Follow-up plan. The team must have a plan of action in case the care plan is not followed or there is improvement followed by disregard of the team’s instructions. All efforts should be made to work with the patient and family.

Evaluation of the nonverbal patient The ethical principles of beneficence (the duty to benefit another) and nonmaleficence (the duty to do no harm) oblige health care professionals to provide pain management and comfort to all patients, including individuals who are vulnerable and unable to speak for themselves.12 According to data reports, about one third of patients referred to hospice care die in the first 7 days after referral,7 and in some hospices, the mortality rate in the first 24 hours is up to 10%; therefore, it is not unusual for the hospice team to deal with patients who are either minimally responsive or nonverbal (Figure 29.1). Much information can be gathered by observing the patient’s setting. As discussed previously, a home visit by the physician is invaluable in helping to direct nursing care, reassure family members, and provide optimal medical treatments. Patient assessment in the hospice setting is often done without the luxury of laboratory data and imaging studies. Thus, one must rely on physical examination and caregiver interviews. Clinical evaluation of the nonverbal patient often focuses on subtle clues such as body language. Observation of a patient’s body language can tell us about his or her condition, fears, and feelings, and give us clues on the quality of his or her life at that particular moment. The evaluation includes an assessment of the challenges the patient’s home environment poses on the

s.p. gomez and p.w. walker delivery of recommended treatments. This truly is holistic care. A brief interview with the caregiver before the examination can alert the physician of any particular problems on which to focus. The patient may need pain medication before the examination to maximize his or her comfort. Premedication in the home setting can be done easily because the medications are readily available at the bedside. Often families are afraid to touch or move their loved ones at home. Many caregivers and family members fear that they lack the skills necessary to avoid hurting their loved one when there is a need to move the patient (e.g., for a bath or a change in linens). Premedicating the patient allows the physician to teach the family how to prevent pain if it is anticipated. Patients who are no longer responsive are often very frail and will use much of their energy reserves to withstand even a simple examination; the slightest activity may potentially cause a great deal of pain. If premedication is required, enough time should be allowed for it to take effect. A systematic approach should be used, and there should be proper documentation of why a self-report on pain is absent or limited. Searching for the usual suspects One should always assume there is pain and consider the most common sources of pain based on the patient’s diagnosis and age. In this regard, the interview of the caregiver should include questions related to common problems or procedures associated with the patient’s cancer (e.g., recent surgery, wound care, recurrent infections, existing venous access, drains, constipation, fractures). Knowledge of the patient’s baseline is important, for acute changes in behavior may indicate discomfort. A full skin examination may lead to the discovery of previously unseen pressure ulcers, which may add to the patient’s discomfort and suffering. This is an excellent opportunity to work with the nursing aid. Nursing aids are highly trained in the art of repositioning patients with minimal effort and discomfort to the patient, and in the long-term care setting, they are effective in recognizing the presence of pain in nonverbal patients.13 Special attention should be paid to keeping the patient warm during the examination. One should be aware of any particular cultural issues when examining patients of the opposite sex. This is of particular importance when providing an examination at home, because this is the patient’s domain; disregard for a patient’s modesty may be overlooked by the family when they are in the hospital or doctor’s office,

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Non-responsive Patient

Assume there is Pain

Caregiver interview

Indentify patient behavior concerning for pain based on interview

No behaviors of concern identified on interview

Examination and treatment of Potential problem

Examination looking for causes of pain

Improved behavior

No improvement of behavior

Physical findings of concern

Trial of analgesia

Treat underlying problem

No physical findings of concern

Fig. 29.1. Clinical evaluation of the nonverbal patient.

but in the intimate setting of the patient’s home, we should be even more respectful. For elderly patients dying from cancer, careful evaluation of common geriatric problems (e.g., pain from arthritis or skin tears) is recommended. The American Geriatric Society has identified mental status changes as a potential pain indicator in elderly people suffering from dementia. Monitoring vital signs Physiologic indicators (e.g., blood pressure, changes in pulse or respiratory rate) are not supported by the literature

as being sensitive markers for discerning pain in chronically ill patients. The absence of increased vital signs does not indicate absence of pain. This is important to know because caregivers and families often are hypervigilant of changes in vital signs. This lack of frequent monitoring may be one of the most important emotional transitions for the caregiver and family. Often, the patient has spent a considerable amount of time in the hospital before hospice admission, and it is not unusual to admit patients to home hospice directly from the intensive care unit. Family members have been known to ask, “If you don’t have the monitors, how do you know she’s OK?” Care must be taken

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What expression is on the patient’s face? Although we can focus on body language, the absence of expressions of pain is extremely helpful but should not completely rule out pain.14 We often concentrate on evaluating and documenting common behaviors that can indicate pain (e.g., crying, grimacing), but these are only signs of discomfort and not always accurate reflections of pain intensity. Caregivers who are knowledgeable about the patient can identify subtle behaviors that may indicate pain and can give us an idea of the patient’s baseline. Asking the question, Do you feel that the patient is in pain? is a simple way of evaluating the situation as well as demonstrating to the family and caregiver that we value and trust their input.

Although family members and caregivers may be invaluable in evaluating behavioral changes that can indicate emotional or spiritual distress in the patient, they are subject to their own personal fears and situations. On the other hand, when a caregiver disputes our evaluation of a patient’s comfort, it is important to listen to his or her concerns. Caregivers may have misconceptions regarding different concepts, including issues relating to addiction. It is not uncommon for a caregiver to fear addiction when opioids are being used. Caregivers must be carefully educated regarding the differences among addiction, tolerance, physical dependence, and, most importantly, pseudo-addiction. Pseudo-addiction, in particular, may lead to undermedication of a dying patient. As the patient is undertreated and asks for more pain medication, the caregiver may interpret this as abusive or addictive behavior, thus leading to the withholding of pain medication. Family education is vital in the home setting because home hospice is based on the philosophy that the family or assigned caregiver provides the majority of care.

Caregiver report

Analgesic trial

Reporting pain to the hospice staff is a vital role assumed by the family or caregiver, and careful and frequent assessment must be encouraged. It must be pointed out that direct observation of a patient for signs of pain places the caregiver in the situation of judging the intensity of the pain. This is difficult to do and affected by many variables, including the emotional state of the caregiver. Take, for example, the case of the caring daughter who frequently calls the hospice office to report that the patient is suffering from a great deal of pain. The hospice nurse rushes to the bedside only to find the patient unresponsive and with no signs of any acute distress. This happens multiple times despite proper assessment by the nurse and physician on the case. The team chaplain is asked to evaluate the situation and discovers that the daughter has been diagnosed with cancer but has been keeping it a secret from her family and friends, and the days she calls the hospice office to complain about her mother’s pain are the days she visits her oncologist. This situation would have remained unresolved and a source of tension for the staff if not for the intervention of another member of the IDT. This daughter was supported by her family and eventually signed over her responsibility as medical power of attorney to one of her other sisters; the patient was transferred to a different home to be cared for.

We have discussed premedication of a patient before performing a procedure or action that may lead to pain. At times, it is prudent to give a patient a trial of analgesia when the patient is demonstrating behaviors that have not been relieved by other measures (e.g., repositioning, spiritual support, other attempts at nonpain symptom management). It is not unusual for patients to display behaviors that lead caregivers and nursing staff to have concerns regarding adequate pain control. All efforts should be made to alleviate other potential causes of these behaviors, such as delirium. A trial of analgesia may be appropriate as well. This trial may begin with acetaminophen, 500–650 mg orally or rectally every 4–6 hours for 24 hours, unless contraindicated because of the patient’s disease process. If the patient appears more comfortable, it is safe to assume that there was a component of pain involved, and analgesia should continue.12 If the behaviors continue, or if they improve and return later, a short-acting opioid should be tried. Morphine elixir, for example, is well tolerated by the nonverbal patient when administered in small amounts orally with a syringe. Morphine is also available in a rapidly dissolving sublingual tablet, which also is well tolerated. One may start with 5–10 mg of morphine orally and observe the response. No research confirms that weight (except in children) should be used to determine starting dose. If the patient shows an

to educate families and caregivers on the reason that vital signs will or will not be monitored. Discontinuation of vital sign monitoring may be distressing, and proper education will help eliminate unnecessary anxiety for the patient and family. Evaluating the patient’s behavior

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improvement in behaviors suggestive of pain, the opioid may be continued on a scheduled basis to achieve adequate analgesia.

on formulary, and speed of delivery by the hospice pharmacy. Common medications used are morphine, hydromorphone, fentanyl, and methadone.

Routes of medication administration in the home setting As discussed previously, hospices are paid a set amount of money per day to care for a patient. This per diem amount must cover all treatments delivered to the patient dealing with a diagnosis of terminal illness, including all medications related to the diagnosis. Hospices budget a certain amount per patient for the daily cost of pharmaceuticals. Hospices often contract with a pharmacy that is responsible for providing the medications and delivering the medications to the patient’s home. Pharmacies can deliver the medications several ways, including via private courier or overnight mail delivery, or the patient’s family can pick up the medications at a contracted pharmacy. It is not unusual for hospices to work closely with compounding pharmacies or those experienced with infusions. In the hospice setting, medication is administered mostly by the family or caregiver. Therefore, it is important to instruct the family in proper handling, storage, and documentation of medication administration. Keeping a log of when and why a medication was given can help the physician determine the effects of treatment, need for any titration of medications, or need to change the current medication plan. It is a common misconception that hospices can administer medications to patients at home only by the oral route. The following is a brief summary of different routes of administration and the most common drugs used. Intravenous Many patients starting on hospice care have recently been discharged from an acute care setting. It is not unusual for patients to still have IV access when they arrive home. The hospice nurse should be comfortable in assessing the viability of this access.

Pros/cons One of the superior benefits of using IV medications is the speed of action to relieve pain. The hospice must have policies in place dealing with the assessment, care, and maintenance of IV access. The competency of the nursing staff in starting and maintaining an IV line is monitored by the hospice, and patients must be monitored for possible complications of IV access. Because IV medication administration is not common in hospice care, particularly in the rural setting, the skill of nursing staff in starting and maintaining IV access may vary greatly. In addition, the hospice must have a reliable supply of the equipment needed to start and maintain IV access and a pharmacy that can readily supply injectable forms of medication. Intramuscular Most hospice physicians consider intramuscular injections in this patient population to be less desirable because of the pain it causes and the current availability of subcutaneous administration. This route of medication administration is discouraged, and subcutaneous administration is preferred when possible. Rectal Rectal administration of medications has been widely used. In the hospice setting, it is common to administer extendedrelease and immediate-release opioids rectally. Subcutaneous Subcutaneous administration of medications in the hospice setting is a growing trend. The placement of a subcutaneous needle requires less skill than that required for IV administration, placement sites are plentiful, and this route is well tolerated by patients.

Indications If a patient is unable to take medications orally or rectally and a current IV site exists and is patent, this is a good alternate way of administering medications.

Indications Indications for subcutaneous administration are as follows:

Medications frequently used Factors influencing the choice of medication are the patient’s condition, the drug’s cost and availability, restrictions

1. Compromised oral administration due to: r Dysphagia – due to weakness, neuromuscular dysfunction, mechanical obstruction r Decreased mental status

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546 Table 29.4. Comparison of complications with subcutaneous versus IV access Complications/side effectsa,b

Subcutaneous Intravenous

Catheter reaction Pain Changes in electrolytes Thrombophlebitis Septicemia/systemic infections Danger of clot formation

5% Rare Rare No No No

a b

25% Common More common Yes Yes Yes

Adapted from ref. 15. Common side effects seen in subcutaneous hydration in the geriatric population.

r Nausea r Vomiting 2. Poor compliance or combativeness, as occurs in patient with: r Dementia r Delirium r Psychosis 3. Symptom control requiring rapid administration and absorption of medication, as in pain crises 4. Imminently dying patient (i.e., death is expected in ⬍72 hours)

Complications A retrospective study evaluating intermittent subcutaneous infusions in 191 hospice patients found that redness, tenderness, inflammation at the catheter site, leaking needles, and catheter malfunction occurred in less than 1% of cases.11 The subcutaneous route is a safe, effective, and practical way of administering opioids and other medications in the home setting. A comparison of complications with subcutaneous versus IV access is shown in Table 29.4. Placement of needle There are two types of needles that may be used: the butterfly steel needle and the Teflon cannula. Table 29.5 provides guidelines on gauge, cost, rotation, and site of insertion.

Guidelines for placing a subcutaneous line (see Fig. 29.3) include the following 1. Always use universal precautions. 2. Explain the procedure to the patient and caregiver. 3. Prepare the area of needle insertion with alcohol using the same sterile technique as with IV insertion. 4. Hold the skin in the area of needle insertion between the thumb and index fingers, pinching lightly to help elevate the skin. 5. Introduce the entire length of the needle into the skin at a 30◦ –45◦ angle with the bevel up. 6. If blood appears in the tubing, remove the needle and attempt insertion at a different site using a new needle. 7. If a butterfly needle is being used, tape it in place as shown in Fig. 29.4. 8. If a Teflon cannula is being used, remove the needle and discard it in a sharps container. 9. Attach the syringe to the hub using sterile technique and draw back to make sure the needle is not in a blood vessel. 10. If no blood is seen, flush the tubing with 1.5 mL of sterile normal saline. 11. Secure the tubing with dressing and label it with the date, time, and initials of the nurse placing the needle. Sites to avoid and monitoring of infusion site One should avoid placing a subcutaneous needle in areas of broken skin, tumor sites, skin folds, sites of irradiation, sites of infection, and lymphedematous regions. Checks should be made at every nursing visit or daily by the family or caregiver. The skin site should be monitored for any redness or other irritation, which should be reported to the hospice. Once the subcutaneous needle is inserted, there are several choices in the equipment available for medication infusion. (See Figs. 29.2–29.7.) The following are just a few examples.

Table 29.5. Subcutaneous needle options

Butterfly Teflon cannula a b

Gauge

Recommended sites of insertion

Costa

Recommended rotation (days)b

24, 25, 26 24, 25, 26

Chest, back, abdomen, thigh Chest, back, abdomen, thigh

$1.52 $2.50

5.3 ± 5 11.9 ± 1.7

Prices are in U.S. dollars and are approximate. The institution should consult current price lists. Ref. 16.

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Fig. 29.4. Subcutaneous needle insertion with dressing. (See color plate.) R Fig. 29.2. CADD-Prism
PSC II. Photo courtesy of Smiths Medical Inc., St. Paul, Minnesota. (See color plate.)

hospice staff for its reliability and needs to be refilled only every 24 hours.

Syringe driver A syringe driver is a small infusion pump used to gradually administer small amounts of fluid with or without medication to a patient. This apparatus is portable and battery operated. It must be pointed out that syringe drivers will not give better analgesia than the oral route of medication administration, unless there is a problem with absorption or administration.17 The two types of SIMS Graseby syringe drivers available are the MS16A and MS26. The MS26 is probably the simplest and safest to use and is the one recommended for use in palliative care.18 The syringe driver is a useful tool that helps preserve the patient’s mobility. It is widely accepted by patients and

CADD pump The CADD is a battery-operated pump the patient can carry easily in a pouch over his or her shoulder. The pump can deliver basal-rate as well as breakthrough medication. The pump offers multiple programming options, including continuous rate, automatic dose, and demand dose. There is a security pass code for setup and programming, minimizing any potential for patients or others to access the programming. The CADD pump provides an event history that outlines the delivery of basal-rate and breakthrough doses administered. It also can infuse medications via the IV, epidural, and intrathecal routes. The average pump weighs 3.2 oz.

Fig. 29.3. Subcutaneous insertion. (See color plate.)

Fig. 29.5. Subcutaneous needle in the upper back. (See color plate.)

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Medication is administered by pulling the syringe from the EI’s barrel protector to withdraw an accurate dose from the medication bag. The medication is then injected slowly over 1–5 minutes, depending upon the patient’s comfort, by pushing the syringe back into the EI’s barrel protector. The EI uses disposable syringes and can be reused by soaking all aluminum pieces in a 1:10 bleach/tap water solution for 24 hours.18 Complications reported have been abscess and bleeding, but these are rare.17 The most frequent reasons for changing the injection site have been accidentally pulling the needle out of the skin and erythema.19–21

Fig. 29.6. Subcutaneous needle in the abdomen. (See color plate.)

In the hospice setting, the pharmacy is available 24/7 to the physician and nursing staff, and instructions on how to change the settings can be provided over the phone. The medication is sent from the pharmacy in a prefilled cassette labeled with the patient’s name, the date it was filled, the concentration of medication, and dosage information. The cassettes can contain medication for multiple days of administration. This instrument is a valuable tool in the rural setting, where delivery of medication may be lengthy. However, pumps may be expensive, and many hospices rent them rather than keeping them in stock (Fig. 29.2). Edmonton Injector The Edmonton Injector (EI) is a reusable device for the delivery and administration of intermittent subcutaneous injections (Fig. 29.7). The entire apparatus can be carried conveniently in a small pouch. Some studies have shown that in developing countries, the EI is ideal because of its safety, low cost, and versatility. It is used as an “injection pump” when cost is a limiting factor.17

Prefilled syringes In cases in which there is a reliable pharmacy with experienced personnel and a reliable caregiver, the use of prefilled syringes is a cost-effective and family-oriented method of providing pain medication. The pharmacy prefills a designated number of syringes that are labeled with the patient’s name, the name of the medication in the syringe, the date the syringe was filled, the concentration, and administration instructions with parameters on dosage and frequency. Family members can inject the medication slowly into the port of the subcutaneous needle, which stays in place for an average of 7 days. In this way, the patient is not required to have repeated needle sticks. Instructions on how to safely store, administer, and dispose of any unused amount are given to the family or caregiver, and a log of any medication administration is kept. The log includes the reason the medication was given, the time, the amount of medication, and the effects it had on the patient. If diversion of medications is suspected, syringes prefilled with opioids may cause increased difficulties and are discouraged.

Difficult types of pain to treat Suffering

Figure 29.7 Edmonton Injector. (See color plate.)

It is not unusual in hospice to hear the phrase I have total body pain or for families to express that their loved one is “suffering.” The relief of suffering appears to be considered one of the primary ends of medicine by patients, laypersons, and families, but not always by the medical profession.21 Families and patients do not make a distinction between physical and nonphysical sources of suffering in the same way physicians do. Suffering often is coupled with the word

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pain, as in pain and suffering.22 This often makes us fall into the trap of thinking that pain is the only source of suffering for a patient. The greater the pain, the greater the suffering will be. This is often what drives our choices in medical treatments. For example:

So what is a physician to do? Just as support groups offer strength to a patient and family, a physician’s role is to lend strength by being an active listener to the patient’s story and to acknowledge his or her fear of the future. This helps ease the burden of illness not only for the patient, but also for family members and caregivers. As in Fernando’s case, one is not always able to predict what will cause the suffering. The patient must be asked. Physicians must be reminded that active listening of patients’ fears does not rob patients of hope; it often strengthens it. As indicated through this vignette, the four main fears are loss of control, pain, the unknown, and the finality of the situation. The goal of hospice care is to address both the fears and the needs of the patient. A physician engaged in active listening can make it easier for the patient and his or her family not only to participate in the patient’s care, but to transfer the desire to be well into one of living each moment pain-free and surrounded by a compassionate community. The final need in the continuum may be addressed by educating the family on giving the patient permission to die. Several factors may contribute. One is reminding the patient that loved ones are surrounded by a supportive community that will continue to care for them after the patient dies. Another is reminding the family that they will survive and be strong again. Finally, the patient is reassured that he or she is loved and is told that it is OK to let go.

Fernando, a Hispanic man in his 60s, was diagnosed with advanced pancreatic cancer. His oncologist recommended a course of chemotherapy to palliate the pain that he commonly observed with the disease. The oncologist explained that he did not expect the prognosis to change but that he wanted to help prevent Fernando’s suffering. Suffering is not all pain, but rather a perception of distress with many facets that threatens the integrity of the person and is complicated by many factors, including physical, social, personal, financial, cultural, and spiritual aspects: all the issues that make us human. Suffering also has been suggested to have a temporal element. For a situation to be a source of suffering, it must influence the person’s perception of future events. Fear itself always involves the future.23 Think of the patients who often make a reference to the future when they voice their distress: “If this weight loss is due to cancer, I will die.” “If the nausea continues like this, I will be overwhelmed.” In Fernando’s case, his oncologist was acting out of kindness and true concern. Although no one was able to predict it, Fernando was able to complete only a few doses of chemotherapy before his body manifested complications from the treatment that prevented him from continuing. Each time a test was returned, he was told that chemotherapy could continue, only to be canceled at the last minute by a complication. His hope was rekindled and then extinguished. Each day was feared, as the anticipation of symptoms was overwhelming. Fernando’s pain did not get out of control, but his suffering was related to his disappointment over not being able to continue the chemotherapy and the fear of what was to come because the treatment was not completed. He suffered not only from his disease but from its treatments. In addition, his devoted caregiver shared in the disappointment and fears and suffered as well. Suffering as described previously has been termed by some as pain of the soul, and this often is not validated by clinicians. Not acknowledging the existence of suffering due to sources other than physical discomfort, and not realizing that they often would not exist if the future were not a major concern, is not providing optimal care.

Depression at the end of life The news of a cancer diagnosis may be catastrophic for both the patient and his or her family. In the event that the cancer is not curable, the patient may spiral into a web of emotional distress. Each patient will cope with this in a different manner; some will use the experience to strengthen their sense of self, others will become withdrawn, and some may become depressed. Twenty-five percent to 35% of cancer patients will suffer from mild to moderate depression, and 5%–10% will develop severe depression.22 Patients receiving hospice care are offered the services of the team chaplain and social worker. These individuals can help assess the patient and develop an appropriate treatment plan that focuses on the spiritual and psychosocial needs of the patient and family. The assessment of the patient should include a physical examination to rule out other disorders that can mimic depression, such as hypoactive delirium and dementia. The review of systems is important, but one must remember

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550 Table 29.6. CAGE questionnaire C – Have you ever felt that you should CUT down on your drinking? A – Have you ever been ANNOYED by people criticizing your drinking? G – Have you ever felt GUILTY about your drinking? E – Have you ever had an EYE OPENER in the morning or to get rid of a hangover?

that common signs and symptoms of depression, such as lethargy, anorexia, and insomnia, also may be attributed to the nature of the cancer itself. It is important for the physician or social worker on the team to document any signs of current or past substance abuse. The hospice team should become familiar with the CAGE (cut down, annoy, guilt, eye opener) questionnaire (Table 29.6) and screen all patients receiving hospice care. This is a good screening tool for substance abuse that uses questions that are nonconfrontational and can be introduced in the conversation during the interview process. This is important because it alerts the team of any issues of current substance abuse and the potential for chemical coping, and provides insight into the coping mechanisms of the patient.24 For geriatric patients, other tools, such as the Five-Item Geriatric Depression Scale, may be used. This scale focuses on five questions used to screen patients. Positive answers for depression are no to the first question and yes to the other four questions. Two or more positive answers are indicative of depression, as shown in Table 29.7. A simple approach, however, is to ask the patient a simple question such as, “Often people can feel down or blue when they are dealing with a condition like yours; have you been feeling hopeless or helpless recently?” Even in the hospice population, one should screen for homicidal or suicidal ideations and refer the patient immediately if there is a concern. Table 29.7. Five-item geriatric depression scalea 1. Are you satisfied with your life? 2. Do you often get bored? 3. Do you often feel helpless? 4. Do you prefer to stay at home, rather than going out to do new things? 5. Do you often feel worthless? a

To score the test: answers positive for depression are no to question 1 and yes to questions 2–4. Two or more positive answers are indicative of depression. Adapted from Rinaldi P, Mecocci P, Beneditti C, et al. Validation of the five-item geriatric depression scale in elderly subjects in three different settings. J Am Geriatr Soc 51:694–8, 2003.

If depression is diagnosed, a treatment plan may include some of the following interventions. 1. Psychosocial intervention by the team social worker or bereavement coordinator 2. Spiritual counseling by the team chaplain or coordination with the patient’s spiritual advisor 3. Family support through the team’s social worker, chaplain, and/or bereavement coordinator 4. Pharmacological treatment The use of antidepressants in hospice care is low. Often, it is believed that because sadness and grief are expected during the course of a terminal illness and because the patient’s prognosis is less than 6 months, there is no role for antidepressants. Thus, the disease often goes untreated or it is recognized too late in the disease process. If one is able to recognize the signs and symptoms of depression and pharmacological treatment is appropriate and available, there are some simple rules that may help in using antidepressants appropriately: 1. Choose a specific agent whose side effects will benefit the patient’s situation. A depressed patient who is also agitated may respond well to a drug that is more sedating versus a stimulating agent. 2. Start low and go slow. Most patients receiving hospice care are frail and underweight, and often respond to lower therapeutic doses. 3. If the hospice is not covering the cost of the antidepressant, consider medications with generic equivalents, which are more affordable for the patient. 4. Reevaluate the patient after allowing sufficient time for the medication to take effect. Often, well-intended physicians initiate treatment but do not follow up on the results. Guidelines on medication choices and initial doses include the following:22 r r r r r r r r

Fluoxetine, 10–20 mg/day Sertraline, 25–50 mg/day Citalopram, 20 mg/day Venlafaxine, 37.5 mg/day Mirtazapine, 15 mg/day at bedtime Methylphenidate, 5–10 mg in the morning and at noon Nortriptyline, 25 mg/day at bedtime Amitriptyline, 25 mg/day at bedtime The evaluation and treatment of depression at the end of life are important services to the patient and family because of depression’s impact on quality of life. Often, patients are

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not screened and family members and caregivers remain silent regarding their disappointment with the hospice team. For example: Chuck, age 59 years, was living at home with his wife of 27 years. He had been diagnosed with bladder cancer that had metastasized to his spine. He had been very active before his illness and had a long history of depression all his life. During a home visit, his wife expressed her disappointment with the treatment of his depression. “Chuck has always been depressed. It’s mentioned in all his medical records, and I worry that he is even more depressed now that he can’t get out of bed.” She expressed deep satisfaction with the nursing care and the attention to his other symptoms but was concerned that the hospice team did not ask about his depression. Eventually, Chuck and his family opted to change hospices, and during a follow-up phone call, Chuck’s wife expressed that she decided to change hospices, not because she was dissatisfied with the nursing care but because she “was worried that his depression did not seem important.” Pain assessment and management in the hospice setting remain important skills that clinicians should continue to improve. Research in this area by hospice and palliative care practitioners continues to be necessary. Despite the barriers, it is an exciting time for physicians in hospice care. As we acquire more knowledge in the relief of complex symptom management and continue to listen to our patients, the art of providing treatment at the end of life remains a rewarding endeavor.

7. National Hospice and Palliative Care organization statistics: NHPCO’s facts and figures – 2005 findings. Available at: www.NHPCO.org. 8. Connor SR. Comparing hospice and non-hospice patient survival among patients who die within a three-year window. J Pain Symptom Manage 33:238–47, 2007. 9. Brookoff D. Chronic pain: 1. A new disease? Hosp Pract (Minneap) 35:45–52, 59, 2000. 10. Steinhauser KE, Christakis NA, Clipp EC, et al. Factors considered important at the end of life by patients, family, physicians, and other care providers. JAMA 284:2476–82, 2000. 11. The Medicare conditions of participation for hospice care; 418.50. Available at: http//www.nho.org/files/public/ COPSRevisedSubpartBFG 0106.pdf. 12. Herr K, Coyne PJ, Key T, et al. Pain assessment in the nonverbal patient: position statement with clinical practice recommendations. Pain Manag Nurs 7:44–52, 2006. 13. Fisher S, Burgio L, Thorn B, et al. Pain assessment and management in cognitively impaired nursing home residents: association of certified nursing assistant pain report, minimum data set pain report, and analgesic use. J Am Geriatr Soc 50:152–6, 2002. 14. James A. Haley Veteran’s Hospital, Tampa, Florida. VA pain policy: hospital policy – memorandum no. 127–4 – March 27, pain management – 1998. 15. Dasgupta M, Binns MA, Rochon PA. Subcutaneous fluid infusion in a long-term care setting. Am Geriatr Soc 48:795–9, 2000. 16. Macmillan K, Bruera E, Kuehn N, et al. A prospective comparison study between a butterfly needle and a Teflon cannula for subcutaneous narcotic administration. J Pain Symptom Manage 9:82–4, 1994. 17. Pruvost M, De la Colina EO, Monasterolo NA. Edmonton Injector: use in Cordoba, Argentina. J Pain Symptom Management 12:372–5, 1996. 18. Caritas Health Group Edmonton Injector protocol for intermittent subcutaneous injection February 2003 K:Data\RPC Program Binder\Clinical Guidelines\Edmonton Injector guidelines.doc February 2003. 19. Bruera E, MacMillan K, Hanson J, et al. The Edmonton Injector: a simple device for patient-controlled subcutaneous analgesia. Pain 44:167–9, 1991. 20. Bruera E, Velasco-Leiva A, Spanchynski K, et al. The use of the Edmonton Injector for parenteral opioid management of cancer pain: a study of 100 consecutive patients. J Pain Symptom Manage 8:525–8, 1993. 21. Fairsinger RL, Bruera E. Hypodermoclysis (HDC) for symptom control vs. the Edmonton Injector (EI). J Palliat Care 7:5–8, 1991. 22. Elsayem A, Driver L, Bruera E. The M. D. Anderson symptom control and palliative care handbook, 2nd ed. Houston: The University of Texas Health Science Center at Houston, 2003. 23. Block S. Psychological considerations, growth, and transcendence at the end of life. JAMA 285:2898–905, 2001. 24. Ewing JA. Detecting alcoholism: the CAGE questionnaire. JAMA 252:1905–7, 1984.

References 1. SUPPORT Principal Investigators. A controlled trial to improve care for seriously ill hospitalized patients: the study to understand prognoses and preferences for outcomes and risks of treatments. JAMA 274:1591–8, 1995. 2. Wright A, Katz I. Letting go of the rope-aggressive treatment, hospice care and open access. N Engl J Med 357:324–7, 2007. 3. Department of Health and Human Services, Centers for Medicare and Medicaid Services. Pub 100-04 Medicare claims processing. Available at: www.CMS.hhs.gov/transmittals/ downloads/R1280CP.pdf. 4. Earle CC, Neville BA, Landrum MB, et al. Trends in the aggressiveness of cancer care near the end of life. J Clin Oncol 22:315– 21, 2004. 5. Christakis NA, Lamont EB. Extent and determinants of error in doctors’ prognoses in terminally ill patients: prospective cohort study. BMJ 320:469–72, 2000. 6. Glare P, Virik K, Jones M, et al. A systematic review of physicians’ survival predictions in terminally ill cancer patients. BMJ 327:195, 2003.

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Other resources Last Acts http://www.lastacts.org Provides a broad range of resources related to end-of-life care, including professional precepts, innovative programs, and community-based resources. End of Life Physician Education Resource Center http:///www.eperc.mcw.edu

s.p. gomez and p.w. walker Provides peer-reviewed end-of-life educational resources for educators. Harvard Medical School Center for Palliative Care http://www.hms.harvard.edu/cdi/pallcare Provides access to faculty development programs in palliative care and medical student educational resources.

30

Pain in medical illness: ethical and legal foundations pauline lesage a and b russell k. portenoy a,b a

Beth Israel Medical Center and Albert Einstein College of Medicine

No moral impulse seems more deeply embedded than the need to relieve suffering . . . it has become a foundation stone for the practice of medicine, and it is at the core of the social and welfare programmes of all civilized nations. Daniel Callahan1

Introduction By introducing major modifications in the historical constructs underlying medical treatments, science and technology have created a certain “chaos” in the care of seriously ill patients. What might have been considered good medical practice for advanced disease before the “biological revolution” is now questioned. Where to draw the line? Where to set limits? Many variables now must be considered in the management of patients with advanced illnesses, including the recognition of ethics as a foundation for clinical practice, the acknowledgment of new rights, and social changes related to health care. Ethical and legal considerations now must constantly inform decision making. Medicine has been caught in a difficult dilemma: Not only does it have to consider its own complexities, but it also has to face a much different social context than existed just a short time ago. Numerous ethical guidelines and recommendations have been proposed by diverse authorities to help clinicians in their decision making. Recommendations can be found in reports of special presidential or national commissions,2,3 in major congressional reports,4 in policy statements of national organizations,5,6 in guidelines from bioethics institutes,7 and in professional journals.8 There is now a body of literature, policy, and law that presents an agreed-upon set of principles and values, as well as recommendations, for clinical practice. Nevertheless, medicine’s appropriation of these guidelines is lagging behind, as demonstrated by numerous studies on medical practices. The Study to Understand

Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT) documented serious problems with terminal care: Patients experienced considerable pain, communication between physicians and patients was poor, and physicians misunderstood patient’s preferences regarding cardiopulmonary resuscitation.9 Other studies have confirmed these deficiencies.10–12 With the aging of society and the increased prevalence of cancer and other devastating diseases, such as AIDS, the goals of medicine need to be refocused. It is essential to reaffirm traditional responsibilities for relieving pain and symptoms, to respond to patients’ concerns, to guide their decision-making process, and to respect their informed choices. The need to address these considerations while striving to optimize the technical aspects of care with more humanistic aspects has become a fundamental challenge in the practice of medicine.13–15

Ethical principles and moral guidelines Ethics is a generic term for different ways to examine moral life. Among many other considerations, bioethics involves practical reasoning about individual patients, balancing their values, hopes, and beliefs with values and principles of medicine and society.16 The most common approach to the resolution of difficult ethical questions is organized around basic principles17 and moral guidelines.18 Ethical principles are general guides that may be applied to the resolution of a particular moral situation and constitute the underlying moral justification for an action. These basic principles – autonomy, beneficence, nonmaleficence, and justice16,19 – must be balanced through case-by-case analyses. None is absolute, and they may compete in the moral resolution of any issue. Autonomy recognizes the right and ability of an individual to decide for himself or herself based on his or her values 553

554 and beliefs. It is an affirmation of the person’s inviolability. It implies that, with rare exceptions, treatments cannot be imposed against the wishes of the individual and that the choices of individuals must be respected, even if they differ from the recommended course of care. Patient’s decisions must be informed and free, never coerced. Respect for autonomy implies that the professional must tell the truth, exchange accurate information, and restrain from undue influence. Informed consent is a direct application of the autonomy principle. Beneficence implies positive acts to maximize the benefits of care. It requires a thoughtful balancing of benefits and harms. It is the most commonly used principle in the application of care. Examples of this principle include delivering effective and beneficial treatment for pain or other symptoms, providing sensitive support, and meeting the obligation to warn against potential dangers. The principle of nonmaleficence supposes that “one ought not to inflict harm deliberately.” It is an application of Hippocrates’ adage, “Do no harm.” It also includes the moral requirement of serving the well-being of patients, following standards of care, and performing risk–benefit assessments. The notion of “harm” interpreted in its broad sense should include physical and mental anguish (suffering). The principle of nonmaleficence supports several moral rules, such as “do not kill” and “do not cause pain.” Violation of this principle may include offering information in an insensitive way, continuing aggressive therapy despite the likelihood of unsatisfactory results, providing unwanted sedation, and withholding or withdrawing treatment without consent. Justice implies fairness in the application of care and allocation of resources. It implies that patients receive care to which they are entitled medically and legally. Justice can be translated into “give to each equally” or “to each according to need” or “to each his due.” The principle of justice supposes societal considerations and a sense of a common good. The right to health care is an example of this principle. The basic ethical principles have generated other important principles of care. For example, the “principle of double effect,” which is central to many decisions in palliative care, is derived from the principle of nonmaleficence. It has been invoked to support statements that an act potentially having a foreseen harmful effect (such as death) does not always fall under moral prohibitions (such as the rule against killing). It is considered when obligations or values conflict and cannot be realized simultaneously.19 According to double effect, there is a moral difference between the intended effects of a person’s action and the

p. lesage and r.k. portenoy unintentional, but foreseen, effects of the action. The desirable effect (good) is linked to an undesirable effect (bad); the good effect is direct and intended, whereas the undesirable effect is indirect and not intended. The principle of double effect has been used widely in moral writings and is particularly useful in end-of-life decision making (see later). Moral concepts have been used to distinguish between what is morally to be avoided and what is morally optional. These are: 1) ordinary and extraordinary care, 2) acts of commission and acts of omission, and 3) motives, intents, and results of a human action (see principle of double effect). In medical ethics, the distinction between “ordinary” treatment and “extraordinary” treatment has a technical meaning referring to an intervention as it relates to a specific person. The concepts are not defined in terms of feasibility or affordability, but in terms of usefulness or burdens. Treatments that are either “useless” or “excessively burdensome” for a particular patient, although ordinary and simple, are ethically extraordinary and therefore beyond what is morally required. The distinction between acts of “commission” and acts of “omission” focuses on the deeds of the moral agent. Acts of commission involve the deliberate use of some agent to alter the life course of a patient; acts of omission involve the deliberate decision not to intervene in the life course of a patient.18 Although ambiguous and complex, the distinction between commission and omission has some ethical significance, especially in situations in which the difference between acting and nonacting is relevant – for example, the difference between withholding and withdrawing a treatment and the difference between “active killing” and “letting die.” In the first case, what matters is not so much the distinction but the moral aim of the decision to start, cease, or defer a particular treatment. In the second case, what matters morally is discerning when it is appropriate to “let die.” In both cases, the underlying question is, What are the benefits for the patient by this action? The previously discussed moral concepts or distinctions represent useful considerations in our quest to deliver ethically sound care to patients, but they cannot be encapsulated in a simple formula or algorithm for calculating the relative weights of benefits and harms, the basis of all ethical decision making. Every case needs special attention and reflection. In the administration of medical care, legal requirements cannot be ignored. Some situations that are defensible under ethical principles may not be acceptable under legal provisions. Because law is based on societal values and represents a societal consensus on particular issues, it is not as

pain in medical illness: ethical and legal foundations universal and justified as ethics. Legal provisions impose limits and sanctions on policies, behaviors, and issues of a determined society. The law provides a framework to guide decisions, practices, and requirements that need to be fulfilled to avoid liability. Health care systems and practices in most countries rely on different legal systems: common or civil law, criminal law, statutory law, regulatory law, and disciplinary law.

Clinical decision making With modern medicine offering countless new technologies and treatments, health care decision making may become a difficult and complex task. The best treatment decisions have been described by medical ethicists as a “combination of medical, emotional, aesthetic, religious, philosophical, social, interpersonal and personal judgments.”16 Considering the complexity involved, patients must be invited to take an active role by bringing their histories, values, philosophies, and emotional needs to the decision-making process.

Goals of care To optimize decision making, the goals of care need to be defined. The determination of goals must consider the stage of the disease (prognosis) and related uncertainty, the possible treatment options, and the personal values, hopes, and understanding of the patient or decision maker. The goals of care are dynamic, not static. They can change rapidly and are sometimes contradictory. They should be realistic. Withholding or withdrawing disease-modifying treatments may be an acceptable alternative in advanced disease, but less so in the early phase of an incurable disease. Continual reassessment of goals is essential to ensure quality of care in accordance with patient wishes. Confusion about goals can derive in part from a false dichotomy: Medical care can either cure disease or alleviate suffering. With the advent of palliative medicine over the past three decades, this distinction is no longer defensible.20,21 In reality, numerous goals are possible, and more than one can be pursued within the context of current realities.22 These may include avoidance of premature death, maintenance or improvement in function, relief of suffering, maintenance of quality of life, and preparation for a good death. Each of these goals may be valid and each must be discussed according to individual circumstances. In clarifying goals, health care professionals have the difficult task of determining the benefits or harms of procedures or treatments. This is a direct application of the proportionality principle. The latter states that “a medical

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treatment is ethically mandatory to the extent that it is likely to confer greater benefits than burdens upon the patient.”2,16 Finding the appropriate therapy and avoiding futile treatment are overriding goals of medicine. This task is based on an understanding of futility, informed consent, and decision making in the setting of an impaired patient. Futility It has long been recognized that the medical profession has no obligation to provide futile medical treatment. Hippocrates advised physicians to “refuse to treat those who are overmastered by their diseases, realizing that in such cases medicine is powerless.”23 This statement may be well understood but does not often simplify the interpretation of medical futility. Futility is a complex, ambiguous, controversial, and subjective concept. Many definitions have been proposed,24–29 and terminology is diverse. It has been equated with impossible, rare, unusual, hopeless, nonbeneficial, inappropriate, and unreasonable care. Usually it is defined according to the goals of a specific therapy, its probability of success (quantitative aspect), and the quality of the expected result (qualitative aspect). A treatment is not futile if there is “a real chance of achieving some desirable end, whether that end is cure of the patient, patient comfort, patient dignity, or even comfort to the family.” Defining futility is replete with ambiguity. Are all goals of a treatment acceptable and valuable? What constitutes a desirable end? For some, a treatment is not futile unless it is unlikely to produce any physiologic effect on the body.26 Considering that health care has been defined as a state of physical, mental, and social well-being,30 this view may be too limiting. If futility is defined in terms of a likelihood of success, what probability of success is acceptable? Considering the uncertainties inherent in medical practice, defining futility based on probability alone cannot be acceptable. This is particularly true given the larger variation in the extent to which patients and physicians are willing to pursue treatments perceived to have a likelihood of failure. In one study, for example, physicians were asked to define futility in terms of the likelihood of therapeutic success; the specified likelihood varied between 0% and 60% (median, 5%).31 The quality of the result adds some insight to the definition of futility because it provides an additional dimension. The overall beneficence of the therapy does not relate only to its effectiveness. This implies the acknowledgment that the goal of a medical treatment is not merely “to cause an effect on some portion of the patient’s anatomy, physiology, or chemistry, but to benefit the patient as a whole.”25

556 Nonetheless, the range of benefits that should be considered is not always clear. If they address quality of life, the complexity of the analysis is great. The definition of futility cannot be based uniquely on medical criteria (physiologic futility) but also must refer to a “reasonable confidence (quantitative aspect) of providing the sorts of benefits (qualitative) that physicians and patients legitimately expect of the medical enterprise.”32 Given the serious ambiguities that threaten its legitimacy and its highly subjective nature, the concept of futility should be used with caution as a rationale to limit therapy or adjust the goals of care. It should be evaluated in a broader context and consider the motives underlying demands for “futile” or “unreasonable” treatments, or the desire to withhold treatment based on a futility rationale. Many factors must be weighed, including medical uncertainty, anguish of the family facing an eventual separation, the fear of death or the unknown, denial, and the health care professional’s attitude of “doing everything that is possible.” Futility is rarely unequivocal or absolute. The issue often is raised in the face of conflicts over treatment, and there may be misunderstanding among team members, family, and patient. Resolving conflict through better communication and objective information often will eliminate the specific issue of futility. As stated by Younger,33 “when therapeutic innovation becomes technological imperative and hope turns into pathological denial, patients and their families suffer unnecessarily. The concept of futility may provide a much needed corrective, but will better fulfill its promise if those applying it also give attention to the social, psychological, and institutional problems that fostered demands for futile care in the first place.” Informed consent Katz34 noted that “the practice of silence was a part of a long and venerable tradition (of medicine) that desired not to be dismissed lightly.” Hippocrates, in the Decorum, wrote, “Perform (these duties) calmly and adroitly concealing most things from the patient while you are attending to him [ . . . ] revealing nothing of the patient’s future or present condition.”35 This historical trend began to change in some cultures during the second half of the 20th century. The theory of informed consent emerged in medicine from a changing perspective about the nature of the doctor– patient relationship, in ethics as the principle of autonomy, and in law as the right to self-determination. Informed consent implies that decisions about medical care are made in a collaborative manner between patient and physician and thus are resolved through good communication. Informed

p. lesage and r.k. portenoy consent is an expression of trust shaped in the doctor– patient partnership. Although consent is well accepted in principle, it may be difficult to achieve because of the problems inherent in medical communication, such as the use of technical language; the focus on medical uncertainties; the failure to adapt to patient limitations, fears, and culture; the limits of the patient’s understanding; and distraction or the effects of medication or illness. Skillful physician communication is essential to the practice of informed consent, and truth telling is critical to the patient’s ability to make reasonable medical decisions. Choices made on the basis of emotion and/or insufficient information can compromise informed consent. Truth telling is particularly challenging in the context of advanced illness because data are often lacking, and the desire to support hope may blur information. Although a decision sometimes is made to limit information for therapeutic purposes (therapeutic privilege), it should be an exception and openly acknowledged when it occurs. Legal requirements for consent may vary with the legal system of different countries. Generally, in routine practice, informed consent must be obtained before a treatment can be administered.34 This usually implies that a competent patient or agent receives appropriate information (disclosure), can make a well-considered decision (is informed), and subsequently can express that consent (consent) without coercion.36 The information provided has to be understood and sufficient for the patient to make the best decision possible under the circumstances. For a patient to be adequately informed, information must be given about the nature and purpose of the proposed treatment or procedure, its risks and benefits, and any available alternatives.36 “Risk” is the element of information most difficult to qualify and to explain. Communications about risk must be consistent with the standard of disclosure (which may vary among different legal systems) and take into account the nature of the risk, its magnitude, and its probability. Serious and frequent risks must be disclosed; remote risks need not be disclosed, unless important and grave. In common law, the legally accepted standard for information is based on conventional professional practice and what any reasonable person would want to know in the same circumstances.36 To be valid, consent to care must be given by a competent patient or his or her designee. The determination of capacity is a matter of clinical judgment, and there is no consensus on a set of criteria for its evaluation.36,37 Most argue that capacity requires the ability to understand the information, evaluate the options in accordance with the patient’s own values, and communicate choices. Although distinct from

pain in medical illness: ethical and legal foundations an assessment of capacity, mental status evaluation often is used as a screening tool. Capacity may fluctuate over time, and it is important to remember that consent is specific to a particular decision and is not necessarily final. Capacity warrants constant reevaluation. When a patient is determined to lack capacity to decide, the evaluation that justifies this determination should be recorded in the medical record. Responsible health care providers should be made aware of and become familiar with the person who will make health care decisions for the person. Decision making for the incompetent If the patient lacks capacity, someone must be designated to make decisions on the patient’s behalf.36,37 This person can be a “guardian” if appointed by the court (rarely the case for terminally ill patients), a “health care agent” designated by written proxy appointed through advance care planning (specifically a living will or durable power of attorney for health care), or a “surrogate” chosen from eligible individuals in a manner that varies with state laws. Decisions made by third parties must conform to a legal standard, either “best interest” or “substituted judgment.”36 In the “best interest” standard, the decision is made in accordance with what is seen as most beneficial for the patient. This is a direct application of the principle of beneficence and proportionality: Maximize benefit and avoid harm. The “substituted judgment” standard aims to implement the subjective preferences of the patient. It takes into consideration the patient’s past behavior, statements, or choices. Laws may vary concerning the level of evidence required to state that the patient had a specific preference. They may vary according to the type of decision made (e.g., higher standard for withdrawal of nutrition). Substituted judgment may be preferable, but is applicable only when patients have expressed their wishes. This criterion is applied to the case of advance directives. Advance directives Advance directives are oral or written instructions specifying the wishes of a person concerning medical treatment in anticipation of future incapacity.38 They also may provide for designation of a health care agent to make decisions under the same circumstances. They constitute a direct application of the autonomy principle and represent a form of consent. Advance directives can take different forms, including personal letters and medical directives. The most common types of advance directive are the living will and the durable power of attorney for health

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care (the person given the power of attorney is known as the health care agent). These directives can be general or specific. A living will is a legal document that specifies the treatments that would be acceptable or unacceptable to a patient in case of incapacity. Usually, it takes the form of a directive to limit life-sustaining treatment in the face of a life-threatening illness. Durable power of attorney is a document appointing a health care agent or proxy to make decisions according to the incapacitated patient’s preference. In the United States, all 50 states and the District of Columbia have laws concerning the use of advance directives.39 Unfortunately, most adult Americans do not have an advance directive; in 2001, the completion rate nationwide remained under 25%.40,41 In a review of literature, Angela Fagerlin and Carl Schneider42 mentioned a number of reasons why people fail to complete living wills: Some persons say they do not know enough about them; others find them too difficult to execute; others simply hesitate to discuss living wills with their doctors; some question their need; others think that they are appropriate only for the elderly or terminally ill; many suspect that living wills do not affect the way patients are treated; and some see living wills as incompatible with their cultural or ethical beliefs. Other than the limited number of people signing living wills, many other problems have been documented that call into question whether they or any other instruction can achieve the pursued goals. Among those problems are the use of terms, the understanding of the clinical conditions that may be faced in the future, clarity, the proper transmission to health care decision makers, and the uncertainty of the side benefits of preparing living wills.18 Although imperfect, the living will and proxy directives have some merits. The latter may represent a better way to ensure the respect of one’s wishes by encouraging conversation with persons who will be present for decisions when they must be made; the emphasis is less on self-determination and more on interdependence and trust. In certain circumstances, however, when there is no possible proxy or family member, a living will may be the best option. For the most part, living wills are statutory documents created by state legislatures. They also constitute advisory documents and therefore can act as evidence of the patient’s expressed wishes and may be binding beyond the state’s borders. Physicians following directives in living wills are granted immunity against allegations based on the type of care rendered to an incompetent patient. Recently, a new form of instruction directive has shown great compliance and effectiveness: Physician Orders for Life-Sustaining Treatment (POLST). A POLST document

558 (unlike a standard living will) is a doctor’s order form signed after consulting with the patient or the surrogate. It is a concise form containing specific medical instructions that can be acted on by nurses, doctors, or emergency personnel. It may include directives on DNR (do not resuscitate), administration of antibiotics, intravenous fluids, feeding tubes, artificial respiration, and other medical interventions. It is best suited for those expecting to die within the year.43 The POLST document was designed to be effective, concise, and easily implemented. Critics argue that too-simple a form might well be too effective and too easy to act on quickly, and does not promote deliberate decision making in light of new information and changing circumstances.

Ethics of pain and suffering The relief of pain and suffering has always been a moral responsibility of physicians.23,44 Nowadays, the accessibility, availability, and effectiveness of various methods of pain control make this duty even more compelling. Knowledge in the use of analgesics is mandatory, and not relieving pain optimally is tantamount to moral45 and legal malpractice.46–48 In principle, physicians are in strong agreement with ethical recommendations regarding pain control. Solomon and colleagues49 showed that 87% of physicians and nurses believed that it is possible to prevent dying patients from feeling much pain, and 81% reported that the most common form of abuse in the care of the dying is underuse of opioids.49 Unfortunately, this acceptance of the need for optimal pain control often is not translated into practice.20,45,46,49 Many factors contribute to the undertreatment of pain, including deficient skills and outdated attitudes on the part of health care professionals, patient underreporting and poor treatment adherence, and system-wide impediments to optimal analgesic therapy.20 Among other factors, undertreatment of cancer pain has been associated with minority status, female sex, and history of substance abuse.10 Opioids are sometimes withheld in the setting of advanced medical illness because of fears of hastening death. This attitude requires careful analysis from the ethical and legal perspectives, as well as the medical perspective. Medically, it is now widely accepted that properly administered opioid therapy will rarely, if ever, cause respiratory depression or hasten death. As Twycross and Lack50 observed, “These views stem from ignorance about and misunderstanding of the correct use of morphine in cancer patients with pain. Indeed patients who are truly sentenced to a ‘kind of living death’ are the ones who are not prescribed an adequate analgesic regimen.” If doses of an opioid

p. lesage and r.k. portenoy sufficient to relieve pain were to hasten death, as an unintended effect, it may be ethically justifiable according to the principle of double effect, if the conditions are met. In the setting of pain in advanced medical illness, physicians’ concerns about the risks of opioid therapy sometimes relate to inadequate appreciation of both medical and ethical considerations. Authoritative bodies, such as the U.S. President’s Commission for the Study of Ethical Problems in Medicine,2 the Law Reform Commission of Canada,3 and the House of Lords in England,51 have stated that the provision of necessary pain relief is not a matter of potential legal liability. In some locales, legislation has been proposed to protect health care professionals from legal liability if they substantially comply with accepted guidelines for treatment of pain.52 The U.S. Supreme Court strongly affirmed the physicians’ obligation to provide adequate pain relief at the end of life, even if it may unintentionally accelerate death, therefore acknowledging a right to pain control and relief of suffering.53 The use of analgesics, even if this might hasten death, is considered a standard of good medical practice, and is not subject to liability if applied in good faith. Conversely, courts have recognized that improper pain management is a breach of good medical practice and is unacceptable.47,48 More and more, end-of-life care is coming under scrutiny. Ann Alpers,54 in a well-documented article involving the care of the dying, mentioned that since 1990, at least 13 physicians have been criminally investigated but not formally indicted or prosecuted. Criminal prosecutions involving care of the dying fall into three categories: withdrawal of life-sustaining treatment and accompanying use of pain medication; administration of opioids, analgesics, or sedatives; and terminal care, including the use of a fatal agent, such as potassium chloride, insulin, or chloroform. Although disturbing, a detailed analysis of the cases illustrates that fear of criminal liability or investigation should not discourage physicians or nurses from aggressively using opioid analgesics to manage terminal pain, provided there is a thorough assessment and treatment of pain, as well as ongoing and open communication between families and professional caregivers.

Sedation in terminal illness Another set of issues related to pain in those with advanced illness concerns the use of sedation to treat refractory symptoms. Good palliative medicine can alleviate suffering caused by pain and other symptoms in most cases.30,55–58 When suffering cannot be managed at the end of life, sedation may represent an option. Sedation at the end of life

pain in medical illness: ethical and legal foundations may be controversial, however, and possibly unacceptable to some patients, families, and health care providers.30,59 Although the definition of terminal sedation, preferably known as palliative sedation therapy (PST), has been debated,60-62 there recently have been major efforts by various groups to better define this concept. An international panel of 29 palliative care experts from various countries recommended the following definition: “Palliative sedation therapy (PST) is the use of specific sedative medications to relieve intolerable suffering from refractory symptoms by a reduction in patient consciousness.”63 They added, “Intolerable suffering is determined by a patient as a symptom or state that he or she does not wish to endure (or by proxy judgment),” and, “Refractory symptoms are symptoms for which possible treatment has failed, or it is estimated that no methods are available for palliation within the time frame and the risk–benefit ratio that patient can tolerate.”63 PST for psychological or emotional distress is less accepted and should be initiated only under exceptional circumstances and after consulting with experts.63 Sedation is considered an exceptional therapeutic measure with specific indications intended to alleviate suffering in the imminently dying. It is a treatment of “last resort.” Although it must be acknowledged that sedation for intractable symptoms could possibly accelerate the dying process, it may be ethically justifiable under the principle of double effect. This approach has been accepted directly by various medical societies and ethicists,15,64–66 and indirectly by the U.S. Supreme Court.53 There is little disagreement among palliative care professionals about the necessity of using sedation to achieve symptom control in some dying patients. However, variability in the use of terminal sedation highlights the uncertainty surrounding this practice.59,67–69 This pseudo-consensus was challenged recently by the media frenzy surrounding the case of Terry Schiavo.70 As Lewis Cohen71 mentioned, “Elected officials, government regulators, members of the health care profession, and a significant portion of the public do not seem to know of this consensus.” Some other recent events have the potential to fuel a backlash against the current ethical basis of palliative care, including the papal allocution regarding food and hydration for patients in a persistent vegetative state as well as America’s “war on drugs,” which is now focusing on the medical administration of opioids.72 In 2006, the board of directors of the American Academy of Hospice and Palliative Medicine (AAHPM) approved a position statement on palliative sedation with the following key elements: In palliative sedation, the intent is to alleviate

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suffering, the degree of sedation should be proportionate to the level of suffering, and the patient and/or his or her agent should provide an informed consent.73 Some have considered sedation in the imminently dying as a form of “euthanasia in disguise.”74 This reasoning fails to note the fundamental differences between the two practices.61,63,75 Their intent is different (death is the unintended, although foreseen, result in sedation, as opposed to the intended result in assisted suicide and euthanasia), and they diverge in the actions undertaken (a sedative dose is not a killing dose). The same reasoning applies in differentiating palliative sedation from physician-assisted death. The option of sedation recognizes the right to be relieved of suffering, not the right to die. To be legally acceptable, sedation should be carried out in a manner consistent with the intent of alleviating suffering. The action should reflect the purpose. The literature shows a lack of consensus with regard to medications, dosages, and routes used to induce sedation.59,60,63 The most widely used drugs are benzodiazepines and barbiturates – or a combination of these agents – but the approach also has been implemented using opioids, neuroleptics, ketamine, propofol, and others; however, most will agree that opioids are not the best agents for sedation.63 Whatever the agent selected, dose titration to achieve relief is required before continuing maintenance therapy at the lowest dosage possible. Because of the serious implications of sedation in the imminently dying, its implementation should follow guidelines based on compassion, consideration, and trust.63,76 When presented as a therapeutic option, sedation may be perceived by the patient or family as a sign of disease severity as well as suffering. Sedation should be implemented only after the medical condition has been clarified, a thorough discussion with the patient and family has taken place, consent has been obtained, and the goals of care have been clearly established. Once sedation has been activated, ongoing information should be provided to family and staff, questions should be answered, and ethical and legal implications should be clarified.76

Other end-of-life issues Withholding/withdrawing therapy In the course of a chronic illness, there may come a point beyond which a treatment becomes futile or disproportionate. At this time, withholding or withdrawing therapy may be considered.2,77 These practices imply that the patient does without a medical intervention that might have been

560 expected to extend life in some circumstances (see President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research,2 page 2, note 1) but now is perceived as futile or averse. Withholding occurs when a treatment is not provided; withdrawing is defined as ending treatment that has no demonstrated value. Both practices relate to the proportionality of treatment and are applied in the context of an incurable or irreversible condition. Refusing the medical intervention, or withdrawing one that has been applied, allows the disease to take its natural course; if death occurs, it is the result of the underlying disease. Although health care professionals often believe that there is a distinction between withholding and withdrawal49 – there may be a tacit belief that once a treatment is started, it cannot be stopped – this assumption has no ethical, legal, or medical basis, and the distinction is more psychologically compelling than logically sound.7,78 Withholding and withdrawing therapies have been well accepted as part of good medical practice by various authoritative bodies.2,13,79 They have received legal acknowledgment in the United States.80,81 Many institutions have drafted policies addressing these issues. Although withholding and withdrawal of therapies have been described mainly in situations related to technical interventions (e.g., ventilator support, hemodialysis), the reasoning also applies to chemotherapy, artificial hydration and nutrition, and any therapy offered at the end of life to delay death.82 In this regard, withholding and withdrawal of treatment must be clearly distinguished from physician-assisted suicide (PAS) and euthanasia (see later). Do-not-resuscitate order Cardiopulmonary resuscitation (CPR) was originally developed as a closed-chest massage for victims of sudden cardiac or respiratory arrest. The overall survival rate averages 15% under the best circumstances (good health status and resuscitation started within 5 minutes of arrest).83 Survival is related to the underlying illness; it is almost never successful in patients with chronic debilitating illnesses (1%–4%).84 The medical, ethical, and legal issues involved in resuscitation have been discussed extensively in the literature.85–87 As for any other treatment, physicians have the obligation to clarify the medical indication for the therapy, as well as patients’ wishes concerning resuscitation. In practice, discussion and implementation of the DNR order seem highly problematic and poorly achieved by medical staff. In

p. lesage and r.k. portenoy the large SUPPORT study, investigators demonstrated that only 47% of physicians knew when their patients preferred to avoid CPR, and 46% of DNR orders were written within 2 days of death.9 These results failed to improve with an intervention designed to facilitate advance care planning and patient–physician communication.9 The lack of focus on goals of care, poor medical training in communication, residual uncertainties about the success rate of DNR, and misinterpretation of futility all contribute to these difficulties. The DNR order must be distinguished from other aspects of care offered near the end of life. A patient who has elected a DNR designation can still receive parenteral nutrition and be treated aggressively for an infection or any other condition. These other issues warrant an open discussion with the patient, who must be informed about the various options for treatment. The discussion about resuscitation should be placed into the broader context of life-prolonging therapies. This will prevent a sense of abandonment, which can be implicit in DNR dialogue. Artificial hydration and nutrition Because of the high symbolic value of nutrition, the question of withholding or withdrawing artificial hydration or alimentation often is difficult to address with the patient and family. It may be perceived as neglect, abandonment, or hastening death. The decision-making process of the patient and family can be helped by an open discussion about the misperceptions, advantages, and concerns associated with artificial nutrition. It has been shown by many authors that, with few exceptions, patients with incurable neoplastic disease do not benefit from artificial nutrition.88,89 It also has been documented that, in certain circumstances, artificial fluids and nutrition may worsen edema, ascites, pulmonary and other secretions, and dyspnea.90,91 In their recommendations, the international group of palliative care experts mentioned that “nutrition and fluids should not be offered to imminently dying patients unless it is considered likely that the benefit will outweigh the harm; (in this case), parenteral fluids are unlikely to influence either symptom control or survival time.”63 The opinions about fluid administration are quite diverse. A systematic review of the literature on fluid status in the dying concluded that there was insufficient evidence to draw firm conclusions about either beneficial or harmful effects of fluid administration to end-stage patients;92 therefore, each case should be analyzed on its own merits. In its revised position statement, the AAHPM recognized that artificial nutrition is a form of medical therapy that should be evaluated by weighing

pain in medical illness: ethical and legal foundations its benefits and burdens in light of the patient’s goals of care and clinical circumstances; it can be withheld or withdrawn according to the patient’s wishes and clinical condition.93 In case law, artificial nutrition and hydration have been considered a treatment and, as such, governed by the same legal and ethical principles of withholding or withdrawal.94,95 Discussion surrounding nutrition and hydration must take into account the emotions and religious beliefs attached to this issue. Although the discourse is rarely neutral, it can strive to be explanatory and place these interventions in the context of the overall goals of care. Ventilator withdrawal The withdrawal of ventilator support from a patient is clinically and ethically challenging for patients, families, and members of the health care team. The uncertainty of the outcome and the dramatic events surrounding the procedure contribute to the challenge, especially in the case of immediate extubation.96 The technique for ventilator removal should be addressed with the patient and family, when possible. In terminal weaning, it is essential to assess the patient’s comfort during the procedure, then provide aggressive interventions to prevent symptoms such as breathlessness and anxiety.97 It is ethical and legal to use a combination of opioid and anxiolytic therapies to treat these symptoms. Physician-assisted suicide and euthanasia Euthanasia and PAS have been the subject of intense debate for centuries.98–102 The current debate is framed by the acceptance of withholding and withdrawing life-sustaining therapies, the self-determination movement, the promotion of choice in decision making at the end of life, and changes in social values. The debate on PAS and euthanasia has been fraught with difficulty, in part because of the use of ambiguous and confusing terms.98,103–105 PAS is best defined as “aiding or helping to bring about death for compassionate reasons.”106 This definition implies that the intention is clear (death of the patient) and the performing agent is the patient, the accessory agent (providing the means) is the physician or a third party, and the motive is usually compassion. Although there have been many definitions of euthanasia – or, more precisely, many categories (active, passive, voluntary, involuntary) – it is now well accepted that euthanasia means to “bring or give death for compassionate reasons.”64,106 In this case, the intention is similarly clear (death of the

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patient), the performing agent is the physician or third party, and the motive is usually compassion. In the clinical setting, a request for PAS or euthanasia should be taken seriously. It is important to clarify the request, assess the underlying motives, reemphasize the commitment to symptom control and provision of palliative care, and discuss alternatives. The debate on euthanasia generally has focused on the principle of autonomy, the distinction between killing and letting die, the relief of suffering, and the “slippery slope” argument.101,106–109 Each of these considerations may be framed to support or oppose euthanasia. Assisted suicide or euthanasia implies the right to be relieved from pain and suffering, as well as the right to die. For many, it is seen as the extrapolation of the principle of autonomy: One can choose the moment and means of one’s death. The debate struggles with the appropriateness of limits to autonomy.110,111 The observation that palliative interventions can lead some patients to change their minds about assisted suicide112 raises fundamental questions about the affirmation of autonomy when patients (and sometimes physicians) are unsure about the potential for further palliative care, which may relieve suffering without the necessity of death. Advocates of euthanasia and PAS may draw comparisons to the withholding or withdrawal of treatment, neglecting the distinction between killing and letting die.45,111,113 This is difficult to justify. Although killing and letting die have the same end result (e.g., the death of the patient), they are quite different in their intent.114 Death is the unplanned but foreseen result in withholding and withdrawal of treatment, as opposed to the intended effect in euthanasia and PAS. The latter represents another application of the principle of double effect. Again, intent or purpose is traditionally used by the law to distinguish between two acts that have the same result.53 Although a patient’s request for PAS can be broadly interpreted as a cry for help, each person has a set of personal reasons for the desire to hasten death. Unrelieved pain may not be the major or sole reason for a request for physician-assisted death.103,115–118 In a Dutch study, unrelieved pain was the sole reason for euthanasia requests in 5% of the cases, was part of the problem in 40%, and was not reported at all in the remaining cases.104 Instead, depression, unrelieved psychosocial distress, loss of dignity, loss of control, other quality of life issues, and perceived burden on the family were the most common justifications.103,115 Other studies also highlighted the importance of depression.119–121 Physicians, patients, and the public find PAS and euthanasia more acceptable for

562 patients in persistent pain than those who wish to spare their families.119 The potential for abuse of euthanasia and PAS is expressed by those opposed to these practices.111,113,122,123 Evidence for abuse of euthanasia may be found in Dutch data, which include 0.8% of deaths without explicit and repeated requests from the patient (in half these cases, there may have been previous discussions with the patient about such measures).124 Data from the United States have shown that 19% of critical care nurses had engaged in some form of euthanasia or PAS, at times without physician supervision or outside the hospital.125 These observations also raise the “slippery slope” argument.107,122,123 If PAS or euthanasia were to become common practice, it may not be possible to limit these practices to terminal illness or to those capable of providing fully informed consent. Determination of guidelines or safeguards remains difficult and somewhat illusory, as the underlying concepts are ill defined.126 What is intolerable pain? What is a terminal condition? Is the consent really informed? In a society that prioritizes cost control, there is even a concern that policy makers or health care professionals would be tempted to shorten a lengthy incurable illness.127 As stated by the New York Task Force on Life and Law, “The dangers of a dramatic change in public policy (legalization of PAS and euthanasia) would far outweigh any possible benefits. In light of the pervasive failure of our health care system to treat pain, and diagnose and treat depression, legalizing assisted suicide and euthanasia would be profoundly dangerous for many individuals who are ill and vulnerable. The risks would be most severe for those who are elderly, poor, socially disadvantaged, or without access to medical care.”121 Over the past two decades, there has been progress in the legal acknowledgment of patients’ rights at the end of life. Patients have the right to refuse unwanted treatment or to stop it once it has been started.128,129 They have the right to forgo life-sustaining therapies.80,130 There also is a recognized right to intensive palliative care and control of pain.53,131 Euthanasia is illegal in all countries except the Netherlands. Assisted suicide was legalized for a time in the Northern Territory of Australia132 and is currently legal in the states of Oregon and Washington. The U.S. Supreme Court ruled that there is no constitutionally guaranteed right to PAS or euthanasia, and therefore no constitutional right to die.53,80,133 The AAHPM, in its position statement, recognizes that deep disagreement persists with regard to PAS and adopts a position of “studied neutrality” on its legalization, and encourages its members to strive to find the proper response to patient’s suffering despite receiving the best possible palliative care.93

p. lesage and r.k. portenoy Access to palliative care Most people die after experiencing a protracted, lifethreatening illness with a slow decline or unpredictable terminal course. Currently, 12 million people around the world develop cancer. By 2015, this figure is expected to rise to 15 million. The size of the population aged 60 years and older is increasing dramatically and will rise from the present 9.3% to 15% in 2030.134 The need to develop health care resources to meet changing needs is critical. One such need is for access to optimal palliative care at the end of life. Although hospices and palliative care programs have emerged to address this need, most countries do not have access to palliative care services. In the United States, 36% of all deaths were under the care of hospice and most referrals to hospice were made late in the course of terminal illness, with a medium length of service of 20.6 days.135,136 There are very few hospital-based and home-based palliative care programs, and there is substantial evidence that undertreatment of pain and other symptoms continues to be a profound problem, as discussed previously.10,134,137 Many reasons are proffered to explain the limited access to palliative care at the end of life.137 Frequently, neither the public nor the health care providers acknowledge the importance of end-of-life care. It is often introduced late in the disease and has little impact. Clinicians receive no formal training in palliative medicine and end-of-life care, lack skills in communication and assessment of the goals of care, and have attitudes and fears that may be barriers to the care of the dying.138,139 Patients’ fears, cultural beliefs, denial, or lack of awareness about prognosis also may interfere with the willingness to be referred to hospice or pursue palliative care. Although there is growing support for access to palliative care, particularly at the end of life, there is still much to do.134 Educating the general public, health care professionals, and policy makers; changing health care systems; and adapting to rapid technological changes remain significant challenges for palliative care. The ability of societies and individuals to pay for optimal palliative care is a great concern. The nature of palliative care, including uncertainties related to prognosis and cost–benefit of interventions, make cost projections difficult.127 Therefore, in a time of cost control and limited resources, societies are moving slowly to introduce palliative care into their health care systems. There are numerous challenges to integrating palliative care and identifying the funds necessary to optimize treatment and support specialists. It will be regrettable if individuals have to choose PAS or euthanasia to alleviate their suffering because of the unavailability of palliative care.140

pain in medical illness: ethical and legal foundations Research The last set of ethical challenges relates to research. Although there is a well-established consensus regarding the use of human subjects under certain conditions, research in advanced illness generates intense ethical debate.141,142 Research in this specific population is ethically charged with the inherent problems of any research, such as informed consent, the depersonalization issue, the balance between risks and benefits, the vulnerability of subjects, the use of placebo, and the possibility of conflicting loyalties of the physician-researcher. These issues may be amplified by the nature of advanced illness.141 Patients’ vulnerability probably represents the most important concern. Because the very diagnosis of incurable illness carries the burden of fear and despair, patients may agree more readily to unproven interventions. The illusion of a cure may have a greater influence on their participation than in other populations. The nature of the disease, with its high level of disability, fatigue, depression, and perhaps cognitive impairment, may alter the patient’s response to proposals that might not be in their best interests. A prerequisite to research, as well as any treatment, is informed consent. In the context of serious illness, particularly when associated with unrelieved pain, patients’ understanding and competence may be altered.143,144 The regulations that govern informed consent for research are more demanding than for usual medical treatments. The subject must be presented with the diagnosis, prognosis, alternative treatments, and the consequences of no treatment. He or she must be told that participation is voluntary, that therapy can be withdrawn at any time, and that access to conventional medical treatments will not be altered by his or her decision to participate or not. In advanced illness, all this information is processed though a filter shaped by the issues inherent in vulnerability. “Selective hearing” is not unusual in this group of patients.145,146 Cognitive impairment may be subtle and go unrecognized unless it is tested for specifically.144 The clinical instability related to advanced illness adds to the ethical complexity of participation in research. The poor performance status of many medically ill patients often is invoked to deny enrollment in different trials and research protocols. Although such an attitude may conform to the proportionality or beneficence principle, too much emphasis on this aspect may be detrimental over time because it limits the scope of research in a manner that may be excessive. The use of placebo in palliative care research also is considered controversial, especially in pain research. The

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Guidelines of the National Council for Hospice and Specialist Palliative Care Services on Research in Palliative Care specify that “giving a placebo is not justified if there is a therapy known to be more effective than a placebo.”147 However, what if there is no known effective therapy or the overriding need is to demonstrate the effectiveness of a therapy? Placebo trials may be ethical if a placebo does not replace standard therapy, patients know they are receiving a placebo, there is uncertainty as to the merits of the treatments being tested in the trial, and patients have access to therapy if distress increases.148 Research in palliative care has been proven to be beneficial to participating patients, as it has for other patients.149 The need to document practices, to promote good palliative care as evidence based, and to expand the scientific basis of this care are valid reasons to pursue research in these patients.142 It would be unfortunate to jeopardize research for patients with serious illness without careful consideration of the benefits and burdens associated with both the withholding of the option to participate and the granting of this option. Review of research protocols by ethics committees and institutional review boards constitutes a warranty of respect for ethical principles and due process The AAHPM, in its position statement on the ethics of palliative care, suggests eight elements for consideration in palliative care research: the study design, indications for placebo, minimization of incremental risks, minimization of burdens, minimization of distress, decision-making capacity, surrogate consent, and voluntary consent.93

Conclusion Medical care is changing significantly. To meet the challenges of the 21st century, some changes in the culture of medicine are necessary. Ethical and legal considerations must be integrated in the clinical decision-making process. By providing an intellectual and pragmatic framework for pursuing the values of autonomy, beneficence, and justice, ethics are central to the development of a comprehensive, compassionate, and respectful practice of medicine, especially in the management of pain and difficult decisions related to palliative care. References 1. Callahan C. The troubled dream of life: in search of a peaceful death. New York: Simon and Schuster, 1993, p 94. 2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to forego life-sustaining treatment: ethical, medical, and legal

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86. Lo B. Unanswered questions about DNR orders. JAMA 265:1874–5, 1991. 87. Council on Ethical and Judicial Affairs, American Medical Association. Guidelines for the appropriate use of do-notresuscitate orders. JAMA 265:1868–71, 1991. 88. Barber MD, Fearon KC, Delmore G, Loprinzi CL. Current controversies in cancer: should cancer patients with incurable disease receive parenteral or enteral nutritional support? Eur J Cancer 34:279–85, 1998. 89. Torelli GF, Campos AC, Meguid MM. Use of TPN in terminally ill cancer patients. Nutrition 15:665–7, 1999. 90. Zerwekh JV. Do dying patients really need IV fluids? Am J Nurs 97:26–31, 1997. 91. Zerwekh JV. The dehydration question. Nursing 83:47–51, 1983. 92. Viola RA, Wells GA, Petersen J. The effects of fluid status and fluid therapy on the dying: a systemic review. J Palliat Care 13:41–52, 2007. 93. AAHPM position Statements. J Palliat Med 10:851–7, 2007. 94. Brophy v New England Sinai Hospital 497 N.E. 2d 626 (Mass. 1986). 95. Cruzan v Director Missouri Dept. of Health, United States Supreme Court, no 88–1503, June 25th, 1990. 96. Edwards MJ, Tolle SW. Disconnecting a ventilator at the request of a patient who knows he will then die: the doctor’s anguish. Ann Intern Med 117:254–6, 1992. 97. Wilson WC, Smedira NG, Fink C, et al. Ordering and administration of sedatives and analgesics during the withholding and withdrawal of life support from critically ill patients. JAMA 267:949–53, 1992. 98. Kelleher MJ, Chambers D, Corcoran P, et al. Euthanasia and related practices world wide. Crisis 19:109–15, 1998. 99. Gittelman DK. Euthanasia and physician-assisted suicide. South Med J 92:369–74, 1999. 100. www.euthanesia.com (accessed 1 May 2009). 101. Brody H. Assisted death – a compassionate response to a medical failure. N Engl J Med 327:1384–8, 1992. 102. Meir DE, Emmons CA, Wallenstein S, et al. A national survey of physician-assisted suicide and euthanasia in the United States. N Engl J Med 338:1193–201, 1998. 103. Van Der Maas PJ, Van Der Wal G, Averkate I, et al. Euthanasia, physician-assisted suicide, and other practices involving the end of life in the Netherlands, 1990–1995. N Engl J Med 335:1699–705, 1996. 104. Van Der Maas PJ, van Delden JJ, Pijnenborg L. Euthanasia and other medical decisions concerning the end of life: an investigation, vol. 2. New York: Elsevier, 1992. 105. Miller IG, Fins JJ, Snyder L, et al. Assisted suicide compared with refusal of treatment: a valid distinction? Ann Intern Med 132:470–5, 2000. 106. Emanuel EJ. Euthanasia: historical, ethical and empiric perspectives. Arch Intern Med 154:1890–901, 1994. 107. Ryan CJ. Pulling up the runway: the effect of new evidence on euthanasia’s slippery slope. J Med Ethics 24:341–4, 1998. 108. Brock DW. Voluntary active euthanasia. Hastings Cent Rep 22:11–22, 1992.

p. lesage and r.k. portenoy 109. Cassel C, Meir DE. Morals and moralism in the debate over euthanasia and assisted suicide. N Engl J Med 323:750–2, 1990. 110. Salem T. Physician-assisted suicide: promoting autonomy – or medicalizing suicide. Hastings Cent Rep 29:30–6, 1999. 111. Callahan D. When self-determination runs amok. Hastings Cent Rep 22:52–5, 1992. 112. Ganzini L, Nelson HD, Schmidt TA, et al. Physicians’ experience with the Oregon Death With Dignity Act. N Engl J Med 342:557–604, 2000. 113. Kass LR. Is there a right to die? Hastings Cent Rep 23:34–43, 1993. 114. Miller FG, Fins JJ, Snyder L. Assisted suicide compared with refusal of treatment: a valid distinction? Ann Intern Med 132:470–5, 2000. 115. Back AL, Wallace JI, Starks HE, Pearlman RA. Physicianassisted suicide and euthanasia in Washington State. Patient requests and physician responses. JAMA 275:919–25, 1996. 116. Seale C, Addington-Hall J. Euthanasia: why people want to die earlier. Soc Sci Med 39:647–54, 1994. 117. Foley K. The relationship of pain and symptom management to patient request for physician-assisted suicide. J Pain Symptom Manage 6:289–97, 1991. 118. Emanuel EJ. Ethics of treatment: palliative and terminal care. In: Holland JC, ed. Psycho-oncology. New York: Oxford University Press, 1998. 119. Emanuel EJ, Fairclough DL, Daniels ER, Clarridge BR. Euthanasia and physician-assisted assisted suicide: attitudes and experiences of oncology patients, oncologists, and the public. Lancet 347:1805–10, 1996. 120. Breitbart W, Rosenfeld BD, Passik SD. Interest in physicianassisted suicide among ambulatory HIV-infected patients. Am J Psychiatry 153:238–42, 1996. 121. The New York Task Force on Life and the Law. When death is sought: assisted suicide and euthanasia in the medical context. New York: NYS Task Force on Life and the Law, 1994. 122. Singer PA, Siegler M. Euthanasia – a critique. N Engl J Med 322:1881–3, 1990. 123. Capron AM. Euthanasia in the Netherlands: American observations. Hastings Cent Rep 22:30–3, 1992. 124. Van Der Maas PJ, van Delden JJM, Pinjnenborg L, Looman CWM. Euthanasia and other medical decisions concerning the end of life. Lancet 338:669–74, 1991. 125. Asch D. The role of critical care nurses in euthanasia and physician-assisted suicide. N Engl J Med 334:1374–9, 1996. 126. Caplan AL, Snyder L, Faber-Langendoen K. The role of guidelines in the practice of physician-assisted suicide. Ann Intern Med 132:476–81, 2000. 127. Morrison RS, Penrod JD, Cassel JB, et al. Cost savings associated with US hospitals palliative care consultation programs. Arch Intern Med 168:1783–90, 2008. 128. Glantz LH. Withholding and withdrawing treatment: the role of the criminal law. Law Med Health Care 15:231–41, 1987– 1988.

pain in medical illness: ethical and legal foundations 129. Meisel A, Grenvick A, Pinkus RL, Snyder JV. Hospital guidelines for deciding about life-sustaining treatment: dealing with health limbo. Crit Care Med 14:239–46, 1986. 130. Miller DK, Coe RM, Hyers TM. Achieving consensus on withdrawing or withholding care for critically ill patients. J Gen Intern Med 7:475–80, 1992. 131. Alpers A, Lo B. Futility: not just a medical issue. Law Med Health Care 20:327, 1992. 132. Ryan CJ, Kaye M. Euthanasia in Australia – the Northern Territory Rights of the Terminally Ill Act. N Engl J Med 334:326–8, 1996. 133. Wecht CH. The right to die and physician-assisted suicide. Medical, legal, ethical aspects. Part I, II. Med Law 17:477– 91, 581–601, 1998. 134. Stjernsward J. The international hospice movement from the perspective of the World Health Organization. In: Saunders C, Kastenbaum R, eds. Hospice care on the international scene. New York: Springer Publishing Co., 1997, pp 9–15. 135. National Hospice and Palliative Care Organization. NHPCO facts and figures: hospice care in America. Available at: http:// www.nhpco.org/files/public/Statistics_Research/NHPCO_ facts-and-figures_2008.pdf. 136. Gazelle G. Understanding hospice – an underutilized option for life’s final chapter. N Engl J Med 357:321–4, 2007. 137. Rhymes JA. Barriers to effective palliative care of terminal patients: an international perspective. Clin Geriatr Med 12:407–16, 1996. 138. Von Roenn JH, Cleeland CS, Gonin R, et al. Physician attitudes and practice in cancer pain management. A survey from the Eastern Cooperative Oncology Group. Ann Intern Med 119:121–6, 1993.

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139. Meier DE, Morrison RS, Cassel CK. Improving palliative care. Ann Intern Med 127:225–30, 1997. 140. Preston TA. Taking charge of the last stages of life. Final victory. Facing death on your own terms. Roseville, CA: Forum, 2000. 141. De Raeve L. Ethical issues in palliative care research. Palliat Med 8:298–305, 1994. 142. Mount BM, Cohen R, MacDonald N, et al. Ethical issues in palliative care research revisited. Palliat Med 9:165–70, 1995. 143. Bruera E, Franco JJ, Maltoni M, et al. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opiate rotation. J Pain Symptom Manage 10:287–91, 1995. 144. Bruera E, Spachynski K, MacEachern T, Hanson J. Cognitive failure in cancer patients in clinical trials [letter]. Lancet 341:247–8, 1993. 145. Schaeffer MH, Krantz DS, Wichman A, et al. The impact of disease severity on the informed consent process in clinical research. Am J Med 1:261–8, 1996. 146. Markman M. Ethical difficulties with randomized clinical trials involving cancer patients: examples from the field of gynecologic oncology. J Clin Ethics 3:193–5, 1992. 147. Guidelines in research in palliative care. London: The National Council for Hospice and Specialist Palliative Care Services, 1995. 148. Ethical issues in palliative care. In: Doyle D, Hanks GW, Cherney N, Calman K, eds. Oxford textbook of palliative medicine, 3rd ed. Oxford: Oxford University Press, 2003. 149. MacDonald N. Suffering and dying in cancer patients: research frontiers in controlling confusion, cachexia, and dyspnea. West J Med 163:278–86, 1995.

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Understanding clinical trials in pain research john t. farrar and scott d. halpern The University of Pennsylvania

Introduction The randomized controlled trial (RCT) is a modern innovation; the first RCT – the British Medical Research Council’s trial of streptomycin for pulmonary tuberculosis – was published in 1948.1,2 Despite this relatively brief history, the RCT now represents the “gold standard” for evaluating the efficacy of new medical interventions and new applications for existing interventions. Unfortunately, the marked increase in the use of RCTs during the past 50 years3 has not been accompanied by corresponding advances in overcoming the method’s several limitations. Indeed, a number of potential scientific and ethical difficulties continue to limit the use of RCTs in some clinical contexts and hinder the interpretation of their results in others. In this chapter, we discuss the various strengths and limitations common to all RCTs, making special reference to trials of pain management interventions when appropriate. We describe the structure of an RCT, consider how several decisions regarding trial design can influence the trial’s results, discuss basic issues in the analysis of trial data, and attempt to guide readers in interpreting a trial’s results. Because no research experiment can ever be perfect, we hope this chapter will provide clinicians with sufficient understanding of the proper structure of, and inherent problems with, RCTs to be able to ascertain whether the results of published trials are likely 1) to be valid, 2) clinically important, and 3) apply to their patients.

Anatomy of a trial Designing and conducting an RCT requires investigators to carefully consider several design issues. The decisions investigators make regarding each component of an RCT can influence the outcome of the trial dramatically. Thus, subtle differences in a trial’s design or conduct may lead 568

investigators and readers to draw inappropriate conclusions from the data obtained. It also is important to understand that even a perfectly designed clinical trial is not guaranteed to find the right answer to a research question. Every RCT has a probability of producing the wrong answer by chance alone. Several statistical parameters can be computed to gauge a trial’s probability of reaching false-positive and falsenegative conclusions, but neither of these probabilities can ever be reduced to zero. Thus, no single trial should ever be considered as providing definitive proof of the efficacy, or lack thereof, of an intervention; evidence of replication of the results in other similarly designed trials will always be preferable before clinicians use the data to make decisions about patient care.

The question The single most important step in designing a trial is to clearly and specifically define the research question to be answered. This may seem relatively straightforward, but to reduce an important clinical question to a testable hypothesis is often a tremendous challenge. This challenge typically arises from difficulties in translating the vagaries of the clinical reality into the research setting. At other times, clinically relevant questions may be translated easily into a research question, but answering such questions would require prohibitively large numbers of participants. Finally, ethical concerns may also influence which questions can be studied, and the ways in which trials are designed to answer these questions. When investigators encounter these problems, they commonly attempt to modify the research question to one that is more readily answerable. However, if we test a different question, we get an answer to a different question; this answer may or may not apply to the original clinical

understanding clinical trials in pain research scenario we set out to investigate. Attempting to answer the right question in the setting of an RCT may require compromises in the study design that sacrifice either precision or protection from bias. Such compromises may reduce the value of the knowledge to be gained from the research, and hence alter the risk–benefit calculus necessary to justify the research.4–6 If, at the outset of the trial, investigators are not confident of the clinical importance of answering the proposed question, or if the design compromises put the validity of the results at risk, then alternative, observational research methods should be considered. The second step in defining the research question is to carefully select and specifically document the primary outcome to be assessed. This must be done a priori, before the data are collected or analyzed. For the probability of finding the correct answer to remain within acceptable limits, both the nature of this outcome and what would be considered a clinically important effect of an intervention on this outcome must be defined. Although multiple outcomes may be tested within a single trial, each needs to be identified at the outset (a priori). The appropriate analysis of multiple outcomes remains controversial, but a number of methods are being explored. Secondary outcomes are important to provide supportive and explanatory evidence, but none should subsequently replace the primary outcome after the data have been collected and analyzed (a posteriori).

General design issues Once the question has been defined, the remainder of the design issues for a clinical trial are approached from the perspective of focusing on providing a valid answer. Randomization allows a single group of recruited patients to be divided into essentially equivalent test groups. Selection of the control treatment groups helps isolate the aspects of the treatment to just those we want to test. Blinding ensures that the measured effects of the treatment are not unduly influenced by the patients’ or investigators’ preconceived expectation of how well the treatment will work. The study population is selected carefully to find patients who have a reasonable probability of responding without incurring an unacceptable level of risk. The sample size is determined to allow for an appropriate statistical likelihood of finding a statistically significant outcome for a clinically relevant benefit. The outcome is selected to accurately and reliably measure the effect that defined in the question being asked. The analysis is selected to be appropriate, not only for the type of data collected, but also for the biological processes that underlie the generation of the data collected. When this is done well, the findings that result from a clinical trial are

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useful for our understanding of the treatment being tested and provide important information for the care of patients. When done poorly, the results are not usable or provide incorrect information, and the immense work involved goes to waste.

Randomization In trials aimed at evaluating new analgesic therapies, patients are randomly assigned from the single group of all enrolled patients to one of two or more treatment groups. This ensures that the groups are as similar as possible in all ways at the beginning of a trial other than their assigned treatment. Randomization attempts to reduce the possibility that the results will be influenced, or confounded, by other variables that are related to outcome, such as age and disease severity. By minimizing the possibility of differences among the groups at the beginning of a trial, the RCTs enable investigators to more confidently attribute observed differences in group outcomes to the assigned treatments. By contrast, observational studies, such as case-control, cohort, or cross-sectional studies, depend on nature to set up the experiment. As such, there is a substantial possibility that known or unknown biases may result in differences among the groups at the start of treatment that may affect the results, and even lead to a wrong conclusion. True randomization requires both a valid means of generating random numbers and a mechanism to protect the integrity of the random assignment. In trials with multiple sites, handling the randomization centrally helps to ensure consistent application of the randomization procedure across sites. Additionally, such central control of the randomization scheme prevents members of the study team, some of whom may not be blinded to a patient’s treatment allocation, from consciously or unconsciously influencing the assignment. When randomization works correctly and sufficient numbers of patients are enrolled, the distributions of all potential confounding variables (some of which can never be measured or controlled) are likely to be equal across groups. However, in smaller trials, or in large multicenter trials with few participants from a given center, chance alone may cause significant differences in the distributions of important demographic or disease-related characteristics between groups. To avoid the bias that may ensue in such cases, investigators may use block randomization to ensure that selected participant characteristics will be distributed equally. For example, if investigators wished to guarantee an equal sex distribution among two treatment arms at

570 each site, they may randomize by blocks of six participants each, within which three participants would be male and three would be female.

Control group A control group is an essential part of all clinical studies. Without a control group, improvements or worsening of the treatment groups cannot be ascribed to the new treatment, because it could have come about for any of a number of other reasons. The changes over time that are observed in all groups of patients are most commonly the result of 1) the natural history of the disease being studied (either worsening or improvement), 2) regression to the mean (e.g., patients who wait to enroll until they are worse will generally get better even without treatment), and 3) the mind– body effect that occurs related to the patient’s belief (e.g., expectation) that the treatment will help him or her, and 4) the mind–body effect that occurs when any patient is placed in a situation in which s/he receives more attention than usual. Two primary types of control group are used in clinical trials to measure the amount of change that can be attributed to these nontreatment effects: 1) placebo control and 2) no-treatment control groups. A third control group has become increasingly important as a procedure to assess the appropriateness of the trial design, namely an active control group. The no-treatment control group is a control for only problems 1 and 2, the blinded placebo treatment control group also controls for problems 3 and 4, and the active control group ensures that the study is adequately designed to detect a positive treatment. Each has a clear role to play in providing information about the validity and meaning of the trial results. Placebo-controlled trials Pain management trials most commonly include a placebo control group. Placebo is defined as an inactive treatment designed to mimic, as closely as possible, the characteristics of the active treatment except for the specific component being tested. In drug trials, this means an inactive substance is formulated to have an appearance similar to the active treatment, including shape, color, taste, and route of administration. Occasionally, in trials of drugs with consistent side effects, the placebo is formulated also to produce the side effect, if that can be done without causing the effect that is being studied. A placebo treatment control group has additional benefits versus a no-treatment control group. It allows the

j.t. farrar and s.d. halpern estimation of the specific efficacy of a new intervention, as distinguished from the variety of nonspecific mind–body effects that come about as a result of treating a patient.7,8 The magnitude of the total nonspecific effects in a given study can be estimated by the mean (or median) response in the placebo control group. It is frequently assumed that the placebo control group response can be subtracted from the mean response in the active treatment group to estimate the specific efficacy of the new intervention. Although this can be done, there are many factors that affect a patient’s response to a placebo that may cause the response level to vary from trial to trial. This variation of effect, especially across trials of diseases of varying severity, have led some to question the importance of nonspecific treatment effects, but it is generally accepted that they are real and of particularly large magnitude in studies of the management of pain.9 In predicting the size of the effect that is likely to be provided by a treatment, the nonspecific mind–body effect is part of the total benefit the patient will experience. To have an effect, a placebo control group must be blinded to the true nature of the treatment. In addition to blinding the patient, a placebo control group allows the study to be conducted in a double-blind fashion, thereby avoiding the biases that also may ensue if investigators and data collectors knew who was receiving which treatment. We discuss the nature of these biases more fully later. The key point for now is that the potential for avoiding these biases is directly related to the ability to keep both patients and evaluators blind. Because it would be impossible to blind participants or evaluators if one group received a treatment and the other did not, bias is more likely to influence trials using no-treatment controls than those using placebo controls (assuming the placebo is indistinguishable from the active treatment; see later). There are costs to using a placebo control. The first and most obvious is that the placebo group patients with pain may not be given active treatment despite the existence of known effective interventions. The ethics of placebocontrolled trials in such settings remain a hotly debated topic10–13 and are considered further at the end of this chapter. The second cost to conducting placebo-controlled trials is that although they remain the gold standard for documenting absolute efficacy, they do not always answer a clinically relevant question. Practicing clinicians, who have several analgesics at their disposal, do not need to know whether another analgesic medication works better than nothing, but rather how the new analgesic compares with existing standards of care.14

understanding clinical trials in pain research No-treatment–controlled trials There are two primary situations in which it is important to consider including a control group of participants who receive no intervention. The first situation arises when determining the overall efficacy of a new intervention is critical, but there are practical and/or ethical problems with using a placebo or sham control. For example, it is often difficult to construct an appropriate sham intervention for many trials of surgical interventions. Even if adequate shams could be constructed, some feel that assigning patients to receive an invasive but nonactive intervention is unethical.15 The second situation arises when a goal of the trial is to ascertain the magnitude of the placebo effect (mind– body interaction). To measure the placebo effect properly requires comparison of patients receiving placebo with those receiving no treatment at all. A recent meta-analysis of 114 trials in which both placebo and no-treatment controls were used has shown that in many areas, the placebo effect is far less than might be expected.9 In pain research, however, these authors found that patients in placebo control groups typically have far more favorable outcomes than those in no-treatment control groups.9

Participant selection Another critical decision for investigators designing trials, and for clinicians attempting to discern whether a trial’s results apply to their patients, involves the selection of study participants. There are two conflicting priorities in the selection of participants: 1) ensuring maximal similarities between participants in the experimental and control groups and 2) testing a new treatment in a broader sample of patients more likely to reflect all those who could benefit from using the intervention. To meet the first goal, investigators attempt to enroll patients who are relatively homogenous. Strict inclusion and exclusion criteria allow greater confidence that the observed outcomes are attributable to the treatments being compared and limit the amount of statistical noise that might obscure the result. By lowering the interpatient variability at baseline, stricter criteria will help reduce the sample size and are generally the design of choice for initial therapeutic assessments. In contrast, meeting the second goal requires enrolling participants from a more heterogeneous population. Because of the large interpersonal variability inherent in such a population, this approach can substantially increase the number of participants required to ensure that the trial

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has adequate statistical power to document a treatment difference, if one exists. Despite this disadvantage, enrolling a heterogeneous sample allows testing of a new therapy in a group that is more representative of the general population. Within such a design, an advantage may be the post hoc subgroup analyses that can be conducted. In addition to identifying potential variations in a treatment’s efficacy among higher- and lower-risk patients, it is often possible to identify the patient group that is more likely to respond. Even if the initial trial is negative, the information gained from a broader look will inform the design of subsequent clinical studies. Thus, there are advantages and disadvantages to enrolling more or less homogeneous participants. As a result, early investigations of efficacy commonly are conducted using a select group of participants, whereas later, more definitive trials attempt to enroll more broadly representative patient samples. Physicians should, therefore, consider the composition of a given trial’s sample to determine the extent to which the results are generalizable to their own patients.

Blinding Over the past century, a growing understanding of the variable nature of illness, the ability of the mind to influence a variety of the body’s functions, and the desire to enhance the experimental rigor of clinical trials have increased appreciation of the need for blinding. Again, the goal of clinical trials is to design the experiment such that any changes seen at the end of the trial may be attributed specifically to the treatment being studied. To accommodate this goal, not only must all comparison groups be similar at the start, achieved by randomization, but participants in all groups must think they are likely to be getting the real treatment. If one group knows they are getting a placebo or control medication, the trial may reveal a benefit in the active treatment group because the patient’s belief in the medication leads to a placebo response. In addition, because control participants’ know they are receiving a less effective intervention, they may reduce the benefit observed in the control group. Thus, blinding of the participants is of substantial importance, and investigators must attempt to overcome the myriad ways in which participants and participating research personnel may decipher the treatment assignment (i.e., unblind themselves). In particular, if a medication has a specific taste, common side effects, or other distinctive traits, it is important that the placebo mimic these characteristics as closely as possible. Thus, it is common practice to use saline injections as controls for intravenous medications.

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572 Even in evaluating surgical interventions, sham procedures occasionally have been used by making skin incisions16 or burr holes in the skull17 to mimic the real surgical procedures. In addition to creating a suitable placebo, investigators should validate that the blinding was maintained by asking participants what treatment they think they received and why. Such questions should be posed to participants occasionally during the trial, and at the trial’s completion.18 If the blinding is successful, the participants’ guesses should be no more accurate than chance (e.g., 50% in a typical two-arm trial). Ideally, all patients will think they received the active therapy. However, ample evidence from many clinical fields suggests that participant blinding is difficult to maintain.18–26 These studies reveal that participants often can determine that they got the placebo because of the absence of side effects, whereas participants receiving an active intervention may be unblinded by noting adverse effects of the intervention. We also are beginning to understand that patients who receive treatments with side effects have a larger placebo effect.27 The labeling of blinding in a study may be confusing. When only participants are blinded to the treatment received, the study is termed a single-blind trial. However, double-blind trials, in which investigators attempt to keep both participants and those evaluating the participants’ response from knowing the treatment assignments, generally are preferable. Blinding of those who evaluate the participants’ outcomes also is critical to minimize the chance that evaluators will rate those known to be receiving the innovative treatment more favorably, thereby biasing the trial toward finding a benefit of that treatment. Although evaluator blinding may seem to be of less importance in trials of interventions for pain, in which the participants typically report their perceived symptoms, it remains essential to minimize the possibilities that investigators would impart different levels of enthusiasm, or prescribe different co-interventions, to patients in the different groups. Concerns about how the data are handled during the analysis phase has led to a growing process of also blinding the statisticians, with the statisticians conducting the analysis by group number, without knowing which group is which. The rationale concerns the need for data cleaning and other data management or to make decisions about the analysis issue after the data collection is complete. If the analyst is aware of the group designation, he or she may make subtle decisions about how to interpret an ambiguous data result, how to analyze the data, or how to deal with missing data that may affect the results.

Sample size The statistical power of an RCT to show a difference between treatments is determined by 1) the number of participants to be enrolled, 2) the effect size (treatment difference) that is deemed to be clinically important, 3) the variability of the outcomes in the two groups, and 4) the P value (type I error rate, or alpha) chosen to connote statistical significance (typically set at 0.05). Ultimately, however, the size of the sample to be tested is the variable investigators adjust most commonly to obtain adequate power – that is, an adequate probability of detecting a meaningful treatment difference when one truly exists. By tradition, researchers consider a study to be adequately powered if it has at least an 80% chance of detecting a clinically significant effect when one exists (that is if beta (␤) level = 0.2). However, this exact value is arbitrary; higher power will always be preferable. Furthermore, in practice, the power of a particular trial is set by considering both the number of participants who can reasonably be enrolled and the relative importance of limiting falsenegative conclusions (i.e., type II errors). The alpha (␣) level of 0.05 is the generally accepted rate of false-positive conclusions (i.e., type I errors) we are willing to accept (i.e., getting a difference even when one does not exist in about one in 20 studies). It is a truism that with a sufficiently large sample size, any real difference between groups, no matter how small or clinically irrelevant, can be shown to be statistically significant. The converse also is true: A large, clinically important difference (CID) between treatments may fail to reach statistical significance when inadequate numbers of participants are enrolled. The most common method of calculating the sample size required to achieve 80% (or greater) power is first to determine 1) the size of the effect that would be considered clinically important, 2) the anticipated response in the control group, and 3) the expected variability of the outcomes in both groups. This last determination may be particularly difficult to estimate and should, when possible, be based on evidence from prior studies of similar diseases and/or treatments. An alternate method of presenting a priori sample-size considerations is to calculate the size of the effect that would have to be present to produce a statistically significant outcome, given a fixed number of participants. Although this approach rarely is preferable to setting the sample size to detect a specified difference, it remains in common use. In such cases, authors should at least present this information in their manuscript to help readers determine whether the trial may be relevant to their clinical practices.

understanding clinical trials in pain research Outcome measurement Another critical decision to be made in planning an RCT is how to measure the chosen outcome of interest. For example, if investigators are interested in studying the effects of a new antihypertensive agent on systolic and diastolic blood pressure, should they measure these values with a mercury sphygmomanometer or via an arterial line? In addition to how the outcome will be measured, investigators must further consider when and how often to measure the outcome. For blood pressure, are single readings once each week adequate, or should participants be equipped with ambulatory blood pressure monitors to obtain multiple readings throughout the day? Finally, investigators must consider how to account for other variables that could alter the measurement, such as body position when the blood pressure is assessed. Regardless of what measurement technique is chosen, it should be characterized by three features. First, the measurement should be reliable – if the same measure is used repetitively in the same person under identical conditions without this person’s condition changing, then the measure should produce the same results each time. Second, the measure should be valid – it should measure what it is intended to measure. Third, the measure should be responsive – it should change over time if the condition being measured has truly changed. Although a full discussion of these concepts is beyond the scope of this chapter, the topics are well covered in many textbooks.28 For present purposes, the critical point is that in evaluating a published trial, readers should be comfortable that the measurement used meets these three criteria in the situation in which it was used. If the outcome measure is not used routinely in clinical practice, its reliability, validity, and responsiveness should be tested formally and documented in the pilot study report. It is also important to understand that a more responsive scale is not necessarily a better one. If a measure records changes in values that are too small to be clinically important, it may be overly responsive. For example, in pain studies, visual analogue scales have been shown to be more responsive than the common integer scales, in part because the 100-mm scale allows a broader range of potential responses. However, changes of less than 10% on a visual analogue scale are unlikely to be clinically important. In addition, recent evidence has demonstrated the improved reliability of asking single questions multiple times, such as collecting the average pain score daily over a week.29 Multiple measurements results in a more accurate assessment, with the 0–10 numeric rating scale approaching the

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accuracy of the 100-mm scale. Thus the usual analogue scale is unlikely to provide a more valid answer than could be obtained on a numerical rating scale from 0 to 10. Whereas the criteria of reliability, validity, and responsiveness may be appreciated readily when measuring blood pressure, they are far more difficult when measuring the effects of treatments intended to alleviate symptoms. For example, in pain management, the primary goal is to improve the patient’s subjective sense of comfort. For this purpose, investigators might ask a simple question, such as, “Do you feel better, yes or no?” Because such a measure has only two possible responses, it may not provide an adequately responsive measure of pain relief. To help differentiate the level of response, investigators might ask, “What percentage of pain relief do you get from the treatment?” However, such questions require patients to remember their previous condition. Alternatively, investigators could use a 0–10 numerical rating scale at both the beginning and the end of the study to measure the change in pain over time. Additionally, a quantification of the usual clinical question “How are you?” has been used successfully, by asking patients to indicate if they are better or worse on a seven-point balanced scale, sometimes referred to as the Patient Global Impression of Change. When the person doing the rating is the clinician, the same scale is called the Clinician Global Impression of Change.30,31 Deciding which measurement is most appropriate for a given clinical situation should be informed by considerations of how much change in the measure would be important to the patient, and the ability of the chosen scale to detect such a change. Another measurement concern in pain management trials is that a change in pain may be only one component of overall quality of life. Thus, symptomatic reports may be considered surrogate markers for changes in the broader outcome of quality of life. Conversely, assessing changes in quality of life may be insufficient because they cannot specifically connote changes in pain. Variables related to but not themselves the disease or effect are called surrogate markers. The use of surrogate markers is widespread in clinical trials. For example, investigators routinely monitor changes in serum cholesterol to provide a surrogate measure for the risk of myocardial infarction. However, using a surrogate measure requires making the assumption that, for example, a reduction in cholesterol also will reduce the risk of myocardial infarction. Alternatively, if the use of an experimental analgesic agent relieves pain but produces substantial side effects, patients may not consider its use to be advantageous from the perspective of their quality of life. Therefore, if investigators wish to know an intervention’s effects on both

574 the level of pain and the overall quality of life, then they must use tools to measure both. In considering the measures that are useful in the study of pain, a group of representatives from academia, the pharmaceutical industry, and government agencies have started to meet yearly to help define issues in the development of clinical pain trials. The first meeting of this group, called the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), defined the domains that should be measured in the study and accounted for in the analysis: 1) pain, 2) physical functioning, 3) emotional functioning, 4) participant ratings of improvement and satisfaction with treatment, 5) symptoms and adverse events, and 6) participant disposition. The IMMPACT members agreed although that pain should be the primary outcome, interpreting study results is not adequately achieved without reporting on some or all of the other outcomes.32 In summary, there is no single measurement strategy that is universally applicable, or always preferable. Investigators and readers should carefully consider what question a trial is specifically attempting to answer, whether this is an appropriate question, and whether the chosen measurement scale is up to the task of answering that question.

Analysis Investigators planning an RCT also should document a specific analytic strategy before commencing the trial. Although different analytic approaches may be statistically valid considering the structure of the data collected, it is important to consider the format of the data and the physiology of the process being measured in choosing how to analyze the data. Each approach will produce an answer to a different research question. Thus, the same data can be used to answer several different questions, depending on which analyses are performed. However, to be valid, the chosen analytic strategy must be appropriate to evaluate the primary research question in addition to being compatible with the nature of the data collected. The most important considerations in planning and conducting a clinical trial are considered here. Size of the effect The first and most important result of any analysis entails the measure of the size of the effect. In RCTs, the size of the effect often is calculated by determining a summary value for the primary outcome in each group and then calculating the difference between these group values to reveal the treatment effect. There are two primary forms for the

j.t. farrar and s.d. halpern summary value of a set of trial data: 1) the central tendency (e.g., mean, median, or mode) of the response among participants and 2) the proportion of participants who achieve a defined level of response. For example, in a hypertension trial, investigators could report the mean change in diastolic blood pressure (central tendency) or the proportion of hypertensive patients who achieved diastolic blood pressures below 90 mm Hg. If one were interested in the effect of an intervention on hospital length of stay, it might be acceptable to report either the median time spent in the hospital for each group (central tendency) or the proportion of patients in each group who were discharged within 3 days, 4 days, or some other predefined time period. Finally, in trials of pain management, in which the outcome of reported pain symptoms is provided on a numeric scale, investigators might report either the mean response in each group or the percentage of patients in each group reporting pain reductions of 33% (or 50%) or greater. In addition, a responder analysis may be carried out by constructing a cumulative distribution in which the percent of responders who achieve a certain level or greater can be graphed over the range of clinically appropriate potential response cutoff points.33 In each case, the units of these summary values should correspond to the units of the outcome measure. Choices regarding how best to present the summary measures should reflect the type of information that is most relevant for practicing clinicians. For example, measures of central tendency typically do not account for the variable responses among individuals in a group. When this variability is great, measures of central tendency will have little application to the corresponding clinical situations. Rather, for most health care providers, the question of interest is the probability of a given treatment working for a given patient. For example, suppose investigators reported that the mean response in the active treatment group was an improvement of 10% on a standard pain scale. This same result could apply to data indicating that 1) every patient in the active treatment group improved by 10% (a unimodal distribution), 2) half the patients in the treatment group improved by 20% and half had no improvement (a bimodal distribution), or 3) half the patients in the active treatment group improved by 40% and half deteriorated by 20% (also a bimodal distribution). Because these three descriptions of the underlying data could yield strikingly different clinical decisions, a central tendency analysis does not produce a unique answer to the critical question. In this case, it may be more useful to present the data by analyzing the proportions of patients in each group who improved or deteriorated by a clinically important amount.

understanding clinical trials in pain research In fact, clinical experience with pain interventions suggests that many medications produce bimodal distributions of response. In patients with cancer-related pain, it is often difficult to discern the predominant type of pain (i.e., somatic nociceptive vs. visceral nociceptive vs. neuropathic). If only one type of pain is likely to be responsive to the therapy, there will be two or more distinct populations in the treatment group. Headache is another area in which investigators now frequently view response as dichotomous, as it is difficult to know the underlying etiology in many headache patients.34–36 Another example is facial neuralgia: anticonvulsant medications work well, but only in some patients.37 A third example involves the use of tricyclic antidepressants for neuropathic pain. These agents also appear to work well in some patients but have virtually no effect in others.38 What is a clinically important difference? A common concern about presenting the proportion of “responders” is the need to define a level of response to be considered clinically important. Thus, the determination of a CID in a patient’s symptoms plays a key role in the interpretation of pain studies. Two methods for determining the CID are “expert opinion” and an assessment of how changes in symptom scales correspond to responses anchors such as global questions.39–41 Regardless of the method used, however, each requires that a somewhat arbitrary decision be made in defining the scale to be considered the standard. Two recent reports have used clinical trial data to estimate the CID for measures of pain. These reports demonstrated that a 33% change in the pain intensity score is considered clinically important by a majority of patients.31,42 Although there may be honest disagreement about how to establish a CID, reporting outcomes in this way provides information that can be translated more readily into improved patient care. Presenting the data as a cumulative proportion of responders (as described earlier) presents the data for all possible definitions of clinical importance and allows readers to see how two or more groups performed over a wide range and to choose the clinically important value they prefer. Statistical considerations Statistical significance (P values and confidence intervals) In addition to the test statistic summarizing the effect size, results of statistical analyses generate an accompanying P

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value, which estimates the probability that this effect size could occur by chance, assuming that the null hypothesis is true. Most commonly, investigators will accept a one in 20 chance of rejecting the null hypothesis when it is, in fact, true (a false-positive conclusion). Thus, the corresponding P value of ≤0.05 generally is used to document statistical significance. However, it is important to recognize that this value is strictly arbitrary; there are frequent occasions when different levels may be appropriate. In addition to the test, this convention implies that apparently significant results still have a 5% chance of having occurred by chance alone. This traditional method of hypothesis testing, in which P values are reported to quantify the significance of a result, is gradually being replaced by methods to gauge the range of plausible results that are compatible with the data. The most common method for presenting this range is to report a point estimate of the effect size, along with a 95% confidence interval around this estimate. A 95% confidence interval will include the true population value of the effect size 19 times out of 20 (95%). Thus, confidence intervals can help readers determine the uncertainty inherent in any result – the narrower the interval, the more precise the estimate of the true effect, and thus, the more confident readers can be that the reported result is “right.” Multiple comparisons It is also important to realize that when investigators choose a P value of 0.05 as an acceptable type I (false-positive) error rate, this value will apply only to a single comparison between groups. In most clinical trials, however, performing multiple outcome comparisons may be informative. The greater the number of comparisons, the more likely it is that at least one of them will be spuriously positive by chance alone. If an a priori decision is made to perform multiple comparisons, some type of adjustment is needed to account for this.43 Of the several available methods for adjusting this value, the simplest is to divide the P value by the number of comparisons to be performed, then to use this new P value as the cutoff for statistical significance across all analyses. However, this is excessively conservative, especially in situations in which the outcomes are not independent. In these cases, other methods may be considered, a discussion of which is beyond the scope of this chapter. One additional point is that any multi-item questionnaire is a version of multiple outcomes. For most questionnaires, the decision about how to combine the answers into one or a few subscales is made in the design of the instrument. A priori decisions about how to combine multiple outcomes into a summary value are an acceptable way of handling

576 multiple outcomes. The design of questionnaires is another topic that will be left to the reader to explore further.28 A related issue is the distinction between comparisons chosen a priori and those that investigators choose to conduct post hoc, or after the data have been collected. There are many times when post hoc comparisons can be informative, but the results of such analyses should never be considered conclusive, because they were not explicitly planned at the outset. To be explicit, running a large number of analyses has a high likelihood of resulting in a false positive. As such, results of post hoc analyses should be considered exploratory, intended to guide future investigations. Authors can help highlight this distinction by reporting which comparisons were chosen a priori and which were not. Evidence from multiple measures In addition to the reported effect size and statistical significance of the results, corroborative evidence from multiple analyses may be used to support or refute a study’s hypothesis. If multiple related measures are obtained, and the analyses of each show similar results, then it is less likely any one of the positive results arose by chance. Conversely, if the primary outcome appears to be positive but most or all of the other measures produce no change or are tending toward the opposite direction, then the result from the primary outcome should be called into question. Although there is no specific statistical test to document this phenomenon, showing that multiple related measures all produce similar types of effects lends support to the validity of the conclusions that are drawn.

Evaluating side effects Evaluating side effects of interventions tested in clinical trials is subject to the same considerations as those used to evaluate measures of efficacy. The major difference is that, in many cases, the side effects to be evaluated are not specified a priori but are evaluated only when they are observed. Even when a side effect is known, most clinical trials for efficacy are not powered to conclusively evaluate side effects that occur at a much lower rate. Because many common side effects occur spontaneously, independent of the treatment received, it is important to compare their incidence in the active treatment and control groups. Again, with many possible side effects requiring multiple comparisons, the chance that one or more will be observed more commonly in the treatment group is increased. Such differences should not be ignored, but they are not conclusive.

j.t. farrar and s.d. halpern Observing similar findings repeatedly in multiple trials may increase one’s confidence that they may be specifically attributed to the treatment received. It is also worth noting that in a typical clinical development program for a new therapy, only a few thousand patients will be exposed to the drug. Thus, at the time of the drug’s approval, it is unlikely that a side effect that occurs less frequently than one per 100 exposures will be detected. Serious side effects caused by the treatment, including death, that occur less frequently will not be dependably detectable until the drug has been used in tens of thousands of people, which occurs only after the drug has been released for use in the population. Although such occurrences thankfully are rare, the potential for this problem leads to two natural conclusions: 1) monitoring of side effects from new therapies should be continued during the initial period of its use in the general population, and 2) if an older drug with a known side effect spectrum is available, it is prudent to use it before trying a new agent.

Noninferiority and equivalence trials Given the foregoing concerns about placebo-controlled trials and the inability of no-treatment control groups to maintain blinding, investigators may decide to show that a new drug is either “no worse than” (a noninferiority trial) or “as good as” (an equivalence trial) a treatment that is commonly accepted as effective. Indeed, in evaluating therapeutics for conditions in which the risks of placebo assignment are widely regarded as too great, such as thrombolytic agents for acute myocardial infarction or stroke, active-controlled, noninferiority trials are the standard.44,45 Examples are trials in mild hypertension, hyperlipidemia, and tolerable pain, in which the risks of temporarily foregoing active treatment are not as obvious. Equivalency trials generally are not considered standard when a placebo can be used, because there are several potential problems with interpreting such studies.10,46–50 First, such trials generally require larger numbers of participants, because equivalence or noninferiority must be documented within relatively narrow margins. Second, demonstrating that two treatments are the same does not necessarily show that either of them worked. This problem has been referred to as a problem with “assay sensitivity,” because such trials require the external assumption that the standard therapy would have proven superior to placebo had a placebo arm been included.10 Third, equivalence trials essentially aim to confirm the conventional null hypothesis of no treatment difference, which may create inappropriate incentives

understanding clinical trials in pain research for conducting “sloppy” research.51 Because of these concerns, current regulatory guidelines still call for placebocontrolled trials to evaluate treatments for problems such as pain.52 The risks and benefits of this guideline remain hotly debated. For some scientific situations, trials that add a novel therapy to a standard therapy are appropriate. This has become the standard for testing of epilepsy therapies and has been used in some types of pain studies.42

Publication Thorough presentation of methods and results Given that many components of a trial are central to interpreting the results, it is vital that trial reports be accurate, complete, and objective in their presentation of all important aspects of the trial. In particular, the a priori hypothesis should be clearly stated and the discovery of other findings properly identified. All randomly assigned participants must be accounted for in the publication, and an intentionto-treat analysis of all participants typically is appropriate, even when some participants drop out early in the study or do not receive a full course of their assigned intervention. Subsequent subgroup analyses may focus on those who complete the trial, but this group should be identified and not be considered as the primary result. A careful description of the randomization and blinding procedures also is important to assure readers that the trial was conducted properly. Finally, brief descriptions of the rationale behind the choice of measurement tools and analytic strategies may be helpful. Negative studies are as important as positive ones There now is good evidence of a publication bias against negative studies, as authors prefer to report positive ones and editors prefer to publish the same,53,54 especially when the studies are relatively smaller. This may lead to difficulties for clinicians who want a true picture of the nature of the evidence for a particular treatment. Recent changes, including the requirement of registration of clinical trials and, in some cases, pre-publication of the protocols for large multicenter clinical trials, will help ensure that at least the larger negative trials are published. Users of published medical information should be aware that even the most careful meta-analytic assessments of small studies cannot be expected to include the small negative studies that were never published. A natural conclusion from this problem is that a meta-analysis of a number of smaller studies is more

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likely to find a positive result than one that includes larger studies, so it should be interpreted with caution.55

Potential limitations of RCTs There are several issues inherent in the design and conduct of RCTs that may threaten the internal validity of the results, that is, the likelihood that the treatment comparison is free from bias. Even when the comparison is internally valid, the external validity, or generalizability of the results, may be limited. Finally, because the conditions in which trials are conducted only weakly approximate clinical reality, physicians must be cautious in using the results as an exact guide to clinical decisions in other populations. We briefly discuss each of these potential problems in the following sections. More detailed discussions of these issues are provided by Feinstein56 and by Kramer and Shapiro.57 Underenrollment Underenrollment occurs when too few research participants are enrolled to provide adequate statistical power to answer the study’s primary research questions. The inability to recruit sufficient numbers of eligible patients is the most common cause of insufficient statistical power in RCTs.58–63 Such underenrollment has been attributed to characteristics of 1) clinicians who refer their patients,64–66 2) patients who choose to be screened67 or enrolled,68 3) investigators who design the trials,69 and 4) institutions at which the trials are conducted.69–71 Among these challenges to adequate participant recruitment, reluctance to enroll in RCTs is likely the most formidable. It has been observed that patients are generally less willing to participate in RCTs than in nonrandomized, observational studies.57 In addition to yielding unacceptably high probabilities for type II errors, the resulting underenrollment substantially reduces the trial’s precision in quantifying the treatment effect. Selective enrollment Even when properly designed and carefully conducted, clinical trials can only provide information specific to the population from which the study participants were drawn. If this population does not include elderly patients, women, or children, for example, then applying the results to these clinical populations requires extrapolation. Although extrapolating results may sometimes be reasonable, it must always be done cautiously, because both the beneficial and the

578 adverse effects of an intervention may vary across populations. In addition, participants in RCTs often differ from the general population in ways that may be related to their outcome. Selective enrollment occurs when particular subgroups within the target population enroll in proportions greater or less than their representation in that population.72,73 Causes of selective enrollment include 1) a narrow recruitment strategy, 2) differential access to the study among subgroups of potential participants, 3) different levels of willingness to participate among potential participants, and 4) different levels of clinicians’ willingness to refer different types of patients for enrollment. Each of these problems limits the generalizability of the trial’s results56,57,73–75 and hence reduces their applicability to clinical practice. These limitations may dramatically alter the conclusions to be drawn from the trial if differences between those who enroll and those who do not are potentially related to outcome. Enrolling a selected sample of participants may prohibit the detection of group differences in the absolute or relative risk reduction for having an adverse outcome (or in the absolute or relative enhancement of the probability of responding favorably). For example, consider a placebo-controlled trial of a novel opiate to treat chronic pain. Patients whose pain is presently well managed on a regimen of other opiates may have different levels of willingness to participate in such a trial versus those whose pain remains debilitating. Specifically, patients for whom currently available drugs have provided good pain control may be less willing to be taken off their medication and risk being assigned to another drug that may not work as well or to placebo. By contrast, those whose pain has not been adequately controlled may be more likely to participate in such a trial because doing so provides an opportunity to receive a promising new drug. However, patients who have not responded well to currently available opiates also may be less likely to respond to the new drug. If so, then the selective enrollment of these patients may reduce the observed efficacy of the drug in the trial, compared with the efficacy that might have been observed among a sample more representative of the population of patients in pain. Therefore, the results of comparing the study drug with placebo would not be generalizable beyond the enrolled sample of patients not responding to standard interventions. If the new drug offered a favorable side effect profile, then using the trial’s results to support a conclusion that the new drug is of limited value

j.t. farrar and s.d. halpern would prevent an otherwise useful agent from being added to physicians’ pain-treating armamentarium. Poor adherence to study treatment In clinical settings, patients often do not adhere to their prescribed treatment regimens. This problem may be more pronounced in RCTs, because many participants receive a treatment they would not have chosen if given the opportunity.57 If patients believe they are receiving a nonpreferred treatment, their enthusiasm for the trial and subsequent adherence to their assigned treatment may wane. There also is accumulating evidence that study participants frequently make concerted efforts to unblind themselves and that participants who become aware of their treatment assignment may be more likely to drop out of the study. For example, many patients assigned to the placebo group in the initial phase II trial of zidovudine (AZT) for AIDS therapy76 and in a randomized trial of vitamin E for patients with Alzheimer’s disease77 appear to have become unblinded, and even to have obtained access to the active agents.78–80 Even more problematically, widespread unblinding in the AIDS Clinical Trials Group 019 study81 not only allowed approximately 9% of those assigned to the placebo to receive AZT, but contributed to the dropout rate in the placebo group, which was one third higher than that in the active treatment group.82 Participant nonadherence and dropout can bias the results of a trial substantially.83 Although intention-to-treat analyses may mitigate this bias, if nonadherence or dropout rates are higher in one group than in the other, such analyses also may prevent a true effect of treatment from being detected. Thus, investigators should make concerted efforts to monitor participant adherence and to report dropout rates in their manuscripts. When such problems exist, the results of the trial must be interpreted cautiously.

Ethical issues in pain research Investigators who conduct clinical pain research must obtain informed consent from participants that meets the guidelines of the Health Information Portability and Accountability Act of 1996 (HIPAA) Privacy Rule.84,85 Obtaining adequate informed consent, however, often is difficult because of uncertainties regarding the kind and extent of information patients want when considering whether to enroll in a trial. Recently, investigators have begun exploring pain patients’ preferences regarding the information about a trial that would be important for them to know

understanding clinical trials in pain research in deciding whether participation is in their best interests.86 Further efforts to qualify and quantify patients’ information needs as well as their preferences for enrolling in different types of trials may substantially increase the ability of informed consent to serve its intended purpose of respecting patients’ autonomy and enhance the efficiency of patient recruitment. Another lingering ethical issue in pain research regards the standard comparison of new pain interventions with placebo. Patients who enroll in such studies typically must forgo known effective treatments for their pain for the duration of the trial. Although investigators typically make analgesics available for participants experiencing intolerable pain, the risk of worsened pain remains a disincentive to enrollment. Previously, we briefly discussed the relative merits of active-controlled and placebo-controlled trials. We suggest that the scientific merits of placebo-controlled trials continue to be considered in light of the risks to enrolled patients, as well as the value of the information such trials can provide for guiding clinicians’ prescribing practices. Ongoing revisions to the Declaration of Helsinki,87 the most widely cited international doctrine of research ethics, may influence the viability of placebocontrolled pain trials in the future.

Conclusions This chapter outlines several fundamental considerations for investigators planning clinical trials and for clinicians attempting to discern the applicability of such trials to their practices. Special consideration is given to the nuances of clinical trials for pain management interventions. In summary, RCTs remain the best available means of evaluating novel pain interventions and for determining how these interventions may be used optimally once they are approved. Despite the strengths of a study’s design, clinicians should be mindful of the many difficulties inherent in extrapolating information from the results obtained in a trial setting for use in clinical practice. References 1. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. Brit Med J 2:769–82, 1948. 2. Anonymous. Fifty years of randomised controlled trials. BMJ 317(7167):0, 1998. 3. Peto R, Baigent C. Trials: the next 50 years. Large scale randomised evidence of moderate benefits. [see comment]. BMJ 317(7167):1170–1, 1998.

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53. 54. 55.

56.

57.

58.

59. 60.

61.

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64.

65.

66.

67.

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Rockville, MD: Department of Health and Human Services, 2001. Begg CB, Berlin JA. Publication bias: a problem in interpreting medical data. J R Statistical Soc A 151:419–63, 1988. Reidenberg MM. Decreasing publication bias. Clin Pharmacol Thera 63(1):1–3, 1998. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. [see comment]. N Engl J Med 358(3):252–60, 2008. Feinstein AR. An additional basic science for clinical medicine: II. The limitations of randomized trials. Ann Intern Med 99(4):544–50, 1983. Kramer MS, Shapiro SH. Scientific challenges in the application of randomized trials. JAMA 252(19):2739–45, 1984. Freiman JA, Chalmers TC, Smith H, Jr., Kuebler RR. The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial. Survey of 71 “negative” trials. N Engl J Med 299(13):690–4, 1978. Altman DG. Statistics and ethics in medical research: III How large a sample? Br Med J 281 (6251):1336–8, 1980. Collins JF, Bingham SF, Weiss DG, Williford WO, Kuhn RM. Some adaptive strategies for inadequate sample acquisition in Veterans Administration cooperative clinical trials. Control Clin Trials 1(3):227–48, 1980. Hunninghake DB, Darby CA, Probstfield JL. Recruitment experience in clinical trials: literature summary and annotated bibliography. Control Clin Trials 8(4 Suppl):6S–30S, 1987. Meinert CL. Patient recruitment and enrollment. Clinical trials: design, conduct, and analysis. New York: Oxford University Press, 1986, pp 149–58. Nathan RA. How important is patient recruitment in performing clinical trials?[comment]. J Asthma 36(3):213–16, 1999. Taylor KM, Margolese RG, Soskolne CL. Physicians’ reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 310(21):1363–7, 1984. Taylor KM. Physician participation in a randomized clinical trial for ocular melanoma. Ann Ophthalmol 24(9):337–44, 1992. Taylor KM, Feldstein ML, Skeel RT, Pandya KJ, Ng P, Carbone PP. Fundamental dilemmas of the randomized clinical trial process: results of a survey of the 1,737 Eastern Cooperative Oncology Group investigators. [see comment]. J Clin Oncol 12(9):1796–805, 1994. Greenlick MR, Bailey JW, Wild J, Grover J. Characteristics of men most likely to respond to an invitation to be screened. Am J Public Health 69(10):1011–15, 1979. Barofsky I, Sugarbaker PH. Determinants of patient nonparticipation in randmized clinical trials for the treatment of sarcomas. Cancer Clin Trials 2:137–46, 1979.

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69. Collins JF, Williford WO, Weiss DG, Bingham SF, Klett CJ. Planning patient recruitment: fantasy and reality. Stat Med 3(4):435–43, 1984. 70. Begg CB, Carbone PP, Elson PJ, Zelen M. Participation of community hospitals in clinical trials: analysis of five years of experience in the Eastern Cooperative Oncology Group. N Engl J Med 306(18):1076–80, 1982. 71. Shea S, Bigger JT, Jr., Campion J, et al. Enrollment in clinical trials: institutional factors affecting enrollment in the cardiac arrhythmia suppression trial (CAST). Control Clin Trials 13(6):466–86, 1992. 72. Mant D. Can randomised trials inform clinical decisions about individual patients? [see comment]. Lancet 353(9154):743–6, 1999. 73. Halpern SD, Metzger DS, Berlin JA, Ubel PA. Who will enroll? Predicting participation in a phase II AIDS vaccine trial. Journal of Acquired Immune Deficiency Syndromes: JAIDS 27(3):281– 8, 2001. 74. Guyatt GH. Methodologic problems in clinical trials in heart failure. Journal of Chronic Diseases 38(4):353–63, 1985. 75. Ellenberg JH. Selection bias in observational and experimental studies. Stat Med 13(5–7):557–67, 1994. 76. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317(4):185–91, 1987. 77. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. [see comment]. N Engl J Med 336(17):1216–22, 1997. 78. Kodish E, Lantos JD, Siegler M. Ethical considerations in randomized controlled clinical trials. Cancer 65(10 Suppl):2400–4, 1990. 79. Epstein S. Impure science: AIDS, activism, and the politics of knowledge. Berkeley: University of California Press, 1996. 80. Karlawish JH, Whitehouse PJ. Is the placebo control obsolete in a world after donepezil and vitamin E? [see comment]. Arch Neurol 55(11):1420–4, 1998. 81. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. [see comment]. N Engl J Med 322(14):941–9, 1990. 82. Merigan TC. You can teach an old dog new tricks. How AIDS trials are pioneering new strategies. N Engl J Med 323(19):1341–3, 1990. 83. Peto R, Collins R, Gray R. Large-scale randomized evidence: large, simple trials and overviews of trials. [see comment]. J Clin Epidemiol 48(1):23–40, 1995. 84. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. Ethical principles and guidelines for the protection of human

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subjects of research. Washington, DC: US Government Printing Office, 1979. 85. World Medical Association. Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. JAMA 277:925–6, 1997.

j.t. farrar and s.d. halpern 86. Casarett D, Karlawish J, Sankar P, Hirschman KB, Asch DA. Obtaining informed consent for clinical pain research: patients’ concerns and information needs. Pain 92(1-2):71–9, 2001. 87. World Medical Association. International Declaration of Helsinki, 1964. 2000.

32

Legal and regulatory aspects of opioid treatment: the United States experience june l. dahl

University of Wisconsin School of Medicine and Public Health

Introduction Pain is one of the most common and feared symptoms of cancer.1–6 Persons may experience pain at the time of diagnosis, during therapy, and even after the disease has been successfully treated.1,4 Although precise prevalence data are not available,5 a recent systematic review found that 59% of patients receiving anticancer treatment were experiencing pain as were 64% of those with metastatic disease; furthermore, about a third of patients had pain after “curative treatment.” More than a third of those with pain rated it as moderate to severe.7 Thus, more than 20 years after the World Health Organization introduced the analgesic ladder and provided guidelines to improve the treatment of cancer pain worldwide,8–10 there is clear evidence that the “prevalence of pain remains unacceptably high in patients with cancer.”11 Essentially all the pain of cancer can be relieved with a multidimensional approach that includes careful assessment of the pain syndrome and appropriate use of the variety of therapies that are available.1,2,11–17 Yet persons with cancer, even those at the end of life, continue to suffer needlessly from pain. Almost three quarters of the general public surveyed in 1997 feared dying in pain;18 others reported they were more afraid of being in pain at the end of life than they were of death.19 The reasons for the undertreatment of cancer pain have been thoroughly documented over the last quartercentury.1,4,18,20–23 Although the focus of this chapter is on the impact of laws and regulations on opioid treatment, the subject cannot be considered in isolation. The nation’s poor record of pain control also is related to the lack of knowledge and inappropriate attitudes among health care professionals, patients, and families, factors that exacerbate the challenges posed by the regulatory system. Furthermore, the nation’s health care system tends to focus on

curing cancer, often to the exclusion of providing effective pain control.4,24 Patients may feel that pain is inevitable with cancer and be reluctant to report pain because they do not want to distract their doctors from treating their disease. Health care professionals may lack basic knowledge of pain assessment and management; they may not have adequate time or be given appropriate reimbursement for pain care. Furthermore, both patients and physicians fear addiction. The good news is that pain management has become a priority in many aspects of health care in the United States. In fact, the U.S. Congress declared this to be the Decade of Pain Control and Research.25 There is growing recognition that the undertreatment of pain is a major public health problem, which has stimulated the development of clinical practice guidelines,26–29 countless professional educational programs, and policy statements that acknowledge the importance of opioids in treating persistent pain.30,31 Various initiatives focused on end-of-life care have emphasized the importance of effective pain control and have recognized and called for the removal of regulatory barriers.32,33 Pain standards became a formal part of the Joint Commission’s accreditation process in 2001.34,35 These standards require more than 19,000 U.S. health care organizations (including 5000 hospitals) to have policies and procedures in place to assess and manage pain in all patients.36 Furthermore, in early 2008, the Joint Commission drafted standards for palliative care as part of its Health Care Services Certification Program.37 There also have been major collaborative efforts among members of the pain community, state legislators, and federal and state regulators aimed at improving the regulatory climate to remove uncertainty and encourage better pain management.38–43 The emphasis has been on promoting balanced policies that protect the public through appropriate and effective drug control measures that prevent diversion and abuse of opioid analgesics while ensuring their 583

584 availability to patients who need them for pain control.40,44–48 The Pain and Policy Studies Group (PPSG) at the University of Wisconsin has provided much needed direction for change.41 A wealth of information about the policies that affect pain control is available on the PPSG website.47 There is evidence that pain management practices are improving. There is greater awareness of the need for effective pain control and of the adverse physiological and psychological consequences of poor management. Many physicians have become more comfortable prescribing opioids, resulting in a significant increase in the use of opioids for pain control.49–52 Unfortunately, there has been a parallel increase in the abuse of these medicines,53–55 leading one prominent pain physician and advocate to observe, “We have two public health crises going on at the same time: one is undertreated pain, the other is prescription drug abuse.”56 Many are concerned that the rise in opioid abuse will “turn back the clock” and exacerbate clinician fears – fears that for years have contributed to poor pain management practices.4,22 Opioid analgesics are the drugs of choice for the management of the moderate to severe pain associated with cancer. Yet in spite of their documented effectiveness, they still may be underused. Physicians may give inappropriate drugs or inadequate doses at inappropriate dosing intervals,57,58 nurses may undermedicate,23 pharmacists may not stock opioids,59 and patients may be unwilling to take these drugs.60 There may be reluctance to prescribe opioids because of lack of knowledge of basic analgesic pharmacology, fear and misunderstanding of tolerance and addiction, and/or concerns that large doses of these drugs may hasten death.1,12,16,61–63 The history of our attitudes about opioids and other drugs that have the potential to be abused has been well chronicled.64,65 At times, there has been an almost hysterical fear of opioids among the general public as well as an almost puritanical reluctance to use painkillers, as evidenced by this statement in a 1941 issue of the Journal of the American Medical Association: “The use of narcotics in the terminal cancer patient is to be condemned. Morphine usage is an unpleasant experience to the majority of human subjects because of undesirable side effects. Dominant in the list of these unfortunate effects is addiction.”66 There has been, and sometimes still is, apprehension surrounding even the routine use of opioids. This “opiophobia”67 has been heightened by the current, very serious prescription drug abuse problem53–55 and by a history of repressive attitudes among drug control and law enforcement officials.4

j.l. dahl Furthermore, there continues to be confusion about the meaning of the word addiction. It often is used synonymously with tolerance and physical dependence. Although there may have been a lack of clarity about the meaning of the term, there is no question that addicts were and are viewed with contempt. As late as 1962, the U.S. Supreme Court described a drug addict as “one of the walking dead” and failed to separate the direct effects of opioids from the effects related to the socioeconomic conditions of addicts.65 It is critical to do so. Addiction is a primary, chronic neurobiological disease characterized by one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.68 Tolerance and physical dependence are normal consequences of sustained opioid use and are not the same as addiction;68–70 to equate physical dependence with addiction is to stigmatize patients and risk underuse of the opioid analgesics needed by some patients for pain control. More than a decade ago, physicians in the Eastern Cooperative Oncology Group ranked excessive regulation of opioids among the top barriers to effective management of pain.58 Subsequent reports from several state commissions71–75 as well as surveys of physicians76–78 showed that medical decisions about opioid use were influenced by regulatory policies or fear of regulators. Particularly striking was the 1998 report from an ad hoc Committee on Pain Management established by the New York State Public Health Council. A majority of the 6000 physicians surveyed indicated they were very concerned about regulatory investigation and they “may underprescribe pain medication due to fear of unwarranted legal consequences.”73 In spite of the documented fears of practitioners, the risk of discipline by federal or state authorities is very small.79–81 Nevertheless, a few well-publicized cases have cast a pall over the professions involved in prescribing and dispensing controlled substances82–85 and have left them with the perception that regulatory sanctions are very common. Furthermore, the impact of an investigative process on professionals who are suspected of or charged with a violation of the law, but are subsequently exonerated, is enormous. Such investigations may take a huge psychological and/or financial toll on a clinician’s personal and professional life. Although the concerns about regulatory scrutiny have been focused primarily on the use of opioids for the treatment of chronic noncancer pain, they may have an impact on long-term cancer survivors.86,87 Survivors whose disease is in remission may experience debilitating pain and become unintended victims of the debate about the

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role that opioids should play in the treatment of chronic pain.88,89

policies and make regulatory changes to increase opioid availability.93

Laws and regulations

Federal laws and regulations

The laws and regulations that govern the production and distribution of controlled substances in general, and opioid analgesics in particular, are intended to prevent the diversion of these drugs to the illicit market and to protect the public from the adverse consequences associated with the abuse of these drugs. Controls are established by international treaties and by federal and state laws and regulations.

Origins of opioid control The laws of the United States recognize that opioids are necessary for the public health. They mandate that there be scientific and medical input into drug control decisions. They guarantee drug availability and place no restrictions on the amount of a drug that can be prescribed or for how long it can be prescribed. However, these very positive aspects of federal law need to be placed in a historical context, because only then can one understand the origins of many opioid myths and misperceptions that still adversely affect pain management practices.64,65 Opium use gradually increased in the United States over the course of the 19th century.94 Many patent medicines contained opium; by the latter part of the century, opium and morphine “were widely prescribed by physicians to treat pain, cough, diarrhea and dysentery, as well as a host of disorders from anemia and angina to diabetes, tetanus, menstrual and menopausal discomforts, the vomiting of pregnancy and to calm teething babies.”65 Physicians referred to opium and morphine as “God’s own medicine.” Physicians prescribed these drugs to bring a sense of tranquility and well-being because at the time, little else was available to treat most diseases. Not everyone was supportive of such liberal practices; eventually “there was medical consensus that morphine had been overused by physicians, that addiction was a substantial possibility, and that the addition of opioids to patent medicines should be stopped.”65 Dr. Oliver Wendell Holmes, Sr., Dean of the Harvard Medical School, stated that the constant prescription of morphine by physicians in the western United States “had rendered habitual use very prevalent.”65 Interestingly, surveys of users showed they were primarily from the middle to upper middle classes and were using morphine as a “tranquilizer”; they did not experience euphoria from the drug. By the turn of the century, there appeared to be a significant population of addicts in the United States, resulting in public and governmental demands to decrease drug availability. The first step was made in 1906, when Congress passed the Pure Food and Drug Act, which required that medicines containing opioids and certain other drugs be clearly labeled. Later amendments required that the quantity of each drug be stated, and eventually standards for purity were established.

International drug control The Single Convention on Narcotic Drugs, adopted in 1961 and amended in 1972, is an international treaty that regulates the production, manufacture, import, export, and distribution of narcotic drugs for medical use.90 Countries that are party to this treaty are required to control all aspects of the use of opioids within their territories and all international movement of opioids. The Convention’s emphasis on combating illicit drug trafficking is not intended to reduce the use of opioids for legitimate medical purposes. The treaty recognizes that opioids are indispensable for the relief of pain and suffering and that adequate provisions must be made to ensure the availability of these drugs for such purposes. The treaty emphasizes the importance of a balanced drug control policy aimed at preventing the diversion and abuse of pain medicines while assuring their availability for legitimate medical purposes.8 The Single Convention requires that reports on production, manufacture, import, export, and consumption of opioids be made annually to the International Narcotics Control Board (INCB) in Vienna, Austria. Each country must supply a realistic estimate of the amounts of these drugs needed to meet the demand for their medical use.91 The United States traditionally has provided a realistic estimate of its needs; however, this may not be true of other countries. The legislative, regulatory, and administrative impediments in a particular nation may lead to underuse of opioids, which in turn may lead to low estimates of that nation’s need for pain medicines. In a 2007 report, the INCB expressed concern about the low levels of consumption of opioid analgesics, particularly in developing countries.92 The PPSG continues to work diligently to remove the barriers that prevent access to pain medicines in other nations by developing methods and resources to help governments and pain and palliative care groups examine national

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586 Another major step toward decreasing drug availability was taken in 1914, when Congress passed the Harrison Act, the first major federal antinarcotic law.95 The Harrison Act was enacted to meet U.S. obligations under new international treaties aimed at reducing opium traffic throughout the world. Before the Harrison Act, there had been few, if any, legal controls over the sale and distribution of opium or its derivatives. The act’s intent was to curb recreational and nonmedical use of opioids, not to regulate medical practice. There was nothing in the act that prevented a physician, dentist, or veterinary surgeon from dispensing or distributing any opioid to a patient in the course of his or her professional practice so long as those professionals were registered as required by the act. At that time, some physicians believed that providing opioids to maintain an addiction was a legitimate part of medical practice. Law enforcement officers asserted that such action was illegal under the Harrison Act, and in 1919, the Supreme Court concurred when it ruled that it was against the law for physicians to prescribe opioids to maintain an addiction.96 In the years that followed, physicians were vigorously prosecuted for prescribing to addicts; some were convicted and sent to prison, and others left their practices in disgrace.65 The addiction problem was blamed on physicians, and admittedly, some members of the medical profession awakened rather slowly to the fact that opioids could be addicting. Once aware, physicians became reluctant to prescribe these drugs for fear their patients would become addicted. Some lay the blame for the current prescription drug abuse problem on physicians, despite the lack of evidence to show that prescriptions for pain control are the primary source of these drugs on the street. The Controlled Substances Act By the late 1960s, there were more than 50 federal laws regulating the various substances and drugs that could be abused. The Food, Drug and Cosmetic Act of 1962 established the U.S. Food and Drug Administration (FDA) to evaluate drugs, including opioids, and determine their safety and effectiveness for medical use. At that time, the regulation of drugs of abuse was split between two bureaus. The Bureau of Drug Abuse Control, which was part of the FDA, regulated stimulants, depressants, and hallucinogens. The Bureau of Narcotics and Dangerous Drugs in the Department of Justice (DOJ) regulated marijuana, cocaine, and opioids. In 1970, Congress repealed the multiple federal laws and passed a single law, the Controlled Substances Act (CSA), to regulate the manufacturing, distribution, dispensing, and delivery of drugs or substances that are subject to, or have the potential for, abuse or physical or

psychological dependence.97 A 1990 revision of the CSA enabled chemical analogues of controlled substances (the so-called designer drugs) to be regulated on an emergency basis.98 In 1973, the CSA was put under the administration of the Drug Enforcement Administration (DEA) in the DOJ. The DEA registers all persons, businesses, and institutions conducting any activity that involves controlled substances by issuing registration numbers that must be renewed every 1–3 years. Separate DEA registrations are required for each individual site at which controlled substances are stored or dispensed. Each pharmacy, even if part of a chain, must be registered individually with the DEA. If a chain has 100 pharmacies, each operating at a separate street address, there must be 100 separate registrations. Additional registrations are required if pharmacies are engaged in wholesale distribution or the disposal of controlled substances (reverse distribution). The DEA also regulates precursor chemicals and machinery that may be used in producing controlled substances and controlled substance analogues. The DEA publishes two manuals to help health care professionals understand the CSA regulations. The Pharmacist’s Manual pertaining to pharmacy practices is in its eighth edition (2004).99 A Practitioner’s Manual was published in 2006 to help practitioners (physicians, dentists, veterinarians, and other registrants) understand the basic requirements for prescribing, administering, and dispensing controlled substances.100 The CSA requires the following to be included on a prescription order for a controlled substance: r r r r

Patient’s name and address Prescriber’s name, address, and DEA registration number Prescriber’s signature and date Name and quantity of the drug prescribed, dosage strength and form, directions for use, and number of refills authorized

The CSA classifies medicinal substances into a hierarchy of five schedules (I–V) based on their medical usefulness and their abuse and dependence-producing potential (Table 32.1). Initially, the CSA gave the FDA the authority to determine whether a drug would be classified as a controlled substance, and if so, in which schedule it would be placed. In 1986, the DEA assumed authority for scheduling drugs and now has primary responsibility for promulgating the regulations that interpret, implement, and enforce the CSA. Most opioid analgesics are in schedules II and III. Schedule II drugs include morphine, hydromorphone,

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Table 32.1. Federal schedules for controlled substances Schedule Description

Agents

Restriction(s)

I

Hallucinogenic substances (e.g., LSD); heroin and certain other opioids; methaqualone, marijuanaa

Available for research, instructional use, and chemical analysis purposes. Marijuana available for a few patients.

Opium, morphine, codeine, hydromorphone, oxycodone, oxymorphone, methadone, fentanyl, dextroamphetamine, methamphetamine, methylphenidate, amobarbital, pentobarbital, secobarbital, nabilone

Written prescription required except in emergencies; however, written prescriptions may be transmitted by fax in some instances

II

III

No currently accepted medical use in the United States High potential for abuse Currently accepted medical use in the United States

High potential for abuse Severe liability to cause psychological or physical dependence Potential for abuse less than for drugs in schedules I and II

No refills

Combination products of codeine or hydrocodone with aspirin, acetaminophen, or ibuprofen; certain sedative drugs; buprenorphine; dronabinol; anabolic steroids

Abuse may lead to moderate or lower physical and psychological dependence than abuse of substances in schedules I and II IV

V

Lower potential for abuse than drugs in schedule III Limited physical or psychological dependence Potential for abuse is less than for drugs in schedule IV

Oral prescription orders allowed

Prescription orders valid for 6 months

Benzodiazepines,b phenobarbital, propoxyphene, certain sedative drugs, butorphanolc Pregabalin, pyrovalerone, and antitussive and antidiarrheal preparations containing moderate quantities of opioids

Five refills allowed in 6 months Same restrictions as for schedule III agents

May be dispensed without a prescription order Some states have made antitussives with codeine prescription drugs

a

Because marijuana is in schedule I, it is against federal law to prescribe it as a medicine. As a result, there is no legitimate source for the substance. Twelve states have laws that effectively remove state-level criminal penalties for growing and/or possessing marijuana. Ten states plus the District of Columbia have symbolic medical marijuana laws that support medical marijuana but do not provide patients who use it with legal protection. Herbal medicines are not controlled substances, so there is no legal prohibition against their sale or use and therefore no regulation of their sale or use. b In New York State, benzodiazepines are in schedule II. c Butorphanol (Stadol) is a mixed agonist–antagonist opioid, but nalbuphine (Nubain), which also is a mixed agonist–antagonist, is not scheduled. Data from the U.S. Department of Justice, Drug Enforcement Administration. Controlled substance schedules. Available at: http://www .deadiversion.usdoj.gov/schedules/schedules.htm.

oxymorphone, methadone, levorphanol, fentanyl, codeine, oxycodone, and combination products with oxycodone and a nonopioid. Federal regulations governing the prescribing of schedule II drugs are most stringent: r Written prescription orders are required except for emergencies; in emergencies, oral prescription orders are permitted, but with two restrictions: the amount prescribed and dispensed is limited to the amount adequate to treat the patient during the emergency period, and a written

prescription order must be received by the pharmacist within 7 days. r If a pharmacist is unable to supply the full quantity of the written or oral emergency prescription, the remaining portion must be filled within 72 hours; a new prescription is required if more drug is needed after that period. r No refills are allowed. r Prescriptions may be sent by fax only to infusion pharmacies and pharmacies that service long-term care facilities.

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588 r A prescription may be filled in partial quantities for patients who are terminally ill or in long-term care facilities; remaining quantities of the drug must be dispensed within 60 days of the prescription date.

Schedule III, IV, and V drugs are subject to less stringent regulations than those in schedule II. Written prescriptions for drugs in schedules III, IV, and V may be transmitted by fax; the faxed prescription is considered equivalent to a written prescription. Schedule III opioid analgesics include combination products that contain hydrocodone or codeine with aspirin, acetaminophen, or ibuprofen, and the partial agonist buprenorphine. Dronabinol and anabolic steroids also are in schedule III. Schedule IV includes propoxyphene and benzodiazepines. Prescription orders for schedule III and IV drugs are valid for 6 months from the date of issue, and a maximum of five refills are allowed within 6 months of issuance of the prescription. Schedule V drugs include the antiepileptic pregabalin, the mild stimulant pyrovalerone, and cough suppressants and antidiarrheals containing limited quantities of opioids. In some states, schedule V cough suppressants and antidiarrheals may be dispensed without a prescription. Federal regulations do not restrict the quantity of a controlled substance that can be prescribed with a single prescription order. However, insurance providers often restrict the quantity to a 30-day supply. Furthermore, practitioners are reluctant to prescribe large quantities to be dispensed at one time, because this could increase the risk of diversion. In December 2007, the DEA ruled that practitioners could issue multiple prescriptions for a schedule II drug at a single office visit. This provides patients with the equivalent of a 90-day supply of medication when it is appropriate.101 The ruling was widely heralded as good news within the pain management community as it eliminates the burden previously imposed on patients with cancer or chronic pain, who were forced to visit their physician every month for new pain medicine prescriptions when there was no medical necessity to do so. However, some states have restrictions on the period of validity of prescriptions, and in those cases, implementation of the rule is not possible.47 Even in states where there are no limitations to implementing this rule, prescribers may be reluctant to issue multiple prescriptions. The DEA intended the 90-day supply in three prescriptions to be an outer boundary only; providers can use this approach to prescribe smaller quantities and for shorter periods for higher-risk patients or patients with other clinical issues. Regulation of medical practice is a function of the states; it was never intended that the federal government

would regulate practice. Nevertheless, there has been federal involvement, as evidenced by the DEA ruling just discussed as well as by other actions and policy statements. In December 2007, the DEA issued an advisory to inform practitioners that as of January 1, 2008, 40-mg methadone tablets would be available only to detoxification and maintenance facilities.102 The 5- and 10-mg dosage strengths continue to be available to treat pain. This action was taken in response to increasing methadone-related adverse events. Government agencies concluded that the increase in methadone-related deaths was most likely a result of the increased use of the drug for pain control rather than its use for the treatment of addiction.54,103,104 In a previous action in May 2007, the U.S. Congress amended the Social Security Act to make payment for outpatient drugs to Medicaid patients dependent on the prescriptions being written on tamper-resistant pads.105 It is not clear whether this requirement will have a specific impact on persons who need controlled substances for pain control, because the payment limitation does not apply to prescriptions faxed to pharmacies or communicated to the pharmacy by telephone. Opioid treatment programs Methadone detoxification and maintenance programs to treat opioid dependence, available since the 1960s, have been subject to rigorous federal and state regulations. The Drug Addiction Treatment Act of 2000 expanded the clinical context of medication-assisted opioid addiction treatment to allow qualified physicians to dispense or prescribe specifically approved schedule III, IV, and V opioids for the treatment of opioid addiction in treatment settings other than the traditional outpatient clinics.106 At this time, only buprenorphine is approved for the treatment of opioid dependence and is available with and without naloxone.107 In 2001, the federal government issued new regulations that make methadone treatment more flexible and give clinicians the same latitude in treating opioid addiction as they have in treating other diseases.108 The Center for Substance Abuse Treatment in the Department of Health and Human Services is responsible for oversight and regulation of Opioid Treatment Programs. State laws and regulations States also have promulgated laws and regulations to prevent diversion and abuse of controlled substances. Practitioners must comply with both the federal and state laws that govern their practice.99,100 The controlled substances laws in most states are based on the 1970 model law established

legal and regulatory aspects of opioid treatment to bring consistency to federal and state laws. Some states have adopted laws and regulations that are more stringent than those on the federal level. A comprehensive analysis of state laws and regulations is available on the PPSG’s website.47 In addition, the website of The Legal Side of Pain offers clinicians a comprehensive resource for regulatory compliance issues associated with the use of controlled substances to treat pain. Much of the website’s material converts the “what” of regulatory requirements into a “how to comply” product for the pain practitioner.109 With access to such resources, ignorance of the law is no excuse. Some state laws do not explicitly recognize that opioids are essential for the public health and do not articulate the importance of balance that is found in federal law. States may limit the quantity of a drug that may be prescribed or dispensed at one time. Some states enforce limits of a 30- or 34-day supply; other states caution against prescribing an “excessive amount,” a term that has no meaning in current pain management practices. Some state laws and regulations contain inaccurate or confusing definitions of addiction. Some appear to prohibit the use of opioids for pain control in persons who have a history of substance abuse.47 Furthermore, as discussed later, more than half the states have implemented special programs for monitoring the prescribing and dispensing of controlled substances, which may affect prescribing practices. States that have granted nurse practitioners prescribing authority may or may not allow them to prescribe controlled substances or may specifically prohibit them from prescribing schedule II drugs.110,111 Medical marijuana Marijuana is a schedule I substance and, as such, is not approved for medical use in the United States. Because of numerous reports that marijuana has medical value in treating patients with serious illnesses such as cancer and AIDS,112 many petitions for rescheduling marijuana have been submitted to the federal government. In 2005, the U.S. Supreme Court ruled in Raich v. Gonzales that the federal government can prosecute persons who use marijuana for medical purposes.113,114 Nevertheless, 12 states have laws that effectively remove state-level criminal penalties for growing and/or possessing medical marijuana. In addition, 10 states and the District of Columbia have symbolic medical marijuana laws (laws that support medical marijuana but do not provide patients with legal protection under state law).115 Obviously, these actions put active users of medical marijuana in a tenuous position.

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Prescription monitoring programs States have established prescription monitoring programs (PMPs) to collect, analyze, and report information about the prescribing, dispensing, and use of controlled substances116–118 based on the assumption that inappropriate prescribing of controlled substances is the cause of prescription drug diversion and abuse. The first of these programs, established in California in 1939, was a paper-based system that required prescriptions for schedule II controlled substances to be written on government-issued, multiple-copy forms. Between 1943 and 1988, other states adopted PMPs that required the use of triplicates, duplicates, or single-copy forms. When pharmacies began to use computers to send information to third-party payors, states moved from paper to electronic tracking of the drugs dispensed. Oklahoma implemented the first electronic PMP in 1991.117 Ten states had electronic PMPs in 1992, and by 2004, 16 states used computerized systems to track the prescribing of controlled substances. By December 2007, 35 states had enacted legislation to establish PMPs118 – 26 of those programs were operational; nine were in start-up phase. State PMPs differ in their scope of coverage and in the type of state agency that administers the program, usually a law enforcement agency, state department of health, or state board of pharmacy. Most PMPs track all controlled substances. Three states – Illinois, Massachusetts, and Oklahoma – track only schedule II drugs. New York requires all prescriptions to be written on bar-coded serialized prescription forms, but only information about controlled substances is reported to the state.119 In Texas, only prescriptions for schedule II drugs must be written on government prescription forms.120 Electronic PMPs offer several advantages over paperbased programs. They allow ready identification of physicians and patients who prescribe or consume large quantities of drugs, they may provide patient-specific information upon the request of the prescriber or pharmacist, and some offer educational programs about the nature and extent of the problem and medical treatment options for drug abusers. Giving individual health care professionals access to data about their individual patients allows them to evaluate their patients’ use of controlled substances. Some of the disadvantages of electronic PMPs include the costs of providing data in a timely fashion and risks to patient confidentiality. The Alliance of State Pain Initiatives urges states to adopt only programs that are balanced, address all sources of diversion, and do not interfere with the use of controlled substances for legitimate medical purposes.121 The implementation of state PMPs has been promoted by the DEA. The DOJ manages a competitive grants program

590 for states that want to create or improve existing PMPs.122 The DOJ-funded efforts emphasize the law enforcement rather than the public health aspects of prescription drug diversion and abuse. The National All Schedules Prescription Electronic Reporting Act authorized a system of federally funded, interoperative, state-based prescription drugmonitoring programs and the promise of an important tool for physicians to use to address patient abuse and diversion of pain medications.123 Although signed into law in 2005, it has not been funded. There are no studies to document the impact of PMPs on diversion and abuse of prescription opioids or on the quality of pain control.116,124–126 PMPs reduce investigation time – that is, improve the timeliness of law enforcement and regulatory investigations – which may be viewed as a positive outcome. PMPs also appear to reduce the per capita supply of opioids in a state: The year after a “triplicate” program was introduced in Texas, there was a dramatic decrease in the prescribing of schedule II controlled substances and a commensurate increase in the prescribing of schedule III drugs.125 Regulators claimed that the decrease indicated a drop in inappropriate prescribing, but others asserted that the drop reflected increased fears of regulatory scrutiny. PMP advocates assert that states that are proactive in their approach to regulation are more effective in reducing the per capita supply than are states that are less proactive.126 Those who advocate for more effective pain control view such an effect with alarm, as this has never been the stated purpose of these programs. PMPs focus on persons who prescribe, dispense, or use controlled substances under the assumption that they are the source of the drugs diverted to illicit use. However, two other important sources exist that are not captured by PMPs: Internet sales and theft from other parts of the distribution system. Internet pharmacies are convenient for individuals who live in remote areas or persons with limited mobility. Unfortunately, the Internet has become one of the fastest methods used to divert large quantities of controlled substances.127 The majority of these Internet sites are based in the United States and operate in concert with unscrupulous physicians and pharmacists. A recent study found more than 300 websites from which prescription opioids could be ordered. These “rogue” Internet sites are estimated to generate millions of dollars in illegal sales.128 In addition to Internet sales, theft from some point in the distribution chain also appears to be an important source of prescription opioids diverted to the illicit market.129 PMPs provide no information about this source of diversion and will not affect the supply of drugs coming from those engaged in criminal activity.

j.l. dahl Intractable pain treatment laws Laws addressing the treatment of intractable pain were promoted by persons with chronic noncancer pain whose physicians were uncertain about the legality of prescribing opioids for extended periods for persons who do not have cancer. The first Intractable Pain Treatment Act (IPTA) was adopted by Texas in 1989; a year later, California adopted a similar law. IPTAs affirming the appropriateness of using opioids to treat intractable pain have been made law in 10 states.130,131 Protection of physicians who prescribe opioids for pain control is a worthy goal. Unfortunately, some IPTAs create barriers, in part because the term intractable pain is ambiguous. Intractable pain is defined as “a pain state in which the cause of the pain cannot be removed or otherwise treated and for which in the generally accepted course of medical practice no relief or cure of the cause of the pain is possible or none has been found after reasonable efforts.”130 This term could be interpreted to include those whose cancer has been “cured” but who continue to experience pain caused by conditions resulting from surgery, chemotherapy, or radiotherapy. Who defines the meaning of the term generally accepted course of medical practice? What constitutes reasonable efforts? How many expensive and invasive procedures must be carried out before it is decided that there have been reasonable efforts? These illdefined parameters present barriers to effective pain control. Additional barriers are presented for patients with a history of substance abuse, as some IPTAs do not allow the use of opioids for the treatment of pain in these persons; others require a second opinion from a specialist in the organ system believed to be the cause of pain. However, that specialist is not required to have specific knowledge about pain assessment and management. State pain commissions Several states have established pain commissions to study and address impediments to effective pain management and palliative care, especially regulatory barriers.71–75 If members of such commissions are well informed and have adequate support and a balanced agenda, they can provide significant support for improving the regulatory climate in a state.132 Medical board guidelines A 1991 national survey of medical board members showed that they lacked understanding of the role of opioids in the treatment of pain and were confused about the meaning and prevalence of addiction.42 Only 75% of the respondents agreed that the prescribing of opioids for cancer patients with pain was legal and generally accepted medical practice.

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Less than half agreed with that statement if the patient with cancer and pain had a history of substance abuse. The survey results stimulated a collaboration between the Federation of State Medical Boards of the United States (FSMB) and the PPSG, which culminated in publication of FSMB’s Model Guidelines for the Use of Controlled Substances for the Treatment of Pain in 1998.133 Its purpose was to encourage state medical boards and other health care regulatory agencies to adopt policies to encourage better pain management and address physicians’ fears of being investigated. The federation believed these guidelines would protect “legitimate medical uses of controlled substances while preventing drug diversion and eliminating inappropriate prescribing practices” and urged state licensing boards to adopt them. In 2004, the FSMB revised its model guidelines to provide state medical boards with an updated template and changed the title to model policy to better reflect the practical use of the document.134 The FMSB Model Policy emphasizes that treating pain with controlled substances is an integral part of medical practice, that good outcomes will weigh heavily in evaluating physician conduct, and that state medical boards should consider inappropriate treatment, including the undertreatment of pain, as a departure from an acceptable standard of care.42,43,135 The boards of medicine in 30 states have adopted either the federation guideline or the updated model policy in whole or in part. Thirteen boards of pharmacy and six boards of nursing also have adopted model pain policies. Joint policy statements have been issued in eight states. The statements vary in their emphasis: Some do not state that quality medical practice dictates that persons have access to appropriate and effective pain relief; others do not recognize that opioid analgesics may be essential in the treatment of pain, including chronic pain. Some suggest, as do certain IPTAs, that opioids are the “court of last resort.” One requires physicians to demonstrate that “other measures and drugs have been inadequate or not tolerated before beginning treatment with opioids.” A few suggest outmoded approaches to therapy such as “drug holidays to monitor compliance and continued need.” However, those exceptions do not detract from the essential role that licensing boards have played in helping reduce barriers to effective pain control.

and/or palliative care.136 Evidence that many physicians lack knowledge about pain management and receive little training in medical school suggests that such policies are needed. Five states have instituted requirements for continuing education of physicians in pain and palliative care. California’s law is the most rigorous as it requires a onetime 12-hour course on pain management. Oregon requires licensees to complete a 1-hour pain management course and a minimum of six credits in the subjects of pain management and/or the treatment of terminally ill or dying patients. Texas law says that a “physician whose practice includes treating patients for pain is encouraged to include continuing medical education in pain treatment among the hours of medical education completed in order to comply with the law.” These policy initiatives are experiments until evaluations demonstrate their value.

Medical education policies for pain and palliative care Most state medical boards require continuing medical education (CME) for physicians to maintain their licensure. Nursing and pharmacy boards may do so as well. There have been recent efforts to require or encourage those CME credits to include education on pain management

Health care providers’ liability for inadequate pain management During the past decade, several states began to address the undertreatment of pain. Some have suggested that instead of sanctioning health care professionals for overprescribing, they should be sanctioned for underprescribing.141 In

Codifying the myth of double effect Myths about opioids provide significant barriers to the effective management of pain. Tolerance and addiction are common concerns, but a third myth has taken hold: the myth of double effect, the unproven assumption that opioids shorten life.137 This myth is now codified in several state IPTAs and appears in guidelines promulgated by certain medical boards – for example, “a licensed health care provider who administers, prescribes or dispenses medications or procedures to relieve a person’s pain or discomfort, even if the medication or procedure may hasten or increase the risk of death.” Although such language is intended to provide comfort to prescribers, it may instead reinforce existing paranoia about the risks associated with the prescribing of opioids, especially the very large doses that may be required to provide pain relief at the end of life. There is no evidence that initiation of treatment or an increase in the dose of opioids (or sedatives) is associated with the precipitation of death. In a statement about physician-assisted suicide, the U.S. Supreme Court described this as pain relief that advances death.138–140 We must help patients understand that treatment for pain is just that; it is not a route to an early grave. Patrick Wall63 wrote that views perpetuate the myths surrounding the use of morphine despite the fact that claims about its addictive potential and safety have now been successfully challenged.

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592 1990, a North Carolina long-term care facility was held liable for failure to treat a resident who died in terrible pain because of the decision by the facility to withhold pain medication that was ordered by the patient’s physician.142 In 1999, the Oregon Board of Medical Examiners sanctioned a physician who failed to provide adequate pain relief for his patients.143 This was surprising in view of the board’s long history of sanctioning physicians for overtreatment. In a statement adopted in 1999, the Oregon board “urges the use of effective pain control for all patients irrespective of the etiology of their pain. The Board will consider clearly documented undertreatment of pain to be a violation equal to overtreatment and will investigate allegations in the same manner.”144 In California, that state’s medical board did not take action against a physician whose elderly patient with cancer died in severe pain. However, the physician was prosecuted under California’s elder abuse statute.145 Subsequently, the California board did sanction a physician for poor pain control.146

Summary The recent dramatic advances in the science and medicine of pain have been accompanied by unprecedented changes in laws and regulations that deal with the use of controlled substances for pain control. The Institute of Medicine’s Report on Improving Care at the End of Life called attention to the fact that prescription drug laws that are intended to minimize drug addiction and diversion can compromise effective pain management. Both the DEA and state regulatory authorities have publicly acknowledged that opioid analgesics may be essential in the treatment of acute and chronic pain but that laws and regulations may discourage the prescribing and dispensing of these drugs. Many states have taken action to reduce or eliminate regulatory barriers. The FSMB has played a prominent role in improving the knowledge and attitudes of medical board members and in encouraging state boards to adopt positive policy statements. Although IPTAs are intended to provide protection for physicians who prescribe opioids for chronic pain, there is no evidence of their benefit and there is concern that they create additional barriers. States also are addressing regulatory barriers by mandating professional education and sanctioning physicians for undertreatment. State pain task forces are particularly effective vehicles for bringing change. The PPSG has identified provisions in state laws, regulations, and medical board guidelines that may impede effective pain management and/or contain ambiguous language.44 In its Guide to Evaluation, the PPSG provides the

information essential for eliminating remaining barriers and encouraging additional change. It is incumbent upon health care professionals who are committed to improving the management of pain to familiarize themselves with the regulations that are operative in their state, to identify barriers, and to engage regulators in dialogue to assure that there is a balanced regulatory climate in the state. It may be useful to promulgate consensus statements, such as those from the FSMB, American Pain Society, and American Academy of Pain Medicine, to clarify the appropriate role of opioids in pain management.30,31,134 They can be used to educate colleagues, regulators, patients, and families about the meaning of tolerance, physical dependence, and addiction. Prescribers must follow the guidelines for the use of opioids for pain control, document their plan of treatment, and regularly assess and document response to the treatment plan. Thorough documentation is critical to protecting a practice from the vagaries of a regulatory challenge. There is a critical need for research to provide definitive data to assess the impact of the increased medical use of opioids on their diversion and abuse, the impact of laws and regulations on pain management, and the impact of laws and regulations on diversion and abuse of controlled substances. In fact, much of the problem arises from misperceptions and inappropriate attitudes of physicians, medical boards, lawmakers, patients, and the public: Reform needs to go beyond revisions in policies written by governmental authorities. It needs to affect societal values, “to help establish appropriate pain management as a component of the standard of care.”141 Only then can we be assured that all persons with cancer and pain have competent and compassionate care. References 1. American Cancer Society. Cancer facts and figures 2007. Atlanta: American Cancer Society, 2007. 2. Bruera E, Kim HN. Cancer pain. JAMA 290:2476–9, 2003. 3. Daut RL, Cleeland CS. The prevalence and severity of pain in cancer. Cancer 50:1913–18, 1982. 4. Davis MP, Walsh D. Epidemiology of cancer pain and factors influencing poor pain control. Am J Hosp Palliat Care 21:137– 42, 2004. 5. Goudas LC, Bloch R, Gialeli-Goudas M, et al. The epidemiology of cancer pain. Cancer Invest 23:182–90, 2005. 6. McGuire DB. Occurrence of cancer pain. J Natl Cancer Inst Monogr (32):51–6, 2004. 7. Van Den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 18:1437–49, 2007.

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1979. April 24, 2004. Available at: http://www.deadiversion .usdoj.gov/pubs/manuals/pharm2/2pharm manual.pdf. U.S. Department of Justice, DEA. Practitioner’s manual: an informational outline of the controlled substances act, 2006 edition. Available at: http://www.deadiversion.usdoj .gov/pubs/manuals/pract/index.html. U.S. Department of Justice, DEA, Office of Diversion. Issuance of multiple prescriptions for schedule II controlled substances, rules – 2007. Available at: http://www .deadiversion.usdoj.gov/fed regs/rules/2007/fr1119.htm. U.S. Department of Justice, DEA. Advisory: methadone hydrochloride tablets USP 40 mg (dispersible). Available at: http://www.deadiversion.usdoj.gov/pubs/pressrel/methadone advisory.htm. Fingerhut LA. Increases in poisoning and methadonerelated deaths: United States, 1999–2005. Centers for Disease Control and Prevention. National Center for Health Statistics. Available at: http://www.cdc.gov/nchs/products/ pubs/pubd/hestats/poisoning/poison.htm. Background information for methadone mortality – a reassessment. July 20, 2007. Available at: http://www.dpt.samhsa .gov/pdf/MethadoneBackgroundPaper 72007 2 .pdf. H.R. 2206: U.S. Troop Readiness, Veterans’ Care, Katrina Recovery, and Iraq Accountability Appropriations Act, 2007. It is Public Law No. 110–28. Substance Abuse and Mental Health Services Administration. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. Rockville, MD: Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment, 2004. Treatment Improvement Protocol (TIP) series #40, DHHS publication no. (SMA) 04-3939. U.S. Food and Drug Administration. FDA Talk Paper. Subutex and Suboxone approved to treat opiate dependence. October 8, 2002. Available at: http://www.fda.gov/bbs/topics/ ANSWERS/2002/ANS01165.html. Substance Abuse and Mental Health Services Administration. Guidelines for the accreditation of opioid treatment programs 2007. Available at: http://www.dpt.samhsa.gov/pdf/ OTPAccredGuidelines-2007.pdf. American Academy of Pain Medicine. Legal side of pain. Available at: http://www.painmed.org/pract mngmnt/legal .html. Phillips SJ. A comprehensive look at the legislative issues affecting advanced nursing practice. Nurse Pract 32:14–17, 2007. Berry PH, Dahl JL. Advanced practice nurse controlled substances prescriptive authority. A review of the regulations and implications for effective pain management at end-of-life. J Hospice Palliat Care Nurs 9:238–45, 2007. Kane B. Medical marijuana: the continuing story. Ann Intern Med 134:1159–62, 2001. Gonzales v. Raich. 545 U.S. 1, 2005. Annas GJ. Jumping frogs, endangered toads, and California’s medical-marijuana law. N Engl J Med 353:2291–6, 2005. Drug Policy Alliance. Marijuana: the facts. Available at: http://www.drugpolicy.org/marijuana/medical/.

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116. Brushwood DB. Maximizing the value of electronic prescription monitoring programs. J Law Med Ethics 31:41–54, 2003. 117. Joranson DE, Carrow GM, Ryan KM, et al. Pain management and prescription monitoring. J Pain Symptom Manage 23:231–8, 2002. 118. Office of Diversion Control. U.S. Department of Justice. A closer look at state prescription monitoring programs. Questions & answers. Available at: http://www.deadiversion .usdoj.gov/faq/rx monitor.htm. 119. New York Public Health Law Section 21 – official New York State prescription forms. Available at: http://law.onecle.com/ new-york/public-health/PBH021 21.html. 120. Texas House Research Organization. Bill analysis: SB1879. Available at: http://www.hro.house.state.tx.us/hrodocs/ba80r/ sb1879.pdf. 121. Alliance of State Pain Initiatives. Statement on state prescription monitoring programs. 2008. Available at: http:// aspi.wisc.edu/state.htm. 122. U.S. Department of Justice. Office of Justice Programs. Bureau of Justice Assistance. Developing and enhancing prescription monitoring programs (PDMPs). Available at: http://www.ojp.usdoj/jov/BJA/grant/prescriptdrugs.html. 123. Bonilla ME. NASPER update: a promise unfulfilled. ASA Newsletter 71:1–3, 2007. 124. Crosse M. Prescription drugs: state monitoring programs may help to reduce illegal diversion. Testimony before the Subcommittee on Health, Committee on Energy and Commerce, House of Representatives. 2004. Available at: http://www.gao .gov/cgi-bin/getrpt?GAO-04–524T. 125. Sigler KA, Guernsey BG, Ingrim NB, et al. Effect of a triplicate prescription law on prescribing of Schedule II drugs. Am J Hosp Pharm 41:108–11, 1984. 126. Simeone R, Holland L. An evaluation of prescription drug monitoring programs. Available at: http://www .simeoneassociates.com/simeone3.pdf. 127. Written statement of Joseph T. Rannazzisi, Deputy Assistant Administrator, Office of Diversion Control, Drug Enforcement Administration, U.S. Dept. of Justice. May 16, 2007. Available at: http://www.usdoj.gov/dea/pubs/cngrtest/ct051607.html. 128. Forman RF, Woody GE, McLellan T, Lynch KG. The availability of web sites offering to sell opioid medications without prescriptions. Am J Psychiatry 163:1233–8, 2006. 129. Joranson DE, Gilson AM. Drug crime is a source of abused pain medications in the United States. J Pain Symptom Manage 30:299–301, 2005.

j.l. dahl 130. Joranson DE, Gilson AM. State intractable pain policy: current status. APS Bulletin 7:7–9, 1997. 131. Rich BA. Overcoming legal barriers to competent and compassionate pain relief for patients with chronic nonmalignant pain. APS Bulletin 2005. Available at: http:// www.ampainsoc.org/pub/bulletin/fal05/law1.htm?print=t. 132. Joranson DE. State pain commission: new vehicles for progress? APS Bulletin 6:7–9, 1996. 133. Federation of State Medical Boards of the United States, Inc. Model guidelines for the use of controlled substances for the treatment of pain. Euless, TX; May 1998. 134. Federation of State Medical Boards of the United States, Inc. Model policy for the use of controlled substances for the treatment of pain. 2004. Available at: http://www .fsmb.org/pdf/2004 grpol Controlled Substances.pdf. 135. Gilson AM, Joranson DE, Maurer MA. Improving state medical board policies: influence of a model. J Law Med Ethics 31:119–29, 2003. 136. Federation of State Medical Boards. Continuing medical education, overview by state. Available at: http://www.fsmb .org/pdf/GRPOL Continuing Med Ed.pdf. 137. Sulmasy DP, Pellegrino ED. The rule of double effect: clearing up the double talk. Arch Intern Med 159:545–50, 1999. 138. Gonzales v. Oregon. 546 U.S. 243, 2006. 139. Burt RA. The Supreme Court speaks – not assisted suicide but a constitutional right to palliative care. N Engl J Med 337:1234–6, 1997. 140. Rich BA. Moral lessons from the jury box. J Pain Palliat Care Pharmacother 16:81–92, 2002. 141. Shapiro RS. Health care providers’ liability exposure for inappropriate pain management. J Law Med Ethics 24:360–4, 1996. 142. Angarola RT, Donato BJ. Inappropriate pain management results in high jury award. J Pain Symptom Manage 6:407, 1991. 143. The Associated Press. Oregon disciplines doctor for undertreating pain. Lexis Nexis Data Base. Sept. 2, 1999. 144. Oregon Board of Medical Examiners. Statement of philosophy: appropriate prescribing of controlled substances. Adopted May 29, 1999. 145. Bergman v. Chin. No H205732 – 1 (Cal App Dept Super Ct), February 16, 1999. 146. In the matter of the accusation against Eugene B. Whitney, MD, Medical Board of California. Case no. 12 2002 133376, December 15, 2003.

33

Role of family caregivers in cancer pain management myra glajchen

Beth Israel Medical Center

Introduction Family caregivers continue to play a vital and everexpanding role in meeting the practical, physical, and psychosocial needs of patients with cancer, including pain management. The past several years have seen a shift toward early hospital discharge, increasingly complex home-based treatment protocols, and rising expectations that caregivers participate actively in treatment-related decision making, the accomplishment of treatment goals – including symptom management – and home care. Yet policy, research, and clinical services for caregivers have not kept pace with these new developments. As cancer treatment has changed, people with cancer have benefited greatly from early detection, aggressive multimodal treatment protocols, outpatient care, and longer survival times.1 These advances have been possible because in the United States, family caregivers form the foundation of the health care system, with an estimated 44.4 million caregivers providing informal care to ill relatives, with an expected economic value of about $350 billion in 2006.2 Of the adults currently providing care to relatives in the United States, 60% are female, the average age is 45 years, and most are providing care for women aged 50 years and older. The amount of time devoted to caregiving is substantial, with most caregivers providing at least 40 hours of care each week and spending an average of 4.3 years as a caregiver.3 In a 1999 national survey of older adults in the last year of life, nearly three quarters reported receiving help from informal family caregivers. These caregivers provided an average of 43 hours of help per week, whereas 84.4% provided daily assistance.4 The prevalence of caregiving in cancer currently is not known. However, according to the National Cancer Institute, an estimated 1.3 million people are diagnosed with cancer in the United States each year, and many are living

longer than ever with the disease. From this, we can infer that many of the nation’s 44.4 million caregivers are taking care of loved ones with cancer. Caregivers of cancer patients are expected to function broadly, providing direct care, assistance with activities of daily living, case management, emotional support, companionship, and medication supervision.3 The literature confirms the increasingly complex demands on family members who serve as informal caregivers for ill relatives. Serving as a family caregiver for a person with cancer now entails multifaceted responsibilities, assuming such roles as home health aide, case manager, and/or legal assistant.5,6 The caregiver is required to navigate the health care system, seek information that may be difficult to find, manage insurance claims, and pay bills. All these “administrative” tasks are ancillary to the primary tasks of providing companionship, accompanying the cancer patient to medical appointments, managing their households, and doing personal errands. Caregivers of cancer patients need information, training, and support to ease their role in addressing the needs of their ill family members. As well, they need information about how to meet their own needs, especially when they have multiple demands from work, children, other family members, and health issues of their own. Findings from recent landmark studies convey a picture of cancer patients’ unmet needs and of caregivers meeting those needs through a variety of medical and support tasks at home. Emanuel and his team6 interviewed terminally ill adults and their caregivers to determine how the patients’ needs for assistance were being met. Unmet needs were reported by 87% of patients, who required help with transportation (62%), homemaking services (55%), nursing care (29%), and personal care (26%). Most patients relied completely on family and friends to provide this assistance, whereas only 15% relied on paid assistance. Similar findings were reported in the 1999 National Long-Term Care 597

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598 and Informal Caregivers Survey, in which 1149 family caregivers across the United States were interviewed to identify their experiences in providing end-of-life care to family members, including those with cancer. The communitybased supports most commonly used by end-of-life caregivers were assistive devices (62.3%), personal or nursing care services (37.2%), and home modifications (28.3%), supportive services designed to help the patient rather than the caregiver. Services for housework (13.6%), delivered meals (11.2%), and transportation (6.2%) were used less commonly. Less than 5% of caregivers in this study had participated in caregiver support groups, used respite services, or enrolled the patient in a program outside the home.4 This implies that available community support services are not well utilized by caregivers of cancer patients. Generally speaking, patients with cancer experience side effects and symptoms as a result of advancing disease and treatments such as chemotherapy, radiation therapy, and surgery.5,7 Because many people with cancer will experience pain at some point along the disease trajectory, their caregivers likely will be called upon to help manage this symptom. An overview of the caregiver’s role in cancer pain management can serve as a prototype for any type of symptom management during the course of the patient’s illness. Caregiver burden is commonly used to describe multiple dimensions of distress arising from an imbalance between care demands and resources to meet those demands. Because cancer affects the patient and his or her family members, and because oncologists rely on family caregivers to coordinate and implement the treatment plan, caregiver strain is a factor of importance to the treating physician and to other members of the health care team. Conclusions from the aforementioned studies provide valuable points of reference for analysis of caregivers’ role in cancer pain management, as well a rationale for the involvement of caregivers in planning and treatment. This chapter discusses the changing role of the family caregiver in cancer pain management, the impact of caregiving on quality of life, caregivers’ adaptational tasks at different points in the disease trajectory, new research on coping strategies, new programs for education and skills training, and challenging caregiver groups.

Caregiving roles and responsibilities in cancer pain management The role of family caregivers in cancer pain management includes assessment and reporting of pain, dispensing medications, refilling prescriptions, promoting compliance,

Table 33.1. Roles and responsibilities of caregivers Assessing and reporting pain Managing high-tech treatments Filling and refilling prescriptions Administering pain medications Promoting medication compliance Providing nondrug interventions Assisting with treatment decision making

providing nonpharmacological therapies, and engaging in decision making that has an impact on treatment planning (Table 33.1). Caregivers are expected to assess and report the patient’s pain, side effects, and new symptoms. This implies that caregivers must function as nurses, attempting to determine the source, nature, and amount of pain.8 This can be problematic, given that patients may underreport pain symptoms whereas caregivers tend to overestimate their loved one’s pain.9,10 In addition, family caregivers lack knowledge about pain management and side effects.11 Because caregivers play an important role in identifying and reporting treatment side effects (most often constipation and drowsiness) that can cause patients to abandon the pain treatment protocol, educating them about anticipated side effects and strategies for their amelioration is essential. With the advent of high-tech home care and pain management, family caregivers may be expected to help manage patient-controlled analgesia pumps, epidural catheters, and home infusions.11–14 The technical aspects of these interventions may be terrifying, even for the most sophisticated caregivers. Education in these areas also is crucial. A recent randomized clinical trial of a nursing intervention found that patients and their caregivers had difficulty in seven areas of pain management, namely obtaining the prescribed medication, accessing information, tailoring prescribed regimens to meet individual needs, managing side effects, cognitively processing information, managing new or unusual pain, and managing multiple symptoms simultaneously.14 These difficulties were more pronounced during times of transition from one care setting to another – for example, hospital to home, home to emergency room, and home care to long-term care. It generally falls to the caregiver of a patient with cancer to fill and refill pain medication prescriptions. This task presupposes skills such as time management, proficiency with insurance reimbursement, competence in following medical instructions, and anticipating the need for refills ahead of time. Caregivers may have to return to the clinic or doctor’s office for a new prescription, or may have to

role of family caregivers in cancer pain management bring the cancer patient back for an appointment before a renewal will be given. Although none of these skills can be presumed, it generally is beneficial to designate one member of the health care team to pay attention to these aspects of pain management. Managing pain medications can contribute substantially to caregivers’ stress.15 Medication administration has been shown to be both stressful and time consuming for caregivers, contributing to caregiver strain over time. Specific issues include information seeking – communicating with physicians, formulating questions, and processing instructions about dosing and side effect management; safety issues – including monitoring side effects and avoiding medication errors; scheduling logistics – incorporating medical appointments and prescription renewal pickups into the caregivers’ schedule; and polypharmacy – maintaining a running list of medications and juggling prescription medications from multiple physicians.16 Although comprehensive discussion of these factors may be beyond the scope of a routine medical appointment or phone call, each issue represents a potential point of breakdown as cancer patient and caregiver attempt to put pain treatment plans into effect. The role of family caregivers in fostering or hindering pain treatment compliance should not be underestimated. Family caregivers frequently dispense pain medication or remind the patient to take a scheduled dose. Administration of pain medication implies deciding which type of medication to give, if and when it should be given, and in what dosage.17 Caregivers can encourage the patient to take medication as prescribed, to take a lesser dose than prescribed, to “wait until the pain really gets bad,” or to abandon a medication protocol completely. Caregiver overestimates of the cancer patient’s pain may lead to overmedication, and vice versa. In a study involving hospice patients in Chicago, more than 80% of the caregivers were involved in administration of pain medications to patients. Even with the support of the hospice nurse and team, caregivers reported concerns about tolerance, side effects, addiction, and the use of morphine. In addition, family caregivers were concerned about doing something wrong and had trouble deciding which medication to give and at what dose.18 Caregiver knowledge and attitudes about pain management may influence the patient. If caregivers harbor fears of addiction, overdosing, or indirectly causing discomfort through side effects, they may guard the pain medication supply, limit its use, and undermedicate the patient.19 If caregivers stigmatize the use of opioids in general or the use of specific drugs, such as methadone and meperidine, they may project these fears onto the patient. In addition,

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the quality of the patient–caregiver relationship may be significantly associated with caregiver depression and burden, as well as depression and medication adherence among patients.1,20 Attitudinal and relationship factors may be influenced by culture, language, and the communication of pain. For example, Lin20 has studied Chinese cancer patients and their caregivers extensively, finding significant correlations between caregiver concerns and hesitancy to administer analgesics, even in the context of high levels of cancer pain. Medical decision making usually falls to the family unit in Chinese families, whereas the patient’s individual needs may be considered secondary in importance.9 If clinicians understand the cultural context in which pain management and caregiving take place, a successful outcome is more likely. Caregivers may play a role in providing nondrug pain management such as massage, use of lotions and ointment, heat and cold compresses, distraction, and relaxation.11,12 Such techniques have been shown to be helpful as an adjunct to pain medication. In addition, through trial and error, caregivers may use positioning with pillows, mobilizing the patient, and assisting with ambulation in an effort to promote pain relief. Of more concern to the pain practitioner may be alternative health practices that may undermine cancer treatment. Toxic side effects such as irreversible neuropathy, bleeding, electrolyte imbalance, and others may result from alternative medical approaches to cancer treatment.21 Families may make erroneous decisions based on biased information in the media and on the Internet. In a recent study of 107 breast cancer patients and their caregivers, 91% of the sample had searched for more information on their cancer and its treatment using the Internet, 66% had checked the information given by the doctor, 63% had researched other treatment options, and 63% had sought information on alternative treatments.22 Because patients and caregivers may be reluctant to disclose their use of alternative therapies to the physician, it is helpful to designate this oversight to another team member, such as the nurse or social worker. Lastly, caregivers face an overwhelming array of decisions to make during the course of the patient’s illness. Decisions about treatment options, role changes, and finances generally are made by the patient–family unit.23,24 Even in the context of a strong doctor–patient relationship, caregivers may be more open to information from other sources, both informal (family, friends) and formal (the Internet, Cancer Information Service, support groups). Therefore, enlisting the cooperation of family caregivers and including

600 Table 33.2. Impact on quality of life of caregivers Physical impact Psychological impact Social impact Financial impact Spiritual impact

them as the unit of care from the outset are critical ingredients to effective cancer pain management.

Impact of family caregiving on quality of life Caregiver well-being is essential if caregivers are expected to manage all their responsibilities, including medication management. Caregivers of cancer patients have described the experience as affecting many domains of life. In general, caregiving is associated with high levels of chronic stress and emotional strain, especially in the context of an illness such as cancer. Ferrell et al.25 developed a conceptual model for studying the impact of pain on quality of life in four distinct dimensions: physical, psychological, social, and spiritual well-being (Table 33.2). This model is applicable to both patients and their caregivers. The physical demands of caregiving are closely related to medical variables such as disease stage, level of symptomatology, functional ability, fatigue level, and side effect profile. Cancer patients require varying levels of practical assistance during the course of the illness. If caregivers are on duty 24 hours a day, or just at night, cumulative sleep disruption and fatigue are common. In the context of advanced disease and pain, it often falls to the family caregiver to manage disease symptoms and treatment side effects in the home setting. The literature shows that the more time the caregiver spends assisting the patient, the more disrupted the caregiver’s schedule and emotional well-being will be. Also, caregivers of patients in palliative care have been shown to have significantly lower quality-of-life and physical health scores than caregivers of patients in active, curative treatment.26 Psychological well-being is linked to anxiety, distress, and depression in the patient and caregiver, as well as to the positive and rewarding aspects of caregiving. Family members confronting serious illness have been found to experience as much, if not more, distress as the person with cancer. This distress arises from the caregiver role itself as well as witnessing the patient’s suffering.26 Related personality characteristics, such as optimism and pessimism, affect the psychological impact of caregiving. Family caregivers burdened by loss, stressful life events, or strife in

m. glajchen the relationship with the patient may enter the new caregiving role already overwhelmed. Although the psychological needs of the caregiver may be beyond the scope of the pain management team, they are significant in that they affect the quality of caregiving, as well as the likelihood of premature and unnecessary hospital admissions.26 Miaskowski and colleagues8,27 studied the impact of pain on mood, health status, and strain among caregivers of oncology outpatients. They found that pain adversely affected the mood states of family caregivers, especially depression and anxiety levels. They found little impairment in health status and moderate caregiver strain. However, these caregivers were caring for patients with high Karnofsky Performance Status scores who were still in active cancer treatment. These findings, therefore, are not generalizable to the experiences of caregivers of patients with more advanced cancer. Caregivers’ quality of life has been found to be influenced by the cancer patient’s stage of illness and goals of care.28 A recent meta-analysis of psychological distress among cancer patients and family caregivers found that both members of the dyad experienced similar levels of distress.29 One prospective population-based cohort study found that caregiver strain increased mortality risk by 63% within 5 years.30 From physical and practical points of view, caregiving has been described as relentless, marked by constant monitoring of the ill person’s health status, provision of personal and nursing care, and assuming the duties of the ill family member. Although such physical impact is often obvious to the health care team, the emotional toll of caregiving cannot be overlooked. In this realm, caregivers describe stress and strain that may parallel or surpass that of the patient. Because family members are at increased risk for stressrelated problems, and we expect them to continue pain management in the home setting, it is essential to monitor them for emotional distress.31 Caregivers assume caregiving for a variety of reasons, including a sense of familial obligation and loyalty, altruism in the face of their loved one’s suffering, and more practical reasons, such as lack of paid help and lack of insurance coverage for services.3,4 The positive aspects of caregiving are noteworthy and should be reinforced by providers. Social roles and relationships are deeply affected by cancer and compounded by cancer pain. The nature and quality of the previous patient–caregiver relationship are important considerations in assessment and treatment. If marital or relationship strain predates the onset of cancer or pain, the caregiver may approach caregiving grudgingly. Dyadic analysis in cancer pain is still in its infancy, but sporadic

role of family caregivers in cancer pain management studies suggest a fertile field for future study. In one such study, Miaskowski et al.8 interviewed 78 oncology patient– caregiver dyads. They found that caregivers in noncongruent dyads reported higher levels of caregiver strain, whereas patients in those noncongruent dyads had higher mood disturbance and poorer quality of life. Subsequent studies have further questioned the accuracy of pain assessment by family caregivers while identifying disagreements between the cancer patient and the caregiver as an enormous source of stress. In an ongoing dyadic study of medication adherence among patients with cancer pain, caregivers acknowledged that under- and overestimates of the patient’s pain by the caregiver frequently led to high levels of strain as well as severe side effects.32 Spouses may be elderly and infirm, in need of their own assistance, when caregiving responsibilities are thrust upon them. For adult caregivers, juggling the multiple demands of work, children, spouses, and caring for the cancer patient may be overwhelming. Approximately 70% of caregivers for cancer patients are spouses, 20% are adult daughters or daughters-in-law, and the remaining 10% are friends or extended family members.33 However, not all relationships are created equal, so the quality of that relationship and caregiving should be assessed on a case-by-case basis. The financial impact and hidden costs of cancer pain management also may have an impact on caregiver burden. For people with limited or no insurance, coverage for adequate pain relief may be sparse. More surprising is the financial burden incurred by families who have insurance, from deductibles, copayments, uncovered services such as transportation and home care, lost salaries and work, over-thecounter medications, household modifications, and alternative treatments such as herbs and vitamins.12 Limited numbers of prescriptions allowed by some insurers, as well as per month and refill limits, only add to caregiver burden in the context of pain management. Costs to caregivers include the time spent traveling to and from care, waiting with the patient for appointments, lost work time, preparation for surgery and medical procedures, hospitalization, and time away from usual activities and relationships.34 Included in the cost analysis for caregivers of cancer patients should be recovery time spent at home, time spent addressing insurance issues, companionship, emotional support, and conversation and other forms of distraction. The social impact of cancer and pain can be ameliorated by social support, financial security, and stability at work. Given the chronicity of cancer in recent years, caregivers may find that support in all these areas erodes over time. Encouraging caregivers to network with other families, and

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linking them with formal resources, can help augment informal sources of social support. Although most commonly used quality-of-life instruments in oncology do not include spirituality as a core domain, spiritual well-being is increasingly recognized as a major contributor to quality of life in cancer. In a large and diverse sample of 1610 cancer patients, spiritual wellbeing was related to the ability to enjoy life even in the midst of pain, making this domain a potentially important clinical target.35 Spirituality can act as a sense of fortification against hopelessness, help caregivers to derive meaning from pain and caregiving, and provide an existential perspective on hope and suffering.36 Degree of religiosity may be both a hindrance and a help in the pain management equation. To the extent that religion provides comfort, a belief system, and a source of social support, religion may be helpful to caregivers. However, if families believe in stoicism and suffering as the road to salvation, agreeing to administer pain medication may become problematic. Finally, the meaning of pain to the patient and caregiver may profoundly affect treatment outcomes in this area. In the setting of a cancer diagnosis, pain generally is emotionally laden in that it signifies advancing disease and eventual death. Because of such fears, patients and their family caregivers may underreport pain and other symptoms.

Adaptational tasks at different points along the disease trajectory Given that most pain management, much end-of-life care, and even death take place at home, it is increasingly important to understand caregivers’ role at different points along the disease trajectory37,38 (Table 33.3). Caregiver quality of life seems to be linked to the functional status of the person with cancer. That is, an increase in the patient’s physical needs is associated with a decrease in the caregiver’s quality of life. In a study involving 263 cancer patients and their caregivers, increased physical needs, including pain and symptom management, were negatively associated with family support, finances, and the caregiver’s own schedule. The authors concluded that more physical demands for the family caregiver may result in social isolation and impairment in other quality-of-life domains.39 Table 33.3. Disease trajectory adaptational tasks Tasks at diagnosis Tasks during treatment Tasks during recurrence Tasks during transitions between care settings Tasks during terminal illness and dying

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602 A family’s response to cancer will vary according to the family’s developmental needs, the demands placed on the family system, the role changes necessitated by the illness, and the repertoire of available coping skills.39 Functional families can act as a buffer for patients dealing with cancer pain through four types of support: informational, emotional, instrumental and affiliational. On the one hand, advice and information can lessen the burden of decision making for the patient, love and encouragement can reduce isolation and distress, tangible support can meet the patient’s concrete needs, and affiliational support can meet socialization needs.39 On the other hand, family problems can undermine the patient’s ability to use medical care effectively, impair compliance with pain protocols, and complicate discharge planning. Caregiver behaviors such as making excessive demands on staff time, interfering directly with treatment, being unsupportive of the patient, and refusing to comply with medical unit guidelines are challenging clinical issues requiring a comprehensive interdisciplinary treatment approach.40,41 During the phase of diagnosis and treatment, caregivers experience a complex array of powerful emotions that may equal or surpass those of the person with cancer.41,42 The caregiver is expected to integrate medical information and play an active role in treatment decision making. This may involve unfamiliar terminology, new treatment settings, and frightening procedures or medications related to pain management.43 During active treatment for cancer and pain, caregivers must juggle competing demands by trying to provide emotional and tangible support to the patient while meeting ongoing obligations of home, work, and family. The demands of transportation, hospital visits, home care, and dealing with insurers may be physically and emotionally exhausting. Family caregivers provide most of the care for cancer patients in both long-term and end-of-life settings. Several studies have documented high levels of assistance provided by family members at the end of life, as well as the emotional, physical, and financial strain that results. However, although the economic value of free caregiving has been well documented in the literature, it has not been well understood as a component of end-of-life care.2 In the context of recurrent illness, terminal illness, or the dying process, the caregiver has to meet a new set of challenges in dealing with increasing functional limitations, increasing dependence of the patient, and greater symptom burden.43 If treatment is prolonged, the capacity of caregivers to meet the daily needs of patients is severely strained. In fact, the physical and emotional demands of caregiving reach their peak as the disease progresses to the

terminal phase.44,45 In addition to assuming many of the patients’ prior domestic responsibilities, family caregivers may be increasingly called upon to function as nurse’s aides. They may have to forego social activities and work duties, which may result in isolation and job insecurity. Weitzner and colleagues26 found that family caregivers of palliative care patients had lower quality-of-life scores and worse overall physical health than caregivers of patients receiving curative treatment. As the cancer patient deteriorates, caregiver quality of life worsens. This is probably related to increased physical demands plus alterations in role functioning as caregivers take on additional responsibilities. Transitions among care settings are particularly stressful for both cancer patients and their caregivers. The immediate post-hospitalization period may be precarious, with mounting concerns by caregivers about managing the cancer patient in the home setting, as well as worrying about their own health.46 One recent study involving 518,240 elderly couples enrolled in Medicare found that hospitalization of a spouse was associated with an increased risk of death for elderly caregivers.47

Strategies for intervention Members of the health care team should include caregivers in treatment planning explicitly and continuously (Table 33.4). Such conscious involvement of family caregivers can do much to reduce caregiver stress, monitor caregivers’ physical health, and prevent medication errors or lack of adherence to pain medication regimens.17 Health care professionals are encouraged to include family members in treatment planning and decision making. This is more likely to promote investment on the part of caregivers in the treatment protocol. However, health care professionals should not presume similarity or treat the patient–family as a single unit of care.37 Instead, decisions regarding treatment, a care plan for pain management, and home care referrals should include careful assessment of the caregivers’ physical and psychosocial status, as well as the home environment.47,48 Table 33.4. Professional intervention strategies Active listening, open communication Information, resources, practical advice Individual and group counseling Tailored instruction in the use of pharmacological interventions Tailored instruction in the use of nonpharmacological interventions Caregiver skill training Nurse coaching Problem solving

role of family caregivers in cancer pain management Moderate evidence suggests that multifaceted interventions such as the comprehensive services provided by palliative care teams or home care programs can relieve burden, although effect sizes generally are small. A clusterrandomized trial found that hospital-based palliative consultation for community oncology patients and caregivers was associated with improved after-death satisfaction for family members. A longitudinal study involving 161 caregivers of cancer patients found that the caregivers of postsurgical patients reported initial optimism but later experienced psychological morbidity with delayed onset.49–51 Such studies suggest that the psychosocial status of caregivers may fluctuate over time, so warrants frequent reassessment. In addition, the involvement of palliative and home care teams most likely will identify psychosocial problems among caregivers that might otherwise be missed. Emanuel and colleagues52 found that caregiver burden was significantly reduced by physicians who practiced active listening. In this study, caregivers experienced less burden and distress if they felt that the treating physician listened to their needs and opinions. In this way, caregivers feel validated in their role, and they receive recognition and support for their caregiving activities. Caregivers also seem to derive benefit and satisfaction from information and clear communication regarding the prognoses of patients, even if the prognosis is poor, as shown by the Study to Understand Prognoses and Preferences for Outcomes and Risks for Treatment.53 In addition to listening, health care professionals are encouraged to provide information about pain management. Obtaining information about pain etiology, medical treatment options, and nondrug interventions may reduce helplessness on the part of caregivers and promote an active role in pain management. Such information may be found in various formats, including books, resource centers, and websites. Learning about available resources and knowing where and when to obtain professional help can help caregivers negotiate the health care system and decrease their sense of burden. Accurate information helps reduce uncertainty and empowers caregivers by giving them a sense of control. In addition, caregivers derive emotional support from time with the pain professional. Caregivers report needing information about their loved one’s cancer, symptom etiology, what to expect in the future, treatment side effects, and management of medical emergencies.10,54 Common misconceptions about pain management include the fact that pain medicine is addictive, treatment involves painful shots, use of opioids for pain implies a terminal prognosis, and

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side effects of pain treatment can be debilitating. If members of the health care team take the time to address these misconceptions, they can be corrected. In the absence of accurate information, patients and caregivers are more susceptible to misinformation from informal sources. The knowledge and information needs of caregivers in palliative care were summarized recently in a qualitative systematic review of 34 studies from eight countries. The evidence was strongest in relation to caregivers’ unmet informational needs and knowledge deficits in pain management. The significance of effective communication and information sharing among patient, caregiver, and provider also was emphasized.55 The authors’ conclusions are noteworthy: First, because cancer treatment and palliative care have been shifted into the home, a more rigorous research agenda should be implemented. Second, research design needs to move beyond the current focus to encompass threeway interactions among patients, providers, and caregivers. In contrast to patient support systems, which are widely available, the sources of support for caregivers have lagged far behind. Caregivers with low levels of emotional support have been identified as being more depressed over time.56 Individual and group counseling may be of enormous benefit to such caregivers. Individual counseling is designed to provide caregivers with support, education, and problemsolving or coping skills. In addition, psychological issues may be managed most effectively with individual intervention. However, these interventions are expensive and may prove too time consuming for working or highly distressed caregivers.57,58 Intervention in the support group format provides emotional support, information, and informal networking for caregivers of cancer patients. Social support needs respond best to group intervention. Some groups provide a combination of group counseling and education. A recent psychoeducational intervention for family caregivers reported mixed results. In this program, caregivers were randomly assigned to one of two groups, one receiving standard care, the other receiving standard care plus the new intervention delivered through home visits, phone calls, a guidebook, and an audiotape. Caregivers were evaluated with respect to caregiving competence, self-efficacy, and anxiety. No treatment effects were reported, although caregivers in the treatment group reported a more positive caregiver experience.58 The health care professional can offer caregivers instruction on the use of pharmacological and nondrug pain interventions to promote an active role in the care plan. Education for caregivers about pain etiology, the rationale for selecting a treatment approach, around-the-clock dosing,

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604 anticipated side effects, and treatment of those side effects should become a routine part of medical practice. Caregivers benefit from specific instruction regarding the timing of pain medication administration, the correct dosage, dose titration, and management of breakthrough pain.10,25 The health care professional can provide caregivers with resources for physical care, home health aides, respite programs, counseling, support groups, financial assistance programs, and other information.16 Members of the team can provide guidance in negotiating the health care system, which may become overwhelming for overburdened and fatigued caregivers. In addition, most caregivers report that they discover nonpharmacological pain management techniques informally, or by trial and error. A brief instructional session, reinforced with materials in print or electronic form, may serve as a catalyst for these techniques and provide guidance for the proper use of heat, cold, massage, positioning, imagery, distraction, and other techniques. Emotional, social, and peer support can do much to alleviate caregivers’ sense of isolation. Caregivers should be encouraged to keep busy, maintain balance, take time away from caregiving, and pursue their own interests and social contacts. Visits from family and friends also may serve to change the home environment and should be encouraged.28 Cognitive reappraisal – that is, changing the meaning of the situation – has been shown to reduce caregivers’ emotional distress. Many caregivers report both positive and negative aspects of caregiving. The positive aspects include an improved relationship with the patient, a sense of satisfaction and mastery over caregiving tasks, and feeling appreciated by the patient.2 Caregivers can be helped to reframe their appraisal of the situation through individual or group counseling, and through empathic listening by the health care team. Skill training for caregivers has proven effective in improving caregiver quality of life, reducing the burden associated with the cancer patients’ symptom management, and strengthening caregiving tasks. Such programs are effective for caregivers of patients at all stages of cancer, including those in end-of-life care and hospice.29 The most effective skills training programs tend to be nursing intervention programs, which combine guidance and support, as well as nursing home visits, during which pain management can be taught.10 Successful nurse-led transition coaching programs have been developed to prepare patient and caregiver for what to expect, coach them on communicating with the doctor, and provide tools such as the personal health record and medication list. In this model, nurses or nurse practitioners follow patients to the nursing facility or

to the home, to reconcile pre- and post-hospital medications and practice or role-play the next medical encounter or visit. In addition, the nurses initiate phone calls 2, 7, and 14 days after discharge, thereby providing continuity of care through a single point of contact.59 Lastly, quality improvement interventions led by nurses have been shown to increase hospice enrollment, improve pain management orders, and promote in-depth discussions about palliative care.60 Caregivers may be taught simple problem-solving techniques, such as taking things one step at a time and selecting what merits attention. Structured educational programs for caregivers have been found to reduce helplessness and improve coping. Such programs may be carried out in a formal setting60–63 or in the home.11,12 In-person instruction, reinforced with printed materials, videotapes, or audiotapes, promotes development of new caregiving skills and offers caregivers an active role in disease and pain management. When developing a pain management care plan, members of the team should take financial realities into account, as cost may become a major factor in noncompliance.11,12 Costs associated with cancer pain management include copayments, deductibles, and over-the-counter drugs as well as hidden costs from transportation, tolls, parking, nondrug materials, environmental modifications, dietary needs, and lost wages.

Challenging caregiver groups Accepting the burden of caregiving may lead to depression, and certain subgroups pose more challenges in the clinical setting. Caregivers from different cultural backgrounds, elderly caregivers, and caregivers of cancer patients with multiple symptom management needs also pose more of a challenge. In working with caregivers of various ethnic backgrounds, staff must consider the cultural context in which pain management is understood. Although the literature describing the cross-cultural issues in caregiving and cancer pain is still in its infancy, most health care professionals confront cross-cultural challenges on a daily basis. In a recent meta-analysis of 116 empirical studies, Asian American caregivers were found to provide more caregiving hours than white, black, and Hispanic caregivers; to use lower levels of formal support services; and to have fewer financial resources, lower educational levels, and higher levels of depression than the other subgroups.64 In a recent study of hospice patients and their caregivers, Asian caregivers expressed greater reluctance to

role of family caregivers in cancer pain management report information about the patient’s pain and to administer medications compared with caregivers of other ethnic backgrounds. Similar findings were noted in previous investigations of cancer patients using the Barriers Questionnaire.19 Caregivers who have no outside help are more depressed than those who receive help from secondary informal caregivers or formal resources. In a study involving unmet needs and service barriers among Asian caregivers, caregivers refused outside help because they felt “too proud to accept it” or “didn’t want outsiders coming in”; other reported barriers included “bureaucracy too complex” or “couldn’t find qualified providers.”64 Access to care may be compromised by a reluctance to discuss the disease within the family; it has been noted, for example, that “among the Chinese, it is bad luck to speak of death or dying, and doing so even for discussing prognosis or for informed consent purposes may offend or elicit fear and uneasiness.”64 Keeping a cancer diagnosis secret from the patient and avoiding discussions of disease progression in light of increasing pain further add to the caregivers’ sense of burden and responsibility. Elderly caregivers also may present a clinical challenge in the context of cancer pain. Older caregivers may have their own comorbid medical conditions, which may decrease their ability to provide care. Social isolation and a fixed income may educe social support and increase the likelihood that the elderly caregiver will assume more responsibility for caregiving without outside assistance. In addition, caregivers with poor emotional and physical health may have fewer reserves upon which to draw if caregiving is prolonged.65 Therefore, education and formal support for elderly caregivers are essential. Caregivers of cancer patients report higher levels of distress when the patients’ symptoms cannot be easily controlled. The presence of fatigue, depression, constipation, and anorexia in addition to pain may be particularly distressing for these caregivers.27,66 The number of symptoms and the need to manage more severe symptoms are associated with an increase in care demands, which, in turn, leads to elevated caregiver distress. Such families should be targeted early on for more intense home care and psychological support.66,67 Researchers in the field have identified several other factors that increase the burden for caregivers of oncology outpatients. These include increasing patient dependency, impaired functioning, length of illness, and younger patient age. The impact of pain on caregiver burden has been studied only recently. Early findings suggest that patient suffering leads to family suffering and that family caregivers tend to overestimate their family members’ pain.26 At least

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one study suggests that male caregivers may have greater concerns than females about reporting patient’s pain and administering medications. In the same study, less educated caregivers, retired caregivers, and caregivers in blue-collar jobs had greater concerns about addiction to pain medication as well as greater fatalism and stoicism.20

Conclusion Although little is known about the steps that cancer patients and their caregivers take in implementing pain regimens in the home, studies suggest that practical and emotional difficulties in caregivers may lead to poor pain control in patients. Health care professionals should ensure that caregivers are included explicitly and continuously in the patient’s cancer pain regimens. Diminishing caregiver distress, monitoring the health and well-being of caregivers, and preventing medication errors should be the ultimate goal of professional intervention. Helping family caregivers cope increases their effectiveness as caregivers and improves their own quality of life. In addition to the practical assistance described previously, caregivers benefit from support and guidance with respect to the emotional aspects of caregiving. Early recognition of psychological vulnerability among family members is essential to develop specific interventions to promote coping, alleviate anxiety, and encourage problem solving.52 References 1. Schumacher KL, Stewart BJ, Archbold PG, et al. Effects of caregiving demand, mutuality, and preparedness on family caregiver outcomes during cancer treatment. Oncol Nurs Forum 35:49–56, 2008. 2. Gibson MJ, Houser A; AARP Public Policy Institute. Valuing the invaluable: a new look at the economic value of family caregiving. AARP issue brief IB-82. Available at: http://assets.aarp.org/rgcenter/il/ib82_caregiving.pdf. 3. National Alliance for Caregiving and AARP. Caregiving in the US, 2004. 4. Wolff JL, Dy SM, Frick KD, Kasper JD. End-of-life care. Findings from a national survey of informal caregivers. Arch Intern Med 167:40–6, 2007. 5. Given BA, Given CW, Kozachik S. Family support in advanced cancer. CA Cancer J Clin 51:213–31, 2001. 6. Emanuel EJ, Fairclough DL, Slutsman J, Emanuel LL. Understanding economic and other burdens of terminal illness: the experience of patients and their caregivers. Ann Intern Med 132:451–9, 2000. 7. Taylor EJ, Ferrell BR, Grant M, Cheyney L. Managing cancer pain at home: the decisions and ethical conflicts of patients, family caregivers and homecare nurses. Oncol Nurs Forum 20:919–27, 1993.

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8. Miaskowski C, Zimmer EF, Barrett KM, et al. Difference in patients and family caregivers’ perceptions of the pain experience influence patient and caregiver outcomes. Pain 72:217–26, 1997. 9. Kornblith AB, Herr HW, Ofman US, et al. Quality of like of patients with prostate cancer and their spouses: the value of a database in clinical care. Cancer 73:2791–802, 1994. 10. Ferrell BR, Taylor EJ, Grant M, Corbisiero RM. Pain management at home: struggle, comfort and mission. Cancer Nurs 16:169–78, 1993. 11. Ferrell BR, Dean G. Ethical issues in pain management at home. J Palliat Care 10:67–72, 1994. 12. Coyle N, Cherny NI, Portenoy RK. Subcutaneous opioid infusions at home. Oncology 8:21–7, 1994. 13. West CM, Dodd MJ, Paul SM, et al. Patient education: the PRO-SELFc: Pain Control Program – an effective approach for cancer pain management. Oncol Nurs Forum 30:65–73, 2003. 14. Schumacher KL, Koresawa S, West C, et al. Putting cancer pain management regimens into practice at home. J Pain Symptom Manage 23:369–82, 2002. 15. Ranelli PL, Aversa SL. Medication-related stressors among family caregivers. Am J Hosp Pharm 51:75–9, 1994. 16. Travis SS, McAuley WJ, Dmochowski J, et al. Factors associated with medication hassles experienced by family caregivers of older adults. Patient Educ Couns 66:51–7, 2007. 17. Juarez G, Ferrell BR. Family and caregiver involvement in pain management. Clin Geriatr Med 12:531–47, 1996. 18. Letizia M, Creech S, Norton E, et al. Barriers to caregiver administration of pain medication in hospice care. J Pain Symptom Manage 27:114–24, 2004. 19. Miller IW, Bishop DS, Herman DS, Stein MD. Relationship quality among HIV patients and their caregivers. AIDS Care 19:203–11, 2007. 20. Lin CC. Barriers to the analgesic management of cancer pain: a comparison of attitudes of Taiwanese patients and their family caregivers. Pain 88:7–14, 2000. 21. Montbriand MJ. An overview of alternate therapies chosen by patients with cancer. Oncol Nurs Forum 21:1547–54, 1994. 22. Pereira JL, Koski S, Hanson J, et al. Internet usage among women with breast cancer: an exploratory study. Clin Breast Cancer 1:148–53, 2000. 23. Warner JE. Involvement of families in pain control of terminally ill patients. Hosp J 8:155–70, 1992. 24. Vachon MLS. Psychosocial needs of patients and families. J Palliat Care. 14:49–56, 1998. 25. Ferrell BR, Rhiner M, Cohen MZ, Grant M. Pain as a metaphor for illness. Part I: impact of cancer pain on family caregivers. Oncol Nurs Forum 18:1303–9, 1991. 26. Weitzner MA, McMillan S, Jacobsen PB. Family caregiver quality of life: differences between curative and palliative cancer treatment settings. J Pain Symptom Manage 17:418–28, 1999. 27. Miaskowski C, Kragness L, Dibble S, Wallhagen M. Differences in mood states, health status and caregiver strain between family caregivers of oncology patients with and without cancerrelated pain. J Pain Symptom Manage 13:138–47, 1997.

m. glajchen 28. McMillan SC, Small BJ, Weitzner M, et al. Impact of coping skills intervention with family caregivers of hospice patients with cancer. Cancer 106:214–22, 2006. 29. Hodges LJ, Humphris GM, MacFarlane G. A meta-analytic investigation of the relationship between the psychological distress of cancer patient and their caregivers. Soc Sci Med 60:1– 12, 2005. 30. Schulz R, Beach SR. Caregiving as a risk factor for mortality: the caregiver health effects study. JAMA 282:2215–19, 1999. 31. Hinton J. Can home care maintain an acceptable quality of life for patients with terminal cancer and their relatives? Palliat Med 8:183–96, 1994. 32. Glajchen M, Homel P, Flynn D, et al. Pilot study on pain medication adherence among patients: are caregiver burden and distress contributing factors? Unpublished study findings. 33. Ferrell BR, Panke J. Emotional problems in the family. In Doyle D, Hanks GW, Cherny N, Calman, K eds, 3rd edition, 2005. 34. Yabroff KR, Davis WW, Lamont EB, et al. Patient time costs associated with cancer care. J Natl Cancer Inst 99:14–23, 2007. 35. Brady MJ, Peterman AH, Fitchett G, et al. A case for including spirituality in quality of life measurement in oncology. Psychooncology 8:417–28, 1999. 36. Ward SE, Berry PE, Misiewicz H. Concerns about analgesics among patients and family caregivers in a hospice setting. Res Nurs Health 19:205–11, 1996. 37. Glajchen M. Psychosocial issues in cancer care. In: Miaskowski C, Buchsel P, eds. Oncology nursing: assessment and clinical care. St. Louis: Mosby, 1999, pp 305–18. 38. Kristjanson LJ, Ashcroft T. The family’s cancer journey: a literature review. Cancer Nurs 17:1–17, 1994. 39. Weitzner MA, Jacobsen PB, Wagner H, Friedland J. The Caregiver Quality of Life Index–Cancer (CQOLC) scale: development and validation of an instrument to measure quality of life of the family caregiver of patients with cancer. Qual Life Res 8:55–63, 1999. 40. Blanchard CG, Albrecht TL, Ruckdeschel JD, et al. The role of social support in adaptation to cancer and survival. J Psychosoc Oncol 13:75–95, 1995. 41. Zabora JR, Smith ED, Baker F, et al. The family: the other side of bone marrow transplantation. J Psychosoc Oncol 10:35–46, 1992. 42. Yeager KA, Miaskowski C, Dibble SL, Wallhagen M. Differences in pain knowledge and perception of the pain experience between outpatients with cancer and their family caregivers. Oncol Nurs Forum 22:1235–41, 1995. 43. Sales E. Psychosocial impact of the phase of cancer on the family: an updated review. J Psychosoc Oncol 9:1–18, 1991. 44. Anderson JL. The nurse’s role in cancer rehabilitation: a review of the literature. Cancer Nurs 12:85–94, 1989. 45. Rose K. How informal carers cope with terminal cancer. Nurs Stand 11:39–42, 1997. 46. McCorkle R, Benoliel JQ, Donaldson G, et al. Randomized clinical trial of home nursing care for lung cancer patients. Qual Life Res 8:55–63, 1989. 47. Christakis MA, Allison PD. Mortality after the hospitalization of a spouse. N Engl J Med 354:719–30, 2006.

role of family caregivers in cancer pain management 48. Hansom LC, Danis M, Garrett J. What is wrong with end-oflife care? Opinions of bereaved family members. J Am Geriatr Soc 45:1339–44, 1997. 49. Berry PE, Ward SE. Barriers to pain management in hospice: a study of family caregivers. Hosp J 10:19–33, 1995. 50. Jepson C, McCorkle R, Adler D, et al. Effects of home care on caregivers’ psychosocial status. Image J Nurs Sch 31:115–20, 1999. 51. Lorenz KA, Lynn J, Dy SM, et al. Evidence for improving palliative care at the end of life. A systematic review. Ann Intern Med 148:147–59, 2008. 52. Emanuel EJ, Fairclough DL, Slutsman J, et al. Assistance from family members, friends, paid care givers and volunteers in the care of terminally ill patients. N Engl J Med 341:956–63, 1999. 53. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). The SUPPORT Principal Investigators. JAMA 274:1591–8, 1995. 54. Nijboer C, Tempelaar R, Triemstra M, et al. The role of social and psychologic resources in caregiving of cancer patients. Cancer 91:1029–39, 2001. 55. Docherty A, Owens A, Asadi-Lari M, et al. Knowledge and information needs of informal caregivers in palliative care: a qualitative systematic review. Palliat Med 22:153–71, 2008. 56. McCorkle R, Pasacreta JV. Enhancing caregiver outcomes in palliative care. Cancer Control 8:36–45, 2001. 57. Harding R, Higginson IJ. What is the best way to help caregivers in cancer and palliative care? A systematic review of interventions and their effectiveness. Palliat Med 17:63–74, 2003.

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58. Hudson PL, Aranda S, Hayman-White K. A psycho-educational intervention for family caregivers of patients receiving palliative care: a randomized controlled trial. J Pain Symptom Manage 30:329–41, 2005. 59. Naylor MD. Transitional care: a critical dimension of the home healthcare quality agenda. J Healthc Qual 28:48–54, 2006. 60. Hanson LC, Reynolds KS, Henderson M, Pickard CG. A quality improvement intervention to increase palliative care in nursing homes. J Palliat Med 8:576–84, 2005. 61. Bucher JA, Houts PS, Nezu C M, Nezu AM. Improving problem-solving skills of family caregivers through group education. J Psychosoc Oncol 16:73–84, 1999. 62. Glajchen M, Moul JW. Teleconferencing as a method of educating men about managing advanced prostate cancer and pain. J Psychosoc Oncol 14:73–87, 1996. 63. Robinson KD, Angeletti KK, Barg FK, et al. The development of a Family Caregiver Cancer Education Program. J Cancer Educ 13:116–21, 1998. 64. Pinquart M, Sorensen S. Ethnic differences in stressors, resources, and psychological outcomes of family caregiving; a meta-analysis. Gerontologist 45:90–106, 2005. 65. Given B, Sherwood PR. Family care for the older person with cancer. Semin Oncol Nurs 22:43–50, 2006. 66. Kurtz M, Kurtz J, Given C, et al. Depression and physical health among family caregivers of geriatric patients with cancer – a longitudinal view. Med Sci Monit 10:CR447–CR56, 2004. 67. Andrews S. Caregiver burden and symptom distress in people with cancer receiving hospice care. Oncol Nurs Forum 28:1469–74, 2001.

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Cancer pain and palliative care in the developing world roberto wenk, a daniela mosoiu, b and m.r.b rajagopal c a c

Programa Argentino de Medicina Paliativa-Fundaci´on FEMEBA, Hospice Case Sperantei Brasov, and Trivandum Institute of Palliative Sciences

Introduction Throughout the world, millions of people suffer from chronic diseases, HIV/AIDS, and the aging process. The majority of these people are living in developing countries, where resources are limited, diseases often are diagnosed late, and curative facilities are scarce.1 The World Health Organization (WHO) estimates that 58 million people per year will die during the projection period 2005–2010, and that most of these deaths (45 million) will occur in less-developed countries.2 At least 35 million (60%) of those dying every year will have a prolonged, advanced illness, with similar needs – physical, psychological, social, and existential – that are relatively independent of the diseases from which they suffer.3 In fact, 60% of cancer patients will have pain. Cancer pain management (CPM) and palliative care (PC) delivered according to WHO guidelines provide costeffective care to relieve suffering and improve the quality of life of patients and families.4 Millions of people need access to them as part of an integral response to their needs. However, the provision of CPM and PC in developing countries is a problem; with very few exceptions, these programs are not yet incorporated into health systems, and tragically the vast majority of patients do not have access to them. Because of the aforementioned reasons, some experts estimate that many patients, most from developing countries, are not getting the quality of care they should receive; effective CPM and PC are not available to all those who need them because of a lack of appropriate policies, inadequate education of health personnel, poor drug availability and accessibility, and lack of public awareness that suffering can be reduced with relatively inexpensive methods. This chapter includes three parts: The first describes the development and progress of CPM and PC in the developing world and the transition from CPM to PC. The second

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part describes current PC resources, processes, results, and outcomes in Eastern Europe, Latin America, and India and includes vignettes of two countries – Romania and Argentina – and one state – Kerala. The third part presents a discussion, including comments on the similarities among these three regions, and formulates questions about possible strategies for PC development. The issues described may be similar in all developing countries.

Cancer pain management Before 1960, mainstream medicine devoted little attention and gave low priority to cancer pain and its treatment; severe undertreatment was the rule. Pain was described as a byproduct of the disease, with the implication that its proper treatment would relieve the symptom. As a result, most health professionals believed that severe pain is unavoidable in advanced-cancer patients and were not aware about pain and suffering, or were indifferent to pain and suffering because they did not think it was their duty to relieve them.5 Textbooks of surgery, oncology, and other specialties rarely mentioned pain management.6 Cancer prevention, diagnosis, and treatment were subjects of interest, but symptom control was excluded. During medical training, pain was poorly covered as an isolated cancer symptom, and there were no training programs in CPM for clinicians; thus insufficient education and limited clinical practice were responsible for the undertreatment of cancer pain. Although there were significant differences among physicians in their ability to provide CPM, most physicians – including anesthesiologists and oncologists – shared similar negative attitudes toward prescribing opioids. The greatest concerns regarding opioid use were safety, side effects, and fear of addiction. These attitudes on the part of physicians and other professionals caused CPM’s inadequacy to endure.

cancer pain and palliative care in the developing world Uncontrolled pain was a common complaint of cancer patients and families. The majority of patients were not treated for pain at all, or were treated inadequately. Those who were more fortunate received intermittent intramuscular injections of meperidine or morphine. Also, some dying patients with uncontrolled pain – perhaps a greater number than reported – received a “lytic cocktail.”7 Around the 1960s, relieving pain progressively became the duty of some anesthesiologists, who were more interested in pain issues and more proactive in assessing and treating pain. With their knowledge in both regional and pharmacological analgesia, these professionals delved into CPM as a part-time activity. Their methods, mostly invasive techniques performed in the hospital, included autonomic nervous system blocks (stellate ganglion, celiac plexus, hypogastric plexus, and sacrococcygeal ganglion), peripheral nerve blocks, intraspinal therapies, and neurosurgical procedures.8 They used local anesthetics, steroids, or neurolytic substances (ethanol or phenol) for the blocks. Some anesthesiologists also used intravenous infusions of alcohol, snake poisons, local anesthetics,9 antidepressives,10 and other agents, with erratic results. Although they were more liberal than their professional peers in using analgesics, many anesthesiologists were reluctant to prescribe opioids as part of their CPM. The anesthesiologists had a catalytic influence on CPM in several ways: 1) they started the establishment of pain clinics in the anesthesia departments of large-city hospitals, 2) they pioneered professional education, 3) they progressively incorporated the use of systemic opioids with measures to improve the availability of and accessibility to oral morphine, and 4) they revealed the magnitude of the cancer pain problem and the potential benefits of relieving it. CPM continued to be insufficient for many years; however, several factors helped change the situation: 1) The work of many leaders around the world and the evolution of human and ethical factors created awareness of the fact that cancer pain patients were underserved. 2) Health professionals, patients, and the public slowly and progressively recognized the importance of effective CPM. 3) Practices and attitudes regarding cancer pain became a matter of concern in cancer treatment settings. Studies revealing the undertreatment of cancer pain11–14 provided the drive for the first international meeting, in 1978, to debate CPM. As a result of this meeting, a draft titled The Method for Relief of Cancer Pain was released in 1982. In 1984, WHO identified cancer pain as a major health problem, and in 1986, it published the monograph Cancer Pain Relief. At the same time, the International Association for the Study of Pain started a collaborative

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program with WHO to make CPM universally available by 2000. This activity was the beginning of the slow, progressive reversal of the negative situation for cancer pain patients. A growing number of health professionals became aware of the magnitude of the cancer pain issue and began to consider it an important health problem. Clinical data showed the efficacy of the WHO method for CPM, and drug therapy with opioid analgesics became the mainstay of cancer pain treatment.15,16

Palliative care Health professionals who were attracted to CPM soon realized that pain was responsive to treatment, and within certain specialties, the enthusiasm to provide pain relief grew. These professionals also realized that pain is seldom the only symptom experienced by cancer patients and that its relief alone does not significantly improve overall quality of life. They recognized both the need to explore all dimensions of distress of patients and families and the benefits of teamwork to deliver comprehensive care, assessing and addressing the patient’s sources of suffering.17 WHO defined palliative care18 in 1990, and the term was introduced into medical language. There was a growing perception that patients are best served when quality of life is the main therapeutic goal. This perception was stimulated and fed by the WHO Cancer and Palliative Care Unit and its network of international experts who offered support and shared their knowledge and experience. In 1990, WHO published the monograph Cancer Pain Relief and Palliative Care, reflecting this broader scope of care.19 This practical and cost-effective model for caring for advanced-cancer patients and their families was put into practice by professionals from disciplines such as oncology and pediatrics, as well as by CPM leaders, mostly volunteers. At first they worked independently and alone in their communities or hospitals, but soon other health professionals and new volunteers joined them to form teams. These teams provided PC in different ways: home care, outpatient consultations, inpatients follow up, and so on. Their activity was adapted to the needs and limitations of each country; their funds came from charity, grants, research protocols, teaching fees, international subsidies, and other sources. Only a few had limited national governmental input. Key to the success of these changes were the team leaders, who had a high level of personal motivation and

610 who, despite working in relative isolation with underrecognition of their activity, invested much time and many resources into their projects. These individual initiatives created awareness of the inadequacies in end-of-life care, demonstrated PC’s effectiveness and efficiency, and identified different barriers to its dissemination. Successful advocacy at the community, professional, and government levels generated interest and stimulated actions that resulted in PC programs of different complexity, national or regional PC associations, and, in some cases, national official PC programs.20 With the rise of PC programs, there was both a gradual reduction in anesthesiologists’ role in CPM using interventional techniques and an increase in noninvasive interventions, including pharmacological, psychological, and physical therapies. CPM was incorporated into PC, with only selected patients with refractory pain referred to CPM specialists. Although the previous description was written in the past tense, in the developing world, many of the attitudes and behaviors resulting in barriers to CPM and PC are still in place, despite several efforts to eliminate them. Perhaps the most important issue is that health personnel lack adequate skills to recognize, assess, and manage cancer pain and suffering. As a result: 1. Only a small fraction of patients with cancer pain receive treatment for it. There is poor use of the WHO analgesic ladder as a guide in selecting analgesics and adjuvant drugs, despite the marked increase in morphine consumption and drug availability in many countries. 2. Access to PC is inconsistent and poorly coordinated. PC is still neglected by most public health systems, and although it is gradually being accepted by health professionals, these professionals are not taking all the necessary steps to bring it about.

Current status of PC in Eastern and Central Europe The countries of Central and Eastern Europe (CEE) frequently are presented together with the Commonwealth of Independent States (CIS), as they share common features resulting from their past communist history. The collapse of communism in these countries has been followed by a process of transition in all major areas: politics, economy, health, social, and others. Transition has been and still is difficult because of the lack of resources, corruption, mentalities, and the lack of experienced leaders.

r. wenk, d. mosoiu, and m.r. rajagopal Historical overview of PC development With the exception of Poland, where the first PC service – the “Society of Friends of the Sick” – was established as a home care service in Krakow during the communist period, most countries in the region started developing their PC services after the change in regime. These programs began as home care services, as those in Hungary (1991), Bulgaria (1992), Romania (1992), Slovenia (1992), and Albania (1993), or as free-standing hospices, as those in Poland (from 1992), the Czech Republic (1992), Bulgaria (from 1998), and Latvia (1997).21 Most of these services were started by the nongovernmental sector with technical and financial support from outside the country. For example, Albania, Romania, and Poland received support from the United Kingdom, and Moldova from the United States. Because the European Association of PC was focused more on Western Europe, in May 1999, Professor Luczak initiated the Eastern and Central European Task Force for Palliative Care (ECEPT) based on the Poznan Declaration.22 This organization immediately attracted not just PC professionals from CEE, but also those from Central Asia. Although ECEPT was a young organization without adequate funding to fulfill all the ambitious tasks on its list,23 it succeeded in attracting attention to the CEE region and the problems it was facing regarding PC development. EAPC started the EAPC-East project, offering reduced rates to congresses for attendees from CEE and CIS. In 2005, the Hungarian Hospice PC Association started a monthly newsletter in English and Russian for those in CEE and the former Soviet Union.24 Development of PC in CEE, especially in the countries with lower incomes, has been stimulated by funding offered by the Open Society Institute and the European Union (EU). Research performed in 2002 in 28 countries in CEE and CIS identified five centers of reference in four countries: Romania, Hungary, Poland (two centers), and Russia.25 These centers have had a crucial role in developing PC and presently are serving as centers of reference.

Current status of PC The International Observatory in End of Life Care based at the University of Lancaster in the United Kingdom has done country reports by using in-depth interviews and field trips and has depicted PC development in a series of world and regional maps. The report classifies countries in one of four categories: 1) those with no known hospice–PC activity,

cancer pain and palliative care in the developing world 2) those with capacity-building activity (but no service yet), 3) those with localized provision of hospice PC, and 4) those where hospice and PC activities are approaching integration with the wider health system.26 According to this study, Hungary, Poland, Romania, and Slovenia are included in group 4 and the other CEE countries in group 3. It is interesting to note that Slovenia, with the greatest development and resources, is not among the countries with the most developed PC services in the region. In Slovenia, there is no recognition of PC as a self-standing discipline and there is a lack of experts willing to work in PC.27 Therefore, the development of PC is not related solely to the wealth of the country but also to the vigor of the PC movement. Measures of development Structure Support of the health authorities In the Czech Republic, Latvia, and Poland, PC is recognized as a discipline; in Latvia, it is recognized as a medical subspecialty. However, there is no strategy to develop a comprehensive PC program that could offer good access to care. Latvia and Moldova have included PC and access to pain medication in their health strategy, but adequate funding is not in place. Moldova, under constant pressure from the local Soros Foundation office and the country’s few PC providers, has taken a public health approach to developing PC. A population-based needs assessment 28 estimated that 23,567 patients/year, 60% in rural areas, need PC in that country. Based on this study, the minister appointed a working group, with several subgroups and deadlines, to work on PC regulation and standards, opioid availability, and costs and funding of services. Romania In Romania, PC is recognized as both a discipline and a medical subspecialty. The Ministry of Health recognizes PC units as self-standing structures, and in the process of reforming the health system, beds in hospitals have been reallocated for palliative care. However, this was not done in a coordinated way, as part of a national plan, but rather was left to the initiative of intrepid managers. Economy Reimbursement for PC services by the government through the insurance system is in place in Bulgaria (inpatient care, 20 days/month in the last 6 months of life), Hungary (100% for home care, 70% for inpatient care), Poland, the Czech Republic, Latvia, Lithuania, Macedonia, and Slovenia.26

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The payment system varies from payment per service to payment per visit, or payment per day of care for the home care services. For inpatient services, payment per day and payment per episode of care are the more frequently encountered modalities. Some countries have promoted a law that allows employees to direct a percentage of their taxes toward charities. Hospices have used this to generate income. Other funding is secured from EU grants allocated to countries in the process of joining the EU. Romania PC to inpatients is reimbursed around 70%. In the few inpatient facilities in public hospitals, PC is 100% financed by the state. The amount contracted by the hospital per day per bed varies in different regions of the country depending on the negotiation process, from $40/day/bed to $130/day/bed.29 The other, nonpublic (nonofficial) services must search for other sources of income to ensure their sustainability. A law allows employees to direct 2% of their taxes to charities. Opioid availability and accessibility In Europe, the amount of opioid analgesics used for pain relief varies greatly among countries.30 Eastern Europe is especially at risk of inadequate availability of essential drugs for patients with cancer, AIDS, and other illnesses. The consumption of opioid analgesics per person in the 10 highest-ranking countries in Eastern Europe is less than 30% of that in Western Europe.31 Removal of regulatory barriers to access is just one step in improving patients’ access to strong opioids. Lack of education of health care professionals in the use of these drugs and misconceptions of health care providers and the general public are other barriers that need to be overcome. Moldova, Serbia, Bulgaria, and Bosnia and Herzegovina have regulatory barriers that pose great difficulty for PC providers. In Moldova, oral morphine and other oral opioids are not available, patients are not allowed to have morphine vials in their homes, and no more than 10 vials (20 mg morphine/vial) can be written on one prescription. In Macedonia, morphine is not available for outpatient use. The cost of treatment with morphine for 1 month as reported by the key country contact varies from €16 in Poland to €90 in Macedonia. All countries except Bosnia, Croatia, and Serbia reported that morphine is the firstchoice opioid, followed by fentanyl TTS (transdermal therapeutic system). In Croatia, fentanyl was the first choice, followed by tramadol and slow-release morphine. This preference may be the result of aggressive marketing by

r. wenk, d. mosoiu, and m.r. rajagopal

612 Table 34.1. Palliative care development

Country Albania Bosnia and Herzegovina Bulgaria Croatia Czech Republic Estonia Hungary Latvia Lithuania Rep. of Moldova Rep. of Macedonia Poland Romania Serbia and Montenegro Slovakia Slovenia

First service (year)

Home care services (no.)

1993 1998 1998 2002 1992 1997 1991 1997 1995 2001

4 1 25 3 4 9 28 1 ped 3 8 2 232 + 30 ped 16 + 5 ped 3 1 2

1987 1992 1999 2001

Hospices (no.)

Hospital units (no.)

1 2 16

Day centers (no.)

1

10 1

Hospital consult teams (no.)

1 10 5 6

1 2 59 + 3 ped 9 + 5 ped

1 ped 69 6 + 2 ped

3

2 1

2 2

11 2

4 1 ped 1 2 2 1 + 1 ped 2

National association 2002 No 2003 1994 2005 No 1991 1996 1995 2006 No 1990 1997 2002 1999 1996

Abbrevation: ped, pediatric.

pharmaceutical companies, with little input from the PC community. Romania Recently, Romania started the process of changing an old and restrictive regulation concerning the medical use of opioids,32 and the PC Association is actively engaged in the implementation process.33 According to the new law, special authorization is no longer necessary for opioids to be prescribed to outpatients. Doctors now have independent prescribing authority; the proposed prescription amount is for 30 days (3 days in the previous law), with no limit on dosage, and up to three opioids are allowed on one prescription. Patient eligibility for opioids is no longer based on diagnosis (under the previous law, only cancer patients were eligible). Also, pharmacies no longer need special authorization to store and dispense opioids, and there is no more police interference in legal medical use. At present, a national education program in opioid prescribing (20 hours) targeted to doctors and pharmacists is facilitating the implementation of the new legislation. The program is run by 40 trainers under the coordination of Hospice Casa Sperantei and with accreditation by the Ministry of Health and Romanian College of Physicians. The program started in November 2006 and will end in December 2007; it has been very successful, with more than 1850 participants so far. Teams and programs PC services in the CEE countries have been developed mainly for cancer patients, who comprise 89% (Hungary, Poland) to 100% (Bosnia) of all patients who receive PC.34

This is not surprising, as cancer is the second leading cause of death in the region, with mortality rates rising, especially in Hungary, the Czech Republic, and Croatia.35 PC is developing steadily in the region; Poland has the most developed system, followed by Hungary, the Czech Republic/Slovenia, and Romania (Table 34.1). Romania Romania ranks third after Poland and Hungary in total number of services (42), with 21 home care teams, nine hospices, eight PC units, two day centers, and two mobile teams. National PC associations Except for Bosnia–Herzegovina and Macedonia, all countries have at least a national organization (Table 34.1), frequently a professional organization focused on education (organizing conferences and seminars, providing book translations). Romania The National Association, created in 1997, is being restructured to allow collective members to play a more decisive role in designing the policy and national development of PC services. Process Education Education of PC professionals, initially done outside the country, has been focused mainly at the postgraduate level. Introductory/advanced courses and seminars have been organized in all the CEE countries. Bulgaria is running

cancer pain and palliative care in the developing world a master’s degree program in PC. Poland and Hungary are constantly organizing international training programs that cover theory and offer clinical exposure. Poland has 14 centers that offer placement for training, with 100 doctors graduating so far.36 Moldova has introduced PC in the compulsory curriculum for basic nursing training. Hungary, Poland, and the Czech Republic offer courses for medical students in universities as local initiatives. Romania Since 2000, PC has been recognized as a medical subspecialty, and 136 doctors have been awarded the diploma. At present, 78 doctors are in the training program at four centers – Brasov, Bucharest, Cluj, and Constanta – under the coordination of the national education and resource center in Brasov. The training is modular and spread over a period of 18 months. In 2006, through a Leonardo EU Project, four major Romanian universities (Cluj, Iasi, Timisoara, and Brasov) and Hospice Casa Sperantei participated in an exchange project with Lancaster University and designed a common curriculum for medical students. However, this curriculum has been implemented only by the University Brasov. A similar project has been started for the nursing colleges. Multidisciplinary introductory and advanced courses in PC are run regularly by Hospice Casa Sperantei, with 1150 participants in 2006. International training programs with clinical exposure, as well as undergraduate local courses for physicians, also are available for countries in the region. Research Because of a lack of resources and expertise, as well as language barriers impeding the presentation of research data, few studies from this region have been published. Romania Two main research projects are currently underway in Romania. One is a national survey of oncologists, hematologists, and PC doctors on their attitudes toward communication and decision making. The second project, funded by the U.S. Agency for International Development, is a looking at the knowledge and attitudes of the general public concerning end-of-life care. Assistance activity Even if data are recorded inside the CEE countries, they are not available internationally. Therefore, there is no information concerning the number of patients who receive PC or about other aspects related to the caring process. Among countries in the region, there is a difference in the place of death. It occurs predominantly in hospitals

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for wealthier nations, such as Poland (53%) and the Czech Republic (59%), and at home for poorer countries, such as Moldova (83.9%)37 and Hungary (61%).26 Romania In Romania, 89% of deaths occur at home. This is the traditional pattern that has been kept despite the general underdevelopment of home care services, as families consider the care of elderly and terminal patients to be their responsibility. Output PC availability, accessibility, and affordability Coverage of patients who need PC remains a problem; patients still do not have the option of receiving adequate care, where and when they need it. Romania A law concerning patients rights38 states that the patient has the right to PC and to die with dignity, and that care should be offered in the place the patient desires. However, these rights remain at the level of text in a law, as there are not enough services and resources to put the law into action. Existing services offer inadequate coverage to patients in need, with an estimated 5% of patients receiving PC. Outcome Although information on how PC services affect patients with advanced or terminal diseases is not available, hospices receive letters from patients who have been in their care and, more often, from their families expressing satisfaction and gratitude. Romania The National Hospice and Palliative Care Organization in the United States is working with the PC association to set up a minimum data set with indicators of process and outcomes to be used nationally by the PC services. Conclusions Development of PC in CEE started after the fall of the communist regime, and Poland is leading the way. All countries in the region have operational services, and some (Poland, Hungary, the Czech Republic, Slovenia, and Romania) have succeeded in having an impact on governmental policy. Charismatic leaders drove the movement initially. Legislative barriers hinder access to adequate medication and do not allow adequate funding for existing services. Although international documents have been signed by CEE countries (Single Convention on Narcotic Drugs, Council of

614 Europe Recommendation), PC guidelines have not been put into practice, and as result, coverage for patients in need is extremely low.

Current status of PC in Latin America The region Latin America and the Caribbean (LA) is a developing region made up of 35 different countries with a population of 551 million. It is challenged by common economic, political, and cultural factors. Many national health systems must deal with inadequate infrastructures, poor administrative systems, poverty, limited educational opportunities, and other challenges. They focus mainly on disease prevention, prenatal assistance, undernourishment, and other issues. Historical overview of PC development

r. wenk, d. mosoiu, and m.r. rajagopal Structure Support of the health authorities In most countries, support is insufficient: Governments are unable and/or reluctant to fulfill the demand for PC. Data from two surveys indicate that PC is not a priority in regional health policies and that in 80% of the countries, it is not yet recognized as a discipline and is not included systematically in the public free or private health system. There are national PC programs reported in seven countries, but there is information that only three of these programs (in Chile, Costa Rica, and Cuba) are active and provide PC nationwide, interacting with their primary care systems. In most countries, effective activity has not yet started.41,42 Many countries have laws and bills that promote – and should guarantee – both PC and opioid availability, but these policies are ignored.

During 1983–1985, diverse professionals started to provide PC in several countries and to promote and teach its concepts. Most countries started developing PC services after 1982: Argentina in 1983–1985, Colombia and Mexico in 1987, Brazil in 1989, Costa Rica and Cuba in 1990, Ecuador in 2000, Guatemala and Bolivia in 2005, and Nicaragua in 2006.

Argentina r There is not yet a national health policy to implement PC. PC was recognized as a discipline in one province in 2006. r There are eight bills and 11 regulations and laws that promote and should guarantee both PC and opioid availability nationwide, but they have not been executed.

Current status of PC

Economy In most countries, PC is not recognized as a medical discipline and PC activity is difficult to finance because their health systems do not pay, or they underpay, for it. This makes sustainability an issue that most countries solve with mixed approaches: resources from charity, work for free on a volunteer basis, and care paid by the patient (when it is possible) or by health care coverage (some plans accept PC and pay for it). Health systems have not yet matched finances with better care – namely, PC, but they continue paying for lifeprolonging interventions, even when they are futile. Hence, they are not using limited health resources efficiently to improve quality of life.

Despite the progress made in the past 20 years, the conditions are still not adequate for developing PC and there are serious deficiencies in the way most of the health systems care for the dying. Patients with advanced incurable diseases suffer in the final stages of their lives and die in pain. Quality of life during the dying process is poor and assistance is fragmented, resulting in uncontrolled suffering, poor communication between professionals and patients and families, and a great burden on family caregivers.39 There is an increasing need for PC as a component of health services, and its development has been successful in terms of number of teams and programs and opioid consumption. However, it has not yet been successful in terms of coverage of the target population; PC still is not available to an acceptable percentage of patients in LA. According to the International Observatory in End of Life Care world map staging system of PC development (see earlier), Argentina, Chile, and Costa Rica are included in group 4; Brazil, Colombia, Cuba, Dominican Republic, Ecuador, Guatemala, Honduras, Mexico, Panama, Peru, Uruguay, and Venezuela in group 3; and Bolivia, Nicaragua, Paraguay, and Puerto Rico in group 2.40

Opioid availability and accessibility LA countries consume less than 1% of the globally consumed morphine. Reasons for the underuse are lack of training of practicing physicians and pharmacists on opioid analgesia, restrictive regulations for opioid prescription and stock, and the high cost of opioids. Also, there are outdated and nonscientific prescribing regulations that restrict the use of potent analgesics. There

cancer pain and palliative care in the developing world is good availability of several opioids, but their high cost relative to mean monthly regional incomes limits their access and use.43,44 Some countries increased the use of opioids – in 2006, morphine consumption in the region was 0.92 mg per capita, exceedingly below the global mean of 5.98 mg per capita45 – as a result of changes in restrictive policies as well as the work of teams guaranteeing the provision of opioids without charge or at low cost with compound and generic preparations. Argentina r There is good availability of commercial and compound preparations of both weak and strong opioids. r There are access difficulties, although morphine and codeine should be supplied free to all patients. Provision is variable to inpatients and limited to outpatients in public hospitals. Distribution is variable in distant cities and places. r Law 23.737 restricts the medical use of opioids: “An individual will be jailed from 2–6 years and fined if publically gives information on the use of controlled substances or promotes somebody else to use them, or uses controlled substances publically and ostentatiously . . . Whoever gives out instructions publically on the production, fabrication, manufacture or use of controlled substances, will be jailed from 2–8 years.”46 Different groups related to CPM and PC are trying to change this law. Teams and programs The number of teams and programs in the region is uncertain. The reported – perhaps underreported – number of services are as follows: Argentina, 80; Costa Rica, 26; Chile, 21; Mexico, 15; Brazil, 14; Uruguay, 17; Colombia, 7; Cuba, 3; Ecuador, 3; Peru, 3; Dominican Republic, 1; Jamaica, 2; Trinidad and Tobago, 1; Barbados, 1; Guadalupe, 1; Guyana, 1; and Panama, 1. There is no information on how successful these programs are in development and service delivery. They vary among countries and cities and from one another, have operative differences related to their development, and treat mostly cancer patients. In general, most PC programs provide partial care. Teams based in the community or in hospitals consist of one or two disciplines with part-time dedication. Care may be given at home, at an outpatient facility, or both, and there is some institutional activity but no specific facilities (e.g., mobile teams without their own beds). Full PC programs with interdisciplinary teams providing 24/7 care in the consulting

615

room, at home, in day care, and in the hospital (with its own specific or designated beds) are not the rule. There are no facilities specifically for PC patients who need long-stay hospitalizations. Patients with uncontrolled symptoms are admitted to acute care facilities, and in most cases, they cannot be discharged if they lack adequate family or social support. In large cities, where 97% of PC is available, a few health systems provide complete PC. In small cities and rural areas, where only 3% of PC is available, all patients receive partial PC. Argentina r The total number of teams is about 75. Most are in large cities. Some were created more than 20 years ago, many in the last 5 years. Some are supported by nongovernmental organizations (NGOs). Teams within the public health system deliver inpatient care; those in the social security system deliver home care. r Many teams are functional; a trained professional works with professionals of other disciplines according to the patient’s needs. r Only a few teams have specific inpatient facilities; there are only 38 PC beds in the whole country. r Home care has limited development, and day care facilities are scarce. r There are two hospices with inpatient facilities. National PC associations A survey conducted in 20 LA countries in March 2006 indicates that only Argentina, Bolivia, Brazil, Colombia, Mexico, Paraguay, Peru, Uruguay, and Venezuela have national associations; however, not all of them are active. Argentina had the first national association in the region (1991). Argentina The Argentinean Association for Medicine and Palliative Care (AAMyCP), an interdisciplinary scientific association created in 1991, has approximately 300 members in 13 of the 23 provinces. It conducts scientific activities and promotes international academic cooperation and diffusion into the community. Process Education Although there is a growing trend for health professionals to learn about end-of-life care issues, undergraduate and graduate education fails to provide these professionals with the attitudes, knowledge, and skills required to provide good care for the dying patient.

616 An on-line survey indicated that although 80% of the respondents delivered PC to patients with different conditions, less than 15% had received any specific education in their undergraduate training and most had gained their knowledge through lectures and self-education programs after graduation. Only a few had received education including a combination of classroom and bedside learning. Results also indicated that 91% of the respondents had enrolled in some kind of learning activity during the previous 5 years.47 Possibilities for training are, in decreasing order, courses with lectures, self-study, and distance learning; most programs are interdisciplinary. Instruction with structured content, curricula, and assessments, as well as clinical practice with mentor guidance, is limited. Because PC still is not recognized as a specialty, residency and licensure examinations are not required. Argentina r There are few undergraduate learning activities for physicians and nurses. r There are multiple graduate programs, including classroom- and classroom/bedside-based activities, workshops, advanced seminars, and e-learning courses. Most are interdisciplinary; some are in collaboration with foreign universities. r Opportunities for intensive training in PC – concurrency for physicians and interdisciplinary residency – are available in only two cities. r Certification in PC by the AAMyCP and the National Academy of Medicine started in 2005. Research The results of an on-line survey conducted to obtain information on PC research in LA countries showed that there has been very little research with heterogeneous quality. The reasons are limited resources, minimal expertise in research, and scarce availability of trained researchers and training opportunities.48 There is an increasing need to formulate a research agenda according to regional needs, to develop protocols for multicentric studies, and to support those who conduct research. Assistance activity Because of the lack of data collection and analysis, there is limited information on the regional and national levels with regard to the number of patients who receive PC,

r. wenk, d. mosoiu, and m.r. rajagopal how and where they die, PC practices, and the clinical, organizational, and economic issues related to the caring process. Output It is estimated that 5%–10% of LA patients who need PC receive it. PC teams generally reach only a minority of patients. More than 50% of patients cannot pay for the services or the medication. Medical, nursing, and social services are not available to these patients, and assistance and PC often are inaccessible and unaffordable, resulting in considerable suffering due to lack of basic care and access to symptom control medication. Many people live in absolute poverty with unmet physical needs, such as food, water, and electricity. They spend their last days, weeks, or months in health care institutions under the care of professionals who have had no instruction in PC. Some of these deficiencies are resolved by informal caregivers who share in the caring process at home. Volunteer groups and religious communities develop networks to help care for patients at home or in the hospital by visiting regularly with food, medicines, or money. Argentina Information on the number of patients who receive free comprehensive PC services in large cities reveals that only about 10% of the patients who need care in their target populations (three cancer patients × 1000 inhabitants × year) receive care. At smaller sites and in rural areas, where teams are few and their activity is partial, the percentage of patients needing PC who actually receive it is even smaller. Outcome Because outcomes have not yet been measured, it is impossible to describe changes in end-of-life care due to PC. Simple outcome measures relevant to LA will allow us to determine the effectiveness of PC and how this effectiveness relates to providers, epidemiological issues, practices, and organizational and economic factors. Argentina The Programa Argentino de Medicina Paliativa-Fundaci´on FEMEBA started in 2006 with the evaluation of quality-ofcare outcomes in terms of the expectations and experiences of patients and their families.49 Both patients and caregivers

cancer pain and palliative care in the developing world

617

reported great satisfaction with the PC provided in terms of symptom control and adequateness of communications and recommendations.50

A look into the history of PC in the country would throw some light on this state of affairs,53 and the lessons learned would be relevant to much of the developing world.

Comments

Historical overview of PC development

PC is impossible to stop in LA, because there is increasing evidence that it is useful and that there is a growing need for it. Many professional and nonprofessional people are working for its implementation, and many PC teams develop every year in every country. Their activity was the impetus for the development in 2001 of the Latin American Palliative Care Association (Asociaci´on Latino Americana de Cuidado Paliativo [ALCP]), whose mission is “to promote the development of PC by communication and integration of all those interested in helping improve the quality of life of patients with incurable progressive diseases as well as their families.”51 Although the ALCP is struggling to sustain itself, it is reaching the region with three different tools:

Two factors contributed to the birth of PC as an entity in India: the creation of Shanti Avedna Ashram in Bombay in 198654 and the introduction of the WHO analgesic ladder.55 However, progress was slow for many years to follow. Shanti Avedna Ashram was an inpatient facility modeled on Western hospices. Although it serves as a spotlight pointing at the need for humane care and compassion in the treatment of people with cancer, it understandably had limitations in the numbers it could reach.56 Over the next few years, two branches of Shanti Avedna Ashram opened – one in Goa and one in Delhi – but that seems to be where the growth stopped. At the same time, more and more “pain clinics” run by anesthetists started to include pharmacotherapy of pain and principles of PC into their practice. Over the next few years, some PC enthusiasts from the West worked in the country to spread the message of PC. They attracted an audience of health professionals, “converting” several people to PC and supporting several others who were already venturing into the field. Their efforts also resulted in the government of India accepting CPM and PC as essential parts of cancer care. Several workshops were held at the government level that reiterated the need for oral morphine and PC; however, little action ensued. There was one positive outcome from these workshops, however. At one of the workshops, held in 1993 at Regional Cancer Center, Trivandrum with government involvement, it was decided to form the Indian Association of Palliative Care (IAPC), which came into being in 1994. In 1993, the Pain and Palliative Care Society (PPCS) came into being in Calicut, Kerala. By providing outpatient care and facilitating patients’ stay at home, by using trained volunteers, by involving the community, and through awareness programs, the PPCS succeeded in giving a reasonable quality of care to a large chunk of the population.57 “Satellite” clinics grew in neighboring towns. In 1995, WHO declared it a demonstration project for its success in developing a culturally suitable model of PC.58 The years following 1993 saw the development of many PC programs in several parts of India – mostly urban areas. Most were institution centered and had limited ability to reach patients once they left the hospital. Some were hospices catering only to inpatients. Some, like Cansupport in Delhi and the DEAN Foundation in Chennai, were started by NGOs and concentrated on home visit programs. Several

1. LA congresses. There is a positive tendency to join and share experiences in regional meetings. The first congress, in San Nicolas, Argentina, in 1990, gathered 35 persons from seven countries. The last one, in Isla Margarita, Venezuela, in 2006, gathered 147 people from diverse disciplines from 17 countries. 2. ALCP newsletter. The newsletter is a free electronic bimonthly publication in Spanish and Portuguese. Its current circulation is 2500 subscribers in 14 countries. 3. Website (www.cuidadospaliativos.org). The site is intended to disseminate information and educational resources, to understand different issues regarding PC development, and to acquire information on the quality of end-of-life care.

Current status of PC in India The region With more than a billion people, India has one sixth of the world’s population.52 As in most developing countries, India’s increases in population and life expectancy tend to increase the incidence and prevalence of cancer and many other life-threatening and debilitating diseases. Growth in health care facilities in India has been most predominant in curative services, which are confined mostly to large private hospitals accessible only to the urban rich. Preventive services have lagged behind, and PC care is still in its infancy, with only a tiny minority having access to it.

618 started education programs, most being developed by “trial and error” in terms of the nature or duration of the training. In the mid-1990s, the WHO Collaborating Center of the Pain and Policy Studies Group (PPSG) began studying the opioid availability problem in India. By interacting with officials, lawyers, and Indian PC workers, it succeeded in assessing the barriers to access to oral opioids and in suggesting remedial action. This collaboration among the PPSG, IAPC, and PPCS so far has succeeded in simplifying narcotics regulations in 13 of India’s 28 states and in ensuring more or less uninterrupted availability of oral morphine from the Government of India’s opium and alkaloid factories.59 Over a 2-year period, the PPCS followed up all 1723 patients who were given oral morphine for treatment of cancer pain and demonstrated that morphine could be used safely in the home setting without misuse or diversion to illicit sources. This practical demonstration helped allay some of the fears regarding oral morphine.60 Several individuals and organizations from the West continued to take an interest in the PC scene in India and to support it with their time, money, and efforts. Current status of PC An overview of the current PC scene in the country shows us that in India, it is mostly NGO driven. On the positive side, this has the advantage of some quality work. After all, voluntary workers are driven by the desire to help people who are suffering and are bound to try their best. However, there also are some disadvantages. Most strikingly, it limits the reach of PC. Rather obviously, it will reach the needy masses only if it becomes an integral part of health care – in both the governmental system and the private sector. This has not happened yet, and for the time being, people in pain and suffering in most parts of the country are left to live and die in agony. In some parts of the country where there is indeed some PC, patients depend on the compassion of a few “do-gooders” who try their best yet have limited access to resources, information, or education.

r. wenk, d. mosoiu, and m.r. rajagopal appointed a task force, in which PC activists formed the majority, to advise it on the development of a strategy for the National Cancer Control Program. This was a major breakthrough. Since 1991, the government had paid lip service to its policy statement that PC should be an essential part of cancer care. The appointment of the task force was the first step toward practical action on the matter. The committee submitted its report in May 2006, and as this is being written in March 2009, action by the government is awaited. However, at the state Government level there has been a major step forward. On April 2008, the Government of Kerala (one of India’s 28 states) acting on a proposal submitted by the Non-Government Organization Pallium India, declared a palliative care policy stipulating that palliative care should be an integral part of routine health care. However, even if the central government policy becomes a reality, it will be only a partial success unless state governments act; they are the ones involved in most of the health care delivery in the public sector. Not one of India’s 28 states has a PC policy so far. Pallium India, a charitable trust working at the national level, has initiated action in some states to work with local activists toward development of PC policy by the state governments. For this to become possible, there are two obvious needs: The system (both government and public) has to accept the fact that it has an obligation to relieve suffering, and it has to have the capacity – in terms of manpower, education of professionals, and drug availability – to do so.

Measures of development

Kerala The state of Kerala has approximately 100 PC centers, most of which are NGO driven. Only a handful operate in government hospitals. Officially, the government has not recognized PC as a discipline and a medical subspecialty. However, over the years, the government has made some budget allocation for PC, albeit without a clear plan of action. In 2005, based on a representation submitted by Pallium India, the government conducted a series of meetings to form a state PC policy, but it has not borne fruit yet. However, some local governments involved in health care delivery in small segments of each district have taken up PC as part of their agenda. They work with and support local NGOs involved in PC.

Structure Support of the health authorities In India, health care is the responsibility of the individual state governments. The central government, however, decides common national policies. As it stands now, neither the central nor the state governments have a declared PC policy. There has been some progress, however. In 2005, the Government of India

Economy There is neither an effective socialized health care system nor a health insurance scheme available to the common person. Responsibility for finding the money for treatment rests with the family. When the only breadwinner of a family becomes sick, the whole family faces financial devastation. Relatives often have to leave jobs to care for the sick person and may not find employment again. The

cancer pain and palliative care in the developing world financial implications may affect several generations, as children often drop out of school when a family member gets ill. PC teams often are overwhelmed by the extent of the social problem. Hence, attempts at rehabilitation of families need to be an important part of PC delivery, although this is no easy job. Kerala Despite maternal and infant mortality rates matching those of the United States, there also is considerable poverty and ill health in the state. There is no effective government or insurance system to fund significant medical needs of the common person. A study in rural Kerala found that 29% of all people below the poverty line had the poverty inflicted on them by medical treatment.61 The majority of patients attending PC clinics cannot afford to pay for even the cheapest pain medication. Most PC services in the state raise the funds to provide them with free drugs. Opioid availability and accessibility India is a legal cultivator of poppy and a prime source for the world’s opioid requirements. However, several barriers prevent opioid availability to millions who need it for pain relief. The predominant barriers are as follows: 1. Complicated regulations. The Narcotic Drugs and Psychotropic Substances Act permits prescription of opioids by any registered medical practitioner. However, the drugs ordinarily are not stocked in pharmacies because of the possibility of penalties for even minor infractions. Hospitals and other institutions can procure opioid preparations under a very complicated licensing system that varies from state to state. Also, a separate licensing system has a statutory requirement – a “drug license” – for any institution that sells any drugs, not necessarily opioids. One of the requirements is the availability of a qualified pharmacist. Recognizing that this would be an almost impossible target for humble PC programs to achieve, the Drugs Controller General exempted all PC services from the need for a drug license. Although in 1998, the central government instructed all state governments to simplify their narcotics regulations, most of them failed to do so. Most of those that complied have no effective system for implementation. In 2007, the Drugs Controller of Tamilnadu introduced a set of structured “standard operating procedures,” which, it is hoped, will be an example for other states to emulate. 2. Professionals’ attitude and lack of knowledge. Principles of CPM are not taught routinely to medical students, and physicians have no experience with oral opioids; there is a general fear of respiratory depression, which prevents use of opioids.

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3. Opiophobia among the public and administrators. Opioids are known as “addictive” drugs and thus generally avoided. 4. Interruptions in opioid availability. Interruptions in manufacturing these drugs in the government-owned factories cause a lack of opioid availability throughout the country. 5. Lack of resources. There is a concept that available resources should be directed toward curative treatment in a resource-poor country such as India and that PC is a luxury that only affluent countries can afford. Obviously, the nonavailability of PC is a factor that forces many clinicians to pursue definitive modalities of treatment, such as chemotherapy and radiotherapy, even when futile. Unfair and unrealistic allocation of resources, rather than a lack of it, is a reason for nonavailability of CPM and PC to those who need it. 6. Limited choice of drugs. With regard to strong opioids, there are no affordable alternatives. Although methadone is manufactured in India, it is only for export, because manufacturers have not gotten permission to sell and distribute it within the country. Recently, the government decided to permit the use of methadone for deaddiction programs. The PC community has appealed to the government to permit its use for pain relief too, as it would provide a cheap alternative. It seems rather obvious that a country with a dearth of resources should promote the use of inexpensive and affordable drugs, but sadly that is not the case. As in most developing countries, there is a tendency toward expensive medications being more easily available than affordable drugs. For example, the only available alternative to morphine is transdermal fentanyl. Many institutions that do not have oral morphine stock transdermal fentanyl, although the same regulations control the use of each. As fentanyl is very expensive, the result is often added suffering for the patient. It is hoped that if and when methadone is added to the list of available drugs, it will be a boon because of its affordability. Another essential step would be for the government to prepare and approve a list of affordable drugs. Kerala Kerala was the first state to develop an effective system for implementation of the simplified narcotic regulations that were established in 1999. Model Minimum Mandatory Requirements (MMRs) were established by the Drugs Controller of Kerala state in consultation with PC experts. These requirements include the availability of a doctor with at least 1 month of clinical training in PC in an approved center. A panel of PC physicians assists the drugs controller in screening applications and ensuring that the

620 applicant institutions satisfy the MMRs. Patients in Kerala can access oral morphine through about 100 PC facilities in the state. Teams and programs There has been no effective consensus on the structure or nature of the PC system in the country. In states in which the narcotic regulations have been simplified, recognized medical institutions providing PC are exempt from having to go through the complicated licensing system. This has raised the question, What would qualify an institution to be considered a PC center? Early in the century, the IAPC had recommended 1 month of training as the minimum requirement. However, recently it has recommended short training programs – less than 1 month – to empower doctors and nurses to practice PC. There are not enough nurses to serve existing PC centers. Hence, trained volunteers or nursing auxiliaries take on much of the responsibility for nursing chores, usually under the supervision of a qualified nurse. Most PC centers depend on the service of volunteers who raise funds to employ part-time doctors and nurses. Thus, the PC team typically consists of a doctor, a nurse, and a volunteer. Qualified social workers are hard to come by, so trained volunteers fill that role. It is accepted that the focus of PC should be to empower the patient to stay at home. Early in the course of the disease, patients may be fit enough to travel to an outpatient clinic, but when they are too sick to travel, they need home visits. Typically in most units, a patient may get to see the team once a week or, if he or she is not too sick, once every 2 weeks. Any support the patient needs in the interim period is given by volunteers in telephone consultation with professionals, or he or she may have to move to an inpatient facility. “Hospices” are few; hence, many patients end up dying in acute care hospitals, where unfortunately much of the work that has taken the PC team weeks to accomplish might get undone by inappropriate aggressive care. Fortunately, as PC services slowly expand their reach, more and more people are empowered to spend their last days at home. Kerala Neighbourhood Networks in Palliative Care have been established in northern Kerala. The local population raises much of the resources from the community. Volunteers in the locality get trained and act as a link between the patient and the medical system. These networks have been shown to improve coverage and have made PC a public movement. National PC associations The annual conferences held by the IAPC have been a major force that has kept

r. wenk, d. mosoiu, and m.r. rajagopal PC professionals together and has helped them exchange information. The IAPC publishes the Indian Journal of Palliative Care, which is available online for free to everyone. This organization has branches in several states, and over time, its fields of activity have expanded from opioid availability to education and policy development. Pallium India is a registered trust working at the national level since 2003 to improve the reach of PC in the country as well as the quality of care. In the first 3 years of its existence, it succeeded in catalyzing the development of PC services in three states where they did not exist as well as two PC education centers. Kerala Kerala is one of the states with a functioning state branch of IAPC. Kerala also is home to the headquarters of Pallium India. Process Education Only five of the 360 medical colleges include PC in their undergraduate medical curriculum. Action by the Medical Council of India is necessary for official introduction of the subject into the curriculum; however, this has not materialized.62 The facilities for PC education are limited in India. Several programs in the country offer educational programs for health care professionals in different formats: 1- to 2-day awareness courses; 7- to 10-day foundation courses; 4- to 6-week certificate courses, including classroom and clinical practice with mentoring; 1- to 2-year fellowship or diploma programs, including classroom and clinical practice with mentoring; and distance education programs with contact classes. PC officially is included in undergraduate nursing curriculum. However, because few institutions have PC services, this part of the curriculum is only theoretic and has little impact on nurses’ training. Volunteers are a strong part of the PC delivery system in the country. Because their roles are multiple, including carrying out nursing tasks, their training is important. Several institutions in India conduct volunteer training programs with classroom sessions and practical training with a mentor. Pallium India currently is trying out a progressive three-level training program for volunteers. Kerala Much of India’s PC education happens in Kerala. Two institutions in the state offer 4–6 weeks of training for doctors and nurses. One conducts a 2-year residential diploma program, and one offers a distance education fellowship program. Three of Kerala’s medical colleges have included PC in their curricula.

cancer pain and palliative care in the developing world Research PC research in India faces most of the same obstacles common to all health research efforts in the developing world. However, it also has some of its own, such as little visibility as part of cancer control strategies and a low level of political acceptability because of its use of opioid analgesics.63 Research is needed to demonstrate the need for PC and to guide plans of action. It also is necessary to study the problems patients face that are indigenous to the country – in physical as well as in psycho-socio-spiritual domains. However, the lack of resources, personnel, and know-how acts as an effective barrier against research. Of 83 publications listed under “palliative care and India” on PubMed, most are descriptions of problems or of the nature of services rendered. Very little material is available on diseases and related problems specific to the country. For example, more than 20% of all cancers in India are in the head and neck and most are detected in an advanced stage, yet there is little information documented on problems peculiar to these cancers. Among the 83 publications, there is only one randomized controlled trial (RCT),64 and although RCTs are not the only valuable form of research, this fact highlights the lack of organized research in the country. Kerala Of the 83 publications mentioned previously, 21 were written by authors from Kerala or were based predominantly on work done in Kerala, including the one RCT. Assistance activity Although most PC services care predominantly for cancer patients, they do not discriminate in terms of diagnosis – they also routinely include people with end-stage renal disease or those with longstanding paraplegia or other chronic diseases. Unfortunately, however, PC reaches people late in the course of their disease, which means they often have gone through months or years of pain and other suffering before eventually reaching a PC facility.65 Kerala Because finances are an overriding concern among patients, many PC facilities try to include social rehabilitation of patients and families among their activities. A major part of this support focuses on children’s education, to make sure the financial threat caused by the disease and its treatment does not result in children dropping out of school. Output PC availability, accessibility, and affordability There are nearly 130 PC centers in India, most of which provide services free to the poor. Yet, even today, these centers reach only about 0.4% of the needy.66 There are many states that

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still do not have even one PC service, which means the vast majority are suffering in silence. Those who do get care often must travel long distances to access it. On the positive side, most PC centers provide affordable, if not free, service. Kerala With roughly 100 of about 130 PC centers in the country located in Kerala, the people of that state have a better chance of accessing affordable PC. Outcome Lack of adequate research and documentation prevents the drawing of satisfactory conclusions regarding the quality of care delivered. However, the warmth with which the community welcomes PC anywhere in the country indeed is testimony to its effectiveness. The 2008 IAPC conference was themed “Quality and Coverage” and discussed the development of ways and means for proper evaluation. Kerala In the absence of reliable studies, the feedback from patients, unsolicited donations from patients’ families, the very positive response of the media, and above all the willing involvement of the community can be taken to mean that the PC movement in Kerala has been a success, although there still is a long way to go. Conclusions Looking back at the 21 years since PC came to India, there are many positive developments. Many centers now provide PC education. The government has taken a stand that barriers to opioid availability should be overcome and that PC must be an essential component of the National Cancer Control Program. However, there are many disappointing areas. One major weakness of the PC scene in the country is poor documentation, resulting in a lack of data showing how successful the PC movement has been. The only possible index of the reach of PC in the country (albeit a very unsatisfactory one) is consumption of morphine. If one assumes that the morphine sold annually by the government’s opium and alkaloid factories reached those who needed it, then based on available data and extrapolations, less than 0.4% of the needy population got morphine for pain relief. This state of affairs 21 years after the introduction of PC to India is deplorable. The following are urgent needs for the future: 1. Adoption of PC policy by the central and state governments aimed at integrating PC into the routine health care delivery system.

622 2. Awareness programs about PC aimed at the public, professionals, and administrators. 3. Recognition of palliative medicine and nursing as independent subspecialties so that university-approved educational programs can be offered widely. This action will be needed from the Medical and Nursing Councils. 4. Simplification of the regulations on opioids by all states so that regulatory barriers to opioid access can be overcome. Along with this, it will be essential to develop standard operating procedures for implementation of the amended regulations. The frustration experienced by the PC community is exemplified by the recent action by the IAPC that moved the Supreme Court in 2007 to act in all four of these areas. Experience in other countries proves that governments working with NGOs can bring relief to the millions who are needlessly suffering now. Will advocacy by NGOs become more effective in the future? Is the government going to act and include PC in routine health care delivery? Is the judiciary going to persuade the government to do so? Time will tell. The last few years also saw a trend toward recognition that PC should not be limited to cancer. However, although PC’s reach is expanding, its use in noncancer conditions is still in the early stages of development. More and more attention is being given to PC in children as well.

Discussion The information in this chapter shows that many countries in the developing world share mostly deficit-related similarities, including the following: 1. The need for PC is great because of multiple factors, including the aging of the population, the increasing incidence of chronic noncommunicable diseases and HIV/AIDS, fragile health systems, and poverty. Moreover, developing nations are where most of the world’s deaths occur. 2. Adequate PC delivery is jeopardized by inadequate policies, poor education, limited finances, and the absence of a skilled workforce. Even in those countries where these factors might be overcome, relief of suffering at the end of life often is either unappreciated or surpassed by other needs. 3. PC is achieving progressive legitimacy and presence as a new caring model. 4. Most of the countries have not yet managed to develop public health strategies toward PC.

r. wenk, d. mosoiu, and m.r. rajagopal 5. PC develops and is maintained by the consistent activity of regional leaders and individual initiatives that challenge many barriers, in most cases, with community support.67 Perhaps the only important difference is that some countries have better opportunities than others to get foreign funds and technical assistance. This information also draws attention to interrelated issues: items 4 and 5 on the list are – or may be – dependent variables of all the other items. Which concepts about them could need clarification to optimize PC availability? How could this situation be effectively improved? Foreign funds and technical assistance Continuous and controlled economic assistance – with CEE being the most advantaged and LA the least – has resulted in well-established PC programs and educational activity in several CEE countries and in India. Also, technical cooperation as a result of international initiatives helped in obtaining information on PC issues in the CEE region and in assessing the barriers to opioid availability – and the changes in restrictive regulations – in CEE countries and India. These results validate the utility of international economic and technical cooperation between wealthy countries and their less-privileged peers. Developing countries need assistance and support from international foundations and institutions to carry out several critical activities. However, collaboration should be guided by at least two basic rules: 1) All the developing regions, even those with different needs, should be included in the distribution process – unfortunately LA has not yet been considered.68 2) The adequacy of the recipients must be verified – and the offers of and requests for assistance must be matched – to avoid the improper use of efforts and to guarantee the accomplishment of the planned objectives. Public health strategy “Governments should incorporate PC into their health care systems”69 through a public health strategy – a method to transform available knowledge and techniques into effective and efficient evidence-based interventions accessible to all – with four components: health policy, education, drug availability, and implementation.70 In the developing world, it seems that the most protracted component is the health policy including PC. The first concept is to acknowledge that legislation is not always equal to

cancer pain and palliative care in the developing world health policy. Some countries have many laws (legislation level) that favor PC, but bureaucracy and inactivity at the public services (executive) level impede their success. The second concept is that a health policy a) implies the definition of health as a public issue in which the state assumes an active and explicit role, b) originates in the identification of problems in the health state (e.g., diseases, aging of the population, new technologies) that generate political demand, and c) uses resources to solve the problems (e.g., organization, financing, access to and use of services) that have political importance.71 The third concept is that if PC does not generate political demand, it will not be included in any health policy; unfortunately, demonstration of its need and the benefits of its implementation are not enough. The key factor is to generate political demand for PC.72 Community support Theories about needs consider that a community may not want PC unless basic needs such as food and sanitation have been met. According to these theories, it is impossible to think about adequate PC without housing, water, and so on. Based on this rationale, the right to PC – a concept involving multiple ethical and legal issues – may be unattainable in a setting of limited resources; PC cannot be isolated from the rights to health, housing, water, and sanitation.73 The linear ordering of PC in developing countries may not apply;74,75 if PC becomes an obligation, without considering resources and needs, the situation will not change as expected. However, the Kerala model – good-quality PC owned by the community, reaching the entire state, and providing care to nearly 70% of the patients who need it – shows that even in adverse situations, PC development is possible. It demonstrates the catalytic consequence of intense social participation. The first concept is that social participation may be understood only in the context of collaboration with PC teams and PC delivery (e.g., home visits, fundraising). Although social participation is necessary – it is the tool for local or regional achievements – it may be not enough for PC dissemination. The second concept is that the key factor to solve the “existential issues of PC” is that “the community must own PC.” This message must be understood as a call to social participation in its full definition: organized activity of a group to express needs, to secure common interests, and to give power to the community; population groups that lack equitable access to valued resources gain control of them. Social participation needs the recognition that in certain

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social situations, political control can be obtained with a) group action and interaction, respect, critical reflection, and commitment, and b) access to education, information, social and political activities, and technology.76 Although medical science will take some of the credit in disseminating PC, it mostly will be attributable to changes in attitudes and behaviors, and intense advocacy is the tool to make these changes possible. Advocacy in incorporating PC into the health care system when the health authority acts erratically, without interest in PC issues, must be aimed at two different specific targets, whose full definitions and implications must be kept in mind: 1. Inclusion of PC in the health policy 2. Social participation and involvement It is imperative to understand and acknowledge that these two goals are interrelated: Social participation must aim to increase the political visibility and demand of PC, the unique fuel and reward for health policies. There also are several operative questions at the PC delivery level that still must be answered in the developing world; perhaps the three most important are how to: 1. Ensure that limited health care funds are spent most effectively, that is, how to shift them from the provision of expensive, futile treatments to the development of PC programs 2. Ensure reimbursement systems according to each country’s resources 3. Deliver basic PC training to the primary level of assistance, recognized as basic for its delivery to the community.77 PC philosophy is attractive and accepted, and knowledge, skills, educational resources, and frameworks for service development are available; however, what constitutes feasible, accessible, and effective PC, and how to develop it, still must be determined. Potential strategies and paths are still intriguing, but again the “enhanced” concepts of health policy and social participation may be the key factors. The transition from available/accessible PC to PC effectively integrated within health systems is difficult; it will require much effort, commitment, and resistance to failures and deceptions. Maybe we need to accept that, at this moment, PC is not possible for all; that way, we will be less discouraged by the lack of enthusiasm for major initiatives in PC.

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Index

Abduction pillow, 366 Aberrant drug-taking behavior assessment of, 424 characteristics of, 424–425 differential diagnosis for, 424 prevalence of, 424–425 specific risk factors for, 425 Ablative neurosurgical procedures, 329–334 cordotomy, 331–332 complications from, 331–332 indications for, 331–332 techniques for, 331 of DREZ, 330–331 complications from, 330–331 indications for, 330–331 techniques for, 330 intracranial, 333–334 brainstem tractotomy, 333 cingulotomy, 333–334 hypophysectomy, 333 thalamotomy, 333 myelotomy, 332–333 complications from, 332–333 indications for, 332–333 technique for, 332 peripheral, 329–330 complications from, 329–330 in DRG, 329 indications for, 329–330 Abstinence symptoms, 178 Abuse of substances definition of, 120, 424 OIN and, 244 prevalence of, in general populations, 423–425 Aceclofenac, 259 Acetaminophen as aniline derivatives, 261–263 as antipyretic analgesic, 256 surgically-induced pain syndromes and, 148 Acidosis, in bone cancer pain, 28–29 ASICs and, 29 TRPV1 and, 29 Acid-sensing ion channels (ASICs), 29

Acupuncture, in pain rehabilitation, 362 Acute pain after analgesic interventions, 57 from opioid therapy, 57 from subcutaneous injections, 57 with anticancer therapies, 54, 55 from cancer, 54–55 organ obstruction/perforation, 55 pathological fractures, 55 rupture of hepatocellular carcinoma, 54–55 with chemotherapy, 57–59 with infusion techniques, 57–58 from toxicity, 58–59 chronic v., 53 from diagnostic interventions, 54–56 lumbar puncture, headaches from, 56 needle biopsies, 56 after hormonal therapy, 59–60 in breast cancer, 60 in prostate cancer, 59–60 with immunotherapy, 60 from infections, 55 herpetic neuralgia, 55 OIH and, 57, 195 with radiotherapy, 60–61 acute plexopathy from, 60 enteritis from, 60 mucositis from, 60 from radiopharmaceuticals, 61 during spinal metastasis, 60 with therapeutic interventions, 54–57 chemical pleurodesis, 57 for CIN, 56–57 from postoperative procedures, 56 from vascular events, 55–56 acute thrombosis, 55–56 superior vena cava obstruction, 56 Acute pain syndromes, 54–61 after analgesic interventions, 57 from cancer, 54–55 with chemotherapy, 57–59 from diagnostic interventions, 56 after hormonal therapy, 59–60 from infections, 55 from opioid therapy, 57

with radiotherapy, 60–61 with therapeutic interventions, 56–57 with vascular events, 55–56 Addiction definition of, 424 hospice care and, 539–540 to opioids, 177–178 Adenosine, as nonopioid analgesic, 296 receptor system, 13 Adenosine receptors, 480 Adjustment disorders, assessment of, 120–121 Adjuvant analgesics, 272–283 ␣2 -Adrenergic agonists, 279 anticonvulsant, 276, 277–279 antidepressants, 274, 275–276 SNRIs, 275–276 SSRIs, 275–276 tricyclic, 275 for bone pain, 281, 282 bisphosphonates, 281–282 calcitonin, 282 radionuclides, 282 for bowel obstruction, 282–283 cannabinoids, 281 classification of, 272–283 co-analgesic v., 272 corticosteroids, 273–274 definition of, 272 GABAergic drugs, 279 multipurpose, 273 for neuropathic pain, 274, 497–499 NMDA receptor agonists, 280–281 for noncardiogenic pulmonary edema, 238 pain assessment with, 114 Adolescent Barriers Questionnaire, 95 Adolescent Pediatric Pain Tool (APPT), 137 Adrenal pain syndrome, 67 ␣2 -Adrenergic agonists, 279 Advanced cancer, prevalence of pain in, 45 Advance directives, 557–558 POLST documents, 557–558 Affective assessment of pain, 105 afferent fibers, in pain physiology, 3–4 A␤-fibers, 482

627

index

628

Age. See also Children, pain in; Elderly, pain in palliative systemic antineoplastic therapy and, 402 perception of pain and, 444–445 Agitation, from opioid toxicity, 113 Agonist-antagonist analgesics, 172 buprenorphine, 172 butorphanol, 172 nalbuphine, 172 pentazocine, 172 Alcohol abuse among palliative care patients, 429 as coping mechanism, 120 Alfentanil, genetic variations of, 188 Allodynia, opioid-induced, 240 Alprazolam for depression, 472 for neuropathic pain, 278 Alternative/complementary medicine, in palliative care, 115 acupuncture as, for rehabilitation, 362 hypnosis as, for cancer pain, 347–348 yoga as, for cancer pain, 348–349, 372 Amantadine, for PMPS, 149 Ambulatory aids, for pain rehabilitation, 366 ␥ -Aminobutyric acid agonists, 294 for neuropathic pain, 498–499 Aminophenazone, 263 Analgesic interventions, acute pain from, 57 from opioid therapy, 57 from subcutaneous injections, 57 Analgesics. See Opioid analgesics Anesthesia use, surgically-induced pain syndromes and, 147–148 Aniline derivatives, 261–263 acetaminophen as, 261–263 Animal models, 15–18 of bone cancer pain, 24 neuropathic component of, 26 carrageenan-induced inflammation, 16 osteoarthritis, 16 for central pain, 17 development of, 17–18 of diabetic neuropathy, 17 formalin-induced inflammation, 15–16 of neuropathic pain, 16 of partial denervation of hindpaw, 16–17 CCI, 17 PSTL, 17 selective SNL, 17 Antiandrogens, 60 gynecomastia from, 71 osteoporosis from, 71 Anticancer therapies acute pain with, 54, 55 common categories of, 407 oral systemic agents, 407 Anticonvulsant analgesics, 276, 277–279 for neuropathic pain, 491 Antidepressants adjuvant analgesics as, 274, 275–276 heterocyclic, 470 for neuropathic pain, 274, 493–495

for pain management with depression, 466–467, 472 SNRIs, 468 SSRIs, 467–468 SNRIs, 275–276, 494–495 for depression, 468 side effects of, 276 SSRIs, 275–276, 494 for depression, 468 tricyclic, 275 as adjuvant analgesics, 275 for neuropathic pain, 275, 494 for pain management with depression, 469–470 Antiestrogens, 407 Anti-inflammatory drugs, for neuropathic pain, 499 Antineoplastic therapy, palliative, 399–415 Antipsychotics, for depression, 472 Antipyretic analgesics, 255–267 acidic, 258–261 NSAIDs, 259–261 biodistribution impact on, 256 for cancer pain, 257–258 COX enzymes in, 255–256, 257 COX-1 inhibitors, 255–256 COX-2 inhibitors, 255–256, 264–267 future developments for, 267 hyperalgesia from, 256–257 indications for, 258 mode of action of, 255–256 nonacidic, 261–264 aniline derivatives, 261–263 pyrazolinone derivatives, 263–264 NSAIDs and, 255–256 pharmacological data of, 260 physiochemical data of, 260 Anxiety disorders, assessment of, 120–121 Anxiolytics, for depression, 472 APPT. See Adolescent Pediatric Pain Tool Arachidonic acid, 5–6 COX enzyme pathways in, 5–6 lipoxygenase enzyme pathways in, 5 NSAID’s influence on conversion of, 5–6 Argentina, palliative care in, 614–617 ␤-Arrestin-2, 186 Arthralgia, 59 immunotherapy and, 60 Arthritides, 359 Artificial hydration and nutrition, 560–561 ASICs. See Acid-sensing ion channels Aspirin, 261 Assessment, of cancer pain, 53–54, 89–100 adjuvant analgesics and, 114 barriers to, 95–96 for cancer stages, 110–112 in cancer survivors, 156 characteristics in, 94–95 quality of, 95 in response to prior treatment, 95 spatial, 94 temporal patterns, 94–95 in children, 97, 130–142, 435 behavioral factors in, 131–132

through behaviors, 435 clinical interviews for, 133–134, 135 clinical practice recommendations in, 136–141 cognitive factors in, 131 developmental considerations in, 132–133 emotional factors in, 132 interviews for, 137 pain scores in, 135–136 psychometric considerations in, 135–136 QOL and, 141 quantitative pain scales in, 133–135 questionnaires for, 135–136, 137 through symbolic expression, 435 validity considerations in, 135–136 through verbal expression, 435 coping in, 117–118 in elderly, 98–100, 445–446 in hospice care, 538–539 inadequate, 89 innovative trends in, 100 with IVR, 100 through medical evaluation, 90 through neurological evaluation, 90 opioid analgesic use and, 113, 114 absorption routes for, 113 dose calculations for, 114 hyperalgesia from, 114 myths and misconceptions about, 113 tolerance levels in, 113–114 toxicity from, 113 of pain impact, 96–97 concurrent symptoms and, 97 with FACT, 96 on mood, 96 on QOL, 96 on social support, 96–97 physical function in, 115–116 psychiatric disorders and, 119–121 of adjustment, 120–121 with anxiety, 120–121 chemical coping and, 120 depression, 120–121 personality disorders, 121 somatization, 119–120 psychosocial distress in, 116–117, 119 coping in, 117–118 somatic symptoms in, 116 spiritual distress and, 118–119 suffering in, 117–118 QOL of patients and, 89 for quality assurance, 100 severity in, 90–94 intensity levels and, 91–94 with questionnaires, 91 scales of, 38, 90–91 spiritual distress in, 118–119 suffering in, 117–118 Assessment tools, 108–110 Atlantoaxial destruction, 62 Autonomy, principle of, 553–554 Axonal sprouting, nerve injury and, 7

index Baclofen, as nonopioid analgesic, 294 Barriers Questionnaire, 95, 605 Base-of-skull metastases, 64–65 clivus syndrome, 64 hypoglossal syndrome, 64 jugular foramen syndrome, 64 middle cranial fossa syndrome, 64 occipital condyle syndrome, 64 orbital syndrome, 64 parasellar syndrome, 64 sphenoid sinus syndrome, 64–65 Beck-Depression Inventory, 96 Behavioral assessment of pain, 105 Behavioral pain scales, for children, 137–139 Beneficence, principle of, 554 Benzodiazepines for depression, 472 for neuropathic pain, 499 for OIN, 243 Benzopyrones, 152 Biopsies. See Needle biopsies, acute pain from Bisphosphonates as adjuvant analgesics, 281–282 for bone pain, 520–523 clinical effects of, 520 osteoclasts and, 28 for osteonecrosis of the jaw, 523 palliative radiotherapy with, 388–389 Blinding, for clinical trials, 571–572 single-blind, 572 Bone fractures, from palliative radiotherapy, 382 for bone metastases, 385–387 pathologic, 382, 387 risk prediction with, 385–386, 387 Bone marrow biopsies, 56 Bone metabolism modulators, 499 Bone metastases clinical features of, 517–518 palliative radiotherapy for, 382–385, 388 complications of, 385–388 impending fractures with, 385–387 with neuropathic pain, 389–390 for pathological fractures, 382, 387 postoperative, 387–388 risk prediction with, 385–386, 387 pathophysiology of, 23–24, 515–517 extravasation and growth in, 515–516 marrow invasion in, 516 nociception in, 516–517 tumor cells in, 515 reirradiation of, 393–394 Bone pain, 515–528. See also Skeletal pain, pain management for acidosis in, 28–29 ASICs and, 29 TRPV1 and, 29 adjuvant analgesics for, 281, 282 bisphosphonates, 281–282 calcitonin, 282 radionuclides, 282 animal models of, 24 from chemotherapy toxicity, 59

629

CIBP, 15 clinical features of, 517–518 COX-1 inhibitors for, 5 COX-2 inhibitors for, 5–6 future research on, 528 incidence rates for, 23, 515 mechanisms of, 15 multifocal, 62 neuropathic component of, 26–28 in animal models, 26 DRG in, 26–28 treatment for, 28 pain syndromes with, 518 continuous pain, 518 incident pain, 518 mixed bone and neuropathic pain, 518 mixed bone and visceral pain, 518 pain transmission with, 24–25, 645 pathophysiology of, 23–24, 30, 515–517 for breakthrough pain, 23 extravasation and growth in, 515–516 marrow invasion in, 516 nociception in, 516–517 of osteoblasts, 25–26 tumor cells in, 515 of tumor growth, 24 for tumor metastases, 23–24 rehabilitation with, 526–527 skeletal remodeling in, 24–25, 28–29 of osteoclasts, 28 treatment of, 23, 518–519 bisphosphonates in, 520–523 calcitonin in, 523 chemotherapy in, 528 corticosteroids in, 520 hormonal therapy in, 528 kyphoplasty for, 527–528 NSAIDs in, 520 opioid analgesics in, 519, 520 with orthopedic surgery, 526–527 radioisotopes in, 524, 525–526 radiopharmaceuticals in, 525–526 radiotherapy in, 520–525 time to expected improvement after, 519 vertebroplasty in, 527–528 tumor-derived products in generation of, 29–30 endothelins, 29–30 kinins, 30 NGF, 30 WDR neurons in, 15 Bowel obstruction, adjuvant analgesics, 282–283 BPI. See Brief Pain Inventory Brachial plexopathy, 69 after postradiation therapy, 72–73 Bradykinin, 6 Bradykinin receptors, 480 Brain metastases, palliative radiotherapy for, 390 reirradiation of, 394 WBRT and, 390 Brainstem tractotomy, 333 Breakthrough pain, 23, 506–512

assessment of, 507–508 categories of, 506, 507 characteristics of, 112–113, 506 classification of, 506–507 with predictable events, 507 definition of, 316–317 treatment of, 508–512 basal analgesia optimization in, 508–510 future developments in, 512 through intrathecal administration routes, 510 with noninvasive fast-delivery systems, 510–511 with nonopioid analgesics, 509–510, 511–512 opioid dosing issues with, 511 of pain flares, 510 underdiagnosing of, 512 Breast cancer flare syndromes in, 60 hormonal therapy for, palliative, 411–412 lymphedema after, 151 Brief Pain Inventory (BPI), 91, 115, 404 Brown-S´equard syndrome, 152 Buccal administration route, for opioid analgesics, 173 Bupivacaine, 292–293 Buprenorphine (Subutex), 172 for elderly, 450 pharmacology of, 214–215 Bupropion, for neuropathic pain, 276 for depression, 469 Burning perineum syndrome, 74 from steroid therapy, 59 Butorphanol, 172 C7-T1 syndrome, 62 CAGE (cut down, annoy, guilt, eye opener) alcohol questionnaire, 244, 550 Calcitonin, for bone pain, 282, 523 CAM. See Confusion Assessment Method Cancer acute pain from, 54–55 organ obstruction/perforation, 55 pathological fractures, 55 rupture of hepatocellular carcinoma, 54–55 antipyretic analgesics for, 257–258 cognitive impairment and, 196 neuropathic pain from, 61 visceral pain syndromes and, 61 Cancer-induced bone pain (CIBP), 15. See also Bone pain Cancer pain in children, 434–435 palliative chemotherapy for, 434 in developing world, management of, 608–609 in elderly, 444–451 multidimensional concept of, 457 psychological factors for, 457–458 Cancer pain, neural blockade for, 315–326 classification of, 315–317

index

630

Cancer pain, neural blockade for (cont.) intensity of, 315 with intraspinal analgesia, 317–319 with epidural trial, 317–318 with permanent intrathecal therapy, 318–319 intraspinal neurolysis in, 325 with nerve blocks, 319 with epidural steroid injections, 319 with neurolytic blocks, 319–325 of celiac plexus, 319–320 of ganglion impar, 324–325 intraspinal, 325 summary for, 325 of superior hypogastric plexus, 323–324 pathophysiology of, 315–316 peripheral neurolysis in, 325 temporal aspects of, 316–317 Cancer Pain Role Model Program, 100 Cancer survivors Internet sites for, 157, 158 interpretation of term, 145 pain syndromes in, 145–158 assessment of pain in, 156 CIPN, 153–154 osteoporosis as, 154–155 radiation-induced, 152–153 research on, 145 surgically-induced, 147–149, 150–152 treatment-related, 146–147 underreporting of, factors for, 156, 157 QOL for, 146 supportive care for, 156–157 Cancer therapies, chronic pain syndromes with, 61–74 after hormonal therapy, 71 postchemotherapy, 70–71 postradiation, 72–74 brachial plexopathy after, 72–73 burning perineum syndrome, 74 enteritis from, 73 lumbar plexopathy after, 73 lymphedema pain, 73–74 myelopathy after, 73 osteoradionecrosis, 74 proctitis, 73 postsurgical, 71–72 for frozen shoulder, 72 after mastectomy, 71 pelvic floor pain, 72 phantom pain, post-radical neck dissection pain, 71 stump pain, 72 after thoracotomy, 71–72 Cannabinoid(s) as adjuvant analgesics, 281 for neuropathic pain, 500 receptors, 480 Capsaicin, 500–501 Capsulitis, 359–360 Carrageenan-induced inflammation, 16 osteoarthritis, 16 Carroll Depression Rating Scale (CDRS), 462

Catecholamines, 185 Catheter tip masses, after epidural opioid administration, 291 Cauda equina, chronic pain from, 62–64 CCI model. See Chronic constriction injury model CDP. See Complete decongestive physiotherapy CDRS. See Carroll Depression Rating Scale Celiac plexus block, 319–320 complications of, 320–321 efficacy of, 321–323 new perspectives of, 323 Central neuropathic pain, 479 Central pain models, 17 Cervical intraepithelial neoplasia (CIN), 56–57 Cervical plexopathy, 68 Chemical coping, assessment of, 120 Chemically dependent patients, 423–430 aberrant drug-taking behaviors for, 424–425 assessment of, 424 characteristics of, 424–425 differential diagnosis for, 424 prevalence of, 424–425 specific risk factors for, 425 clinical management of, 426–430 alcohol abuse during, 429 assessment in, 426–427 for inpatients, 428–429 for outpatients, 428 for patients in recovery, 429–430 for patients with advanced disease, 428 treatment planning in, 427 urine toxicology screening in, 427–428 definition of abuse and addiction for, 424 palliative care for, 425–426 patient selection for opioid therapy, 426 risk factors for, 425–426 prescription drug abuse among, 430 prevalence of, 423–425 Chemical pleurodesis, 57 Chemotherapy, 57–59 for bone pain, 528 chronic pain syndromes after, 70–71 bony complications of steroid therapy, 71 peripheral neuropathy, 70–71 Raynaud’s syndrome, 71 CIPN and, 153–154 with infusion techniques, 57–58 in hepatic artery, 57 in immunotherapy, 58 intraperitoneal, 58 intravenous, 57 intravesical, 58 neuropathic pain from, 485–487 palliative care for, 114–115 palliative radiotherapy with, 389 toxicity from, 58–59 acute limb ischemia from, 59 arthralgia from, 59 bone pain from, 59

5-Fluoroucil-induced angina from, 59 gynecomastia from, 59 headaches as result of, 58 mucositis from, 58 myalgia from, 59 palmar-planted erythrodysesthesia syndrome from, 59 perineal burning from, 59 peripheral neuropathy from, 58–59 Chemotherapy-induced peripheral neuropathy (CIPN), 153–154 clinical reviews for, 154, 155 incidence rates for, 153–154 nonpharmalogical/alternative therapies for, 154 treatment therapies for, 154 Chest wall pain, 65 Children, pain in, 433–441 from cancer, 434–435 neuropathic, 434 palliative chemotherapy for, 434 pelvic tumors, 434–435 diagnosis of pain in, 433–434 hydromorphone for, 441 management of pain in, 438–441 WHO pain ladder in, 438–439 measurement of pain in, 435–438 through color tool, 436 for QOL, 438 through VAS, 436 methadone for, 440–441 morphine for, 440 pain assessment in, 97, 130–142, 435 behavioral factors in, 131–132 through behaviors, 435 clinical interviews for, 133–134, 135 clinical practice recommendations in, 136–141 cognitive factors in, 131 developmental considerations in, 132–133 emotional factors in, 132 interviews for, 137 pain scores in, 135–136 psychometric considerations in, 135–136 QOL and, 141 quantitative pain scales in, 133–135 questionnaires for, 135–136, 137 through symbolic expression, 435 validity considerations in, 135–136 through verbal expression, 435 pharmacological pain management in, 439–441 dosage recommendations for, 440 nonopioid analgesics, 440–441 opioid analgesics, 440 physiology of pain in, 434 self-reporting by, of pain, 97, 139, 140–141 tramadol for, 441 Children’s Comprehensive Pain Questionnaire, 97, 137 Chlorpromazine, for OIN, 243

index Chronic constriction injury (CCI) model, 17 Chronic intestinal obstruction, 67 Chronic pain syndromes, 61–74 acute v., 53 from base-of-skull metastases, 64–65 in cancer survivors, treatment-related, 146–147 from cancer therapies, 61–74, 147 in chest wall, 65 ear pain, 65 from epidural spinal cord compression, 62–64 eye pain, 65 from hip metastases, 64 from multifocal bone pain, 62 in muscles, 65 from paraneoplastic syndromes, 65–66 from pelvic metastases, 64 in soft tissues, 65 tumor-related, 62, 66–70 vertebral, 62 CIBP. See Cancer-induced bone pain CIN. See Cervical intraepithelial neoplasia Cingulotomy, 333–334 CIPN. See Chemotherapy-induced peripheral neuropathy Cisplatin, neuropathic pain from, 485–486 Clinical trials, 568–579 analysis of, 574–576 clinically important differences in, 575 size of effect in, 574–575 statistical considerations in, 575–576 anatomy of, 568 blinding in, 571–572 double-blind, 572 single-blind, 572 control groups for, 570 no-treatment, 571 with placebos, 570 design issues for, 569 equivalence, 576–577 ethical issues in, 578–579 limitations of, 577–578 poor adherence to treatment as, 578 selective enrollment as, 577–578 underenrollment as, 577 multiple measures evidence in, 576 noninferiority, 576–577 outcome measurement in, 573–574 for palliative systemic antineoplastic therapy, 408–410 participant selection in, 571 publication of, 577 questions in, 568–569 randomization and, 569–570 sample size in, 572 side effects evaluation in, 576 Clivus syndrome, 64 Clodronate, for bone pain, 499, 520–521 Clonazepam, for neuropathic pain, 278 Clonidine morphine v., 293–294 for neuropathic pain, 294 as nonopioid analgesic, 293–294

631

for OIN, 243 side effects of, 294 Co-analgesics, adjuvant analgesics v., 272 Codeine for mild to moderate pain, 197 pharmacogenetics of, 187 Cognitive status in elderly, with cancer pain, 446–448 behavioral expressions of, 448 impairment of, from OIN, 238–240 pain assessment and, 105 palliative care and, 107 for delirium, 107 Cold, superficial, in pain rehabilitation, 363–364 Color Analogue Scale, 139 Color tool, pain measurement through, 436 Complementary/alternative medicine, in palliative care, 115 acupuncture as, for rehabilitation, 362 hypnosis as, for cancer pain, 347–348 massage as, for rehabilitation, 361–362 yoga as, for cancer pain, 348–349, 372 Complete decongestive physiotherapy (CDP), 360 Complex regional pain syndrome (CRPS), 487–488 Compression garments, 367 Compression, in pain rehabilitation, 367–368 Confusion Assessment Method (CAM), 446 Constipation, opioid-induced, 176 clinical presentations of, 234 in elderly, 450–451 management of, 233–235 with contact cathartics, 234 with laxatives, 234 with suppositories, 235 side effects of, 233–235 precipitating factors for, 234 Constipation, palliative care for, 108 Contact cathartics, for opioid-induced constipation, 234 Continuous infusion administration routes, for opioid analgesics, 173–174 Continuous pain, in bone pain, 518 Continuous subcutaneous infusion administration route, for opioids, 174 Controlled Substances Act of 1970, 585–586, 587 Coping, assessment of, 117–118 chemical, 120 self-efficacy in, 118 Coping skills training (CST), for cancer pain, 344–345 Cordotomy, 331–332 complications from, 331–332 indications for, 331–332 techniques for, 331 Corticosteroids, 273–274 adverse effects of, 273 for bone pain, 520 for neuropathic pain, 499 COX-1 inhibitors in antipyretic analgesics, 255–256

for bone pain, 5 prostaglandins and, 29 COX-2 inhibitors in antipyretic analgesics, 255–256, 264–267 for bone pain, 5–6 physiochemical and pharmacological data of, 265 prostaglandins and, 29 COX enzymes. See Cyclooxygenase enzymes Cranial neuralgias, 68 glossopharyngeal, 68 trigeminal, 68 Criterion-based diagnostic systems, for assessment of depression, 461 Cryotherapy, 363 CST. See Coping skills training, for cancer pain Cyclooxygenase (COX) enzymes, 5–6 in antipyretic analgesics, 255–256, 257 Cytokines, in neuropathic pain, 482 Data extraction, in epidemiology of cancer pain, 39 DEGR. See Douleur Enfant Gustave-Roussy, for pain measurement Delirium assessment of, 107 hyperactive, treatment for, 243 from OIN, 240 opioid analgesics for, 107 subtypes of, 107 Dependence, on opioids, 177–178 physical, 177–178 psychological, 177 Depression, with pain, 457–472 alternative clinical correlates for, 459 assessment of, 120–121, 459, 460–463 criterion-based diagnostic systems for, 461 diagnostic interviews for, 461–462 research methods for, 461 self-report measures for, 462–463 criteria for, 460 Endicott substitution criteria for, 461 with ESCC, 459 under hospice care, 549–551 inadequate pain management and, 464–465 major, differentiation from mood disorders, 459–460 management of, 465–472 antidepressants in, 466–467, 472 antipsychotics in, 472 with ECT, 460, 472 general principles of, 465 lithium carbonate in, 471–472 monamine oxidase inhibitors in, 471 pharmacological treatment in, 466 psychosocial treatment in, 465–466 psychostimulants in, 470–471 prevalence of, 458–459 with advanced disease, 458–459

index

632

Depression, with pain (cont.) psychological factors in pain experience and, 466 secondary, 460 suicide and, 464 Detoxification dose, 178 Developing world, palliative care in, 608–623 accessibility of, 613 cancer pain management and, 608–609 community support for, 623 current status of, 610–611 development measures for, 611–612 foreign funds for, 622 historical development of, 610, 612 in India, 617–622 in Latin America, 614–617 processes for, 612–613 public health strategies for, 622–623 technical assistance for, 622 Dexamethasone for neuropathic pain, 273 for pain flares, 382 Dextroamphetamine for depression, 470 for sedation management, 232 Dextromethorphan (Delsym) as adjuvant analgesic, 280–281 pharmacology of, 215–216 for postamputation pain, 151 Dextropropoxyphene, 199 DFIs. See Disease-free intervals Diabetic neuropathy models, 17 Diagnostic interventions, acute pain from, 56 lumbar puncture, headaches from, 56 needle biopsies, 56 Diagnostic Interview Schedule (DIS), 461 Diagnostic interviews, for assessment of depression, 461–462 Diamorphine, 214 Diclofenac, 259 Dihydrocodeine, for mild to moderate pain, 197–198 Dipyrone, 263–264 DIS. See Diagnostic Interview Schedule Disease-free intervals (DFIs), 402 Distress. See Psychological distress; Psychosocial distress, assessment of; Spiritual distress, assessment of DNR orders. See Do-not-resuscitate orders Do-not-resuscitate (DNR) orders, 560 Dorsal root entry zone (DREZ), 330–331 complications from, 330–331 indications for, 330–331 techniques for, 330 Dorsal root ganglia (DRG), 6–7 in bone cancer pain, 26–28 in peripheral ablative neurosurgical procedures, 329 Double-blind clinical trials, 572 Douleur Enfant Gustave-Roussy (DEGR), for pain measurement, 436–438 DREZ. See Dorsal root entry zone DRG. See Dorsal root ganglia

Drug use as coping mechanism, 120 prevalence rates of, in general populations, 423–424 Duloxetine, for neuropathic pain, 276 Early disease, prevalence of pain in, 45 Ear pain syndromes, 65 primary otalgia, 65 secondary otalgia, 65 Eastern and Central European Task Force for Palliative Care (ECEPT), 610 Eastern Cooperative Oncology Group (ECOG) scale, 115, 400–584 performance assessment methods of, 315, 316 EBRT. See External beam radiotherapy ECEPT. See Eastern and Central European Task Force for Palliative Care ECOG. See Eastern Cooperative Oncology Group scale ECS-CP. See Edmonton Classification Symptom for Cancer Pain ECT. See Electroconvulsive therapy Edmonton Classification Symptom for Cancer Pain (ECS-CP), 110, 112 Edmonton Functional Assessment Tool (EFAT), 115 Edmonton Injector, 548 Edmonton Symptom Assessment System (ESAS), 38, 97, 109, 463 EFAT. See Edmonton Functional Assessment Tool Elderly, pain in, 444–451 assessment tools for, 445–446 buprenorphine for, 450 cancer and aging and, 444 cognitive impairment in, 446–448 behavioral expressions of, 448 constipation in, 450–451 fentanyl for, 450 hydromorphone for, 449–450 meperidine for, 449 methadone for, 449 morphine for, 449 multidisciplinary evaluation of, 444 neuropathic pain in, 450 nonpharmacological management for, 451 oxycodone for, 449 oxymorphone for, 450 pain assessment in, 98–100, 445–446 pain management for, 448–451 perception of pain and aging in, 444–445 pharmacodynamics and, 445 pharmacokinetics and, 445 pharmacological management for, 448–451 for neuropathic pain, 450 with nonopioid analgesics, 448 with opioid analgesics, 448–451 side effects of, 450 respiratory depression in, 451 tramadol for, 449 undertreatment of, 444

Electroacupuncture, 362 Electroconvulsive therapy (ECT), for depression, 460, 472 Emotional suffering, during hospice care, 548–549 Endicott substitution criteria, for depression, 461 Endocrine system, opioids’ influence on, 245–246 after spinal administration, 291 End-of-dose failure, 316 End-of-life care depression and, 466 emotional suffering during, 548–549 in hospices, 539, 540–542 medication diversion and, 541–542 Endothelins, 29–30 Energy conservation, in pain rehabilitation, 368 Enteritis, radiation-induced, 60, 73, 153 EORTC questionnaire. See European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire Epidemiology of cancer pain, 37–48 assessment issues in, 37–39 acute v. chronic, 38 classification system in, 39 within health care settings, 37–38 severity scale as, 38 in studies, 38 definitions in, 37 future challenges for, 47–48 literature identification and, 39 prevalence and, 39–42, 47 in advanced cancer, 45 at all stages, 45 data extraction and, 39 in early disease, 45 for high-risk groups, 47 inclusion/exclusion criteria and, 39 by primary tumor site, 45, 46 severity and, 45–47 with terminal disease, 43–44 Epidural administration routes delivery systems for, 299–303 with catheters, 300–301 complications from, 301 with infusion pumps, 301 mechanical issues with, 302–303 for nerve blocks, 319 for nonopioids, 293–296 for opioids, 174, 288–291 catheter tip masses as side effect of, 291 efficacy of, 288–289 noncardial peripheral edema as side effect, 291 pharmacodynamics of, 288–289 pharmacokinetics of, 288 Epidural fibrosis, 302 Epidural hematomas, from spinal delivery systems, 302

index Epidural spinal cord compression (ESCC), 62–64 depression with, 459 imaging of, 63 neuropathic pain and, 484 presentation of, 63 treatment for, 63–64 with radiotherapy, 63–64 with steroid therapy, 63 Epworth Sleepiness Scale (ESS), 231 Equivalence clinical trials, 576–577 Equivalence trials, 576–577 ESAS. See Edmonton Symptom Assessment System ESCC. See Epidural spinal cord compression ESS. See Epworth Sleepiness Scale Ethical issues, 553–563 access to palliative care, 562 artificial hydration and nutrition, 560–561 clinical decision making and, 555–558 advance directives and, 557–558 futility and, 555–556 goals of care in, 555 for incompetent patients, 557 informed consent and, 556–557 DNR orders, 560 ethical principles and, 553–555 euthanasia and, 559, 561–562 pain and suffering and, 558 euthanasia for, 559 terminal sedation for, 558–559 physician-assisted suicide, 561–562 in research, 563 SUPPORT and, 553 ventilator withdrawal, 561 withholding/withdrawing therapy, 559–560 Ethnicity, pharmacogenetics of pain and, 188–189 Etidronate, for bone pain, 499 European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire, 38 Euthanasia physician-assisted-suicide as, 561–562 PST and, 559 External beam radiotherapy (EBRT), 379 Eye pain syndromes, 65 Faces Pain Rating Scale, 141 FACES Pain Scale, 141 Faces Pain Scale, 100 Facial Affective Scale, 141 Facial scales, for pain in children, 141 FACT. See Functional Assessment of Cancer Therapy Family caregivers, 597–605 adaptational tasks at different points in disease trajectory and, 601–602 breaking bad news to/for, 406 challenges of, by demographic group, 604–605 hospice care reports by, 544 intervention strategies for, 602–604

633

palliative systemic antineoplastic therapy and, 405–406 physical demands on, 600 psychological well-being of, 600 QOL for, 600, 601 roles and responsibilities of, 598, 600 FDA. See Food and Drug Administration Fentanyl, 171 for elderly, 450 FBTs, 214 genetic variations for, 188 OTFC, 213–214 pharmacology of, 212–214 spinal administration of, 290 transdermal administration for, 172–173 Fentanyl buccal tablets (FTBs), 214 Fentora (Cephalon), 173 5-Fluoroucil-induced angina, 59 Flare syndromes in breast cancer, 60 in prostate cancer, 59–60 Fluoxetine, 468 Food and Drug Administration (FDA), 408–409 Formalin-induced inflammation, 15–16 Frozen shoulder syndrome, 72 FTBs. See Fentanyl buccal tablets Functional Assessment of Cancer Therapy (FACT), 96 Futile treatment, 555–556 GABAergic drugs, for neuropathic pain, 279 Gabapentin for neuropathic pain, 7–8, 276–278, 491 for PMPS, 149 for surgically-induced pain syndromes, 148 GABA receptors, as inhibitory transmission system, 13 Ganglion impar block, 324–325 complications of, 324 efficacy of, 324–325 Glossopharyngeal neuralgia, 68 Guided imagery as psychological intervention for cancer pain, 348 with relaxation, in rehabilitation, 372 Gynecomastia from antiandrogen therapy, 71 from chemotherapy toxicity, 59 paraneoplastic, 66 HADS. See Hospital Anxiety and Depression Scale Hallucinosis, from OIN, 240 Haloperidol, for hyperactive delirium, 243 Harrison Act of 1914, 585–586 Headaches in cancer survivors, 153 from chemotherapy toxicity, 58 chronic pain syndromes from, 65 from lumbar puncture, 56 SMART syndrome and, 153 Health-related quality of life (HRQOL), 105

Heat, superficial, in pain rehabilitation, 363–364 Hepatic artery infusion pain, 57 Hepatic distention syndrome, 66 Hepatocellular cancer, acute pain from, 54–55 Herpes zoster, neuropathic pain and, 489–490 PHN and, 489–490 Herpetic neuralgia, acute pain from, 55 Heterocyclic antidepressants, 470 High-risk groups, for pain, 47 Hip metastases, 64 Hormonal therapy acute pain from, 59–60 in breast cancer, 60 in prostate cancer, 59–60 for bone pain, 528 chronic pain with, 71 palliative, 411–413 for breast cancer, 411–412 for prostate cancer, 412–413 toxicity of, 409, 413 Horner’s syndrome, 69 Hospice care, 535–551 addiction issues and, 539–540, 550 analgesic trials in, 544–545 barriers to referral for, 537–538 caregiver reports in, 544 case studies for, 537, 540 cognitive awareness in, 539 cultural and psychosocial issues and, 540 depression and, treatment for, 549–551 development of, 535–537 emotional suffering and, treatment of, 548–549 end-of-life issues with, 539 evaluation of pain in patients, 538–539 financial reimbursement for, 536–537 levels of care under, 536 medication administration for dying patients in, 540–542 medication administration routes in, 545–548 intramuscular, 545 intravenous, 545 rectal, 545 subcutaneous, 545, 546–548 medication diversion and, 541–542 nonverbal patient evaluation in, 542–544 overmedication in, 540 pain assessment in, 538–539 intensity scales for, 538 statistics for cancer patients in, 538 treatment barriers in, 539–540 Hospital Anxiety and Depression Scale (HADS), 462 HRQOL. See Health-related quality of life Hydrogen ions, inflammatory pain and, 6 Hydromorphone, 170 for children, 441 for elderly, 449–450 oral administration of, 209–210

index

634

Hydromorphone (cont.) pharmacology of, 209–210 spinal administration of, 289 Hydrotherapy, for pain rehabilitation, 364–365 Hyoscine hydrobromide, for bowel obstruction pain, 283 Hyperactive delirium, 243 Hyperalgesia, opioid-induced, 114 from antipyretic analgesics, 256–257 from OIN, 240–241 after spinal administration, 290–291 Hypertonia, rehabilitation for, 360 Hypertrophic pulmonary osteoarthropathy, 66 Hypnosis, as psychological intervention for cancer pain, 347–348 Hypoglossal syndrome, 64 Hypogonadism, opioid-influenced, 245 Hypophysectomy, 333 Ibandronate, for bone pain, 281, 522 IDDS. See Intrathecal drug delivery system Immune system opioids’ influence on, 245 PMNs in, 245 Immunotherapy, acute pain with, 58, 60 for arthralgia, 60 with growth factors, 60 for myalgia, 60 Incident pain, 518 characteristics of, 112 Incompetent patients, clinical decision making for, 557 India, palliative care in, 617–622 Infections acute pain from, 55 herpetic neuralgia, 55 from spinal delivery systems, 301 Inflammatory pain, 5–6 arachidonic acid and, 5–6 COX enzyme pathways in, 5–6 lipoxygenase enzyme pathways in, 5 NSAID’s influence on conversion of, 5–6 bradykinin and, 6 carrageenan-induced, 16 from osteoarthritis, 16 hydrogen ions and, 6 mast cells and, 6 serotonin and, 6 sumatriptan and, 6 Informed consent, 556–557 Interactive voice response (IVR), in pain assessment, 100 Interleukins, 186 Intracerebroventricular opioids, 291–292 Intracranial ablative neurosurgical procedures, 333–334 brainstem tractotomy, 333 cingulotomy, 333–334 hypophysectomy, 333 thalamotomy, 333 Intractable pain treatment, 590

Intraperitoneal chemotherapy, acute pain from, 58 Intraspinal analgesia, with cancer pain, 317–319 with epidural trial, 317–318 with neuropathic pain, 496–497 with permanent intrathecal therapy, 318–319 Intraspinal neurolysis, 325 Intrathecal administration routes for breakthrough pain, 510 concentration and dosage levels in, 298, 299, 300 for neurosurgical procedures, 334–337 complications from, 336–337 for pain treatment, 334–337 pump technique in, 335 for opioids, 174 Intrathecal drug delivery system (IDDS), 297 Intravenous bolus administration routes, for opioid analgesics, 173–174 in hospice care, 545 Intravenous infusion pain, 57 Intravesical chemotherapy, acute pain from, 58 Ion channels, in neuropathic pain, 480–482 Ionsys, for analgesics, 173 IVR. See Interactive voice response, in pain assessment Jugular foramen syndrome, 64 Justice, principle of, 554 Karnofsky Performance Scale, 115 Karnofsky Performance Status, 239, 400 Ketamine as adjuvant analgesic, 280 for neuropathic pain, 498 Ketobemidone, 12 Kinins, 30 Kyphoplasty, for bone pain, 527–528 Lamotrigine, for neuropathic pain, 278, 492 Laxatives, for opioid-induced constipation, 234 lubricant, 234 Legal and regulatory issues, 583–592 development of, 583–585 federal laws and regulations, 585–592 Controlled Substances Act, 585–586, 587 Harrison Act, 585–586 international drug control and, 585 origins of opioid control, 585–586 treatment programs under, 588 state laws and regulations, 588–592 double effect myth codification under, 591 intractable pain treatment laws, 590 liability of health care providers under, 591–592 medical board guidelines under, 590–591

medical education policies for pain and palliative care, 591 for medical marijuana, 589 for PMPs, 589–590 for state pain commissions, 590 Leptomeningeal metastases, 67–68 Levetiracetam, for neuropathic pain, 279 Levorphanol, 171 pharmacology of, 215 Liability, of health care providers, under state law, 591–592 Lidocaine as adjuvant analgesic, 279–280 for neuropathic pain, 500 Ligamentous and tendinous injuries, rehabilitation for, 359–360 Limb ischemia, from chemotherapy toxicity, 59 Lipoxygenase enzymes, 5 Lithium carbonate, 471–472 Liver, palliative radiotherapy for, 391 Local anesthetic agents, 292–293 bupivacaine, 292–293 for neuropathic pain, 495–496 ropivacaine, 293 toxicity of, 292 Lubricant laxatives, for opioid-induced constipation, 234 Lumbar puncture, headaches from, 56 Lumbosacral plexopathy, 69–70 after postradiation therapy, 73 symptoms of, 69 Lungs, palliative radiotherapy for, 390–391 Lymphedema pain, 73–74 rehabilitation for, 360 with CDP, 360 Malignant bone pain. See Bone pain Malignant painful plexopathy, 68–70 cervical, 68 lumbosacral, 69–70 symptoms of, 69 Malignant painful radiculopathy, 68 Malignant perineal pain, 67 Massage, in pain rehabilitation, 361–362 with ice, 363–364 Mast cells, 6 Mastectomy, postsurgical pain after, 71 M.D. Anderson Symptom Inventory (MDASI), 97 MDASI. See M.D. Anderson Symptom Inventory Medical board guidelines, under state law, 590–591 Medical education policies for pain and palliative care, under state law, 591 Medical marijuana, state laws for, 589 Meditation, in pain rehabilitation, 373 Melanocortin, 185–186 Memorial Delirium Assessment Scale, 241, 446 Memorial Pain Assessment Card (MPAC), 91 Memorial Symptom Assessment Scale (MSAS), 38, 109

index Meperidine (pethidine), 171–172 for elderly, 449 spinal administration for, 290 Metastatic disease. See also Base-of-skull metastases impact of prior therapy and, 401–402 DFIs and, 402 palliative systemic antineoplastic therapy and, 401, 402 Methadone, 12, 170–171 for children, 440–441 for elderly, 449 equianalgesic potency of, with other opioids, 207–208 genetic variations of, 188 limitations of, 170–171 for neuropathic pain, 493 NMDA receptors in, 170 for OIN management, 242 oral, 205–209 pharmacokinetics of, 206–207 rectal administration of, 206 spinal administration for, 290 switching to, 208–209 Methadone maintenance treatment program (MMTP), 493 Methylnatrexone for opioid-induced constipation, 235 for opioid-induced nausea and vomiting, 236 Methylphenidate for depression, 470 for sedation management, 232 Mexiletine, as adjuvant analgesic, 279 Midazolam as nonopioid analgesic, 294 for OIN, 243 Middle cranial fossa syndrome, 64 Midline retroperitoneal syndrome, 66–67 pancreatic cancer and, 66–67 Milnacipran, for neuropathic pain, 276 Mind-body techniques, in pain rehabilitation, 372 Mini Mental State Examination (MMSE), 107, 241, 446 Mirtazapine, for neuropathic pain, 276 for depression, 469 MMSE. See Mini Mental State Examination MMTP. See Methadone maintenance treatment program Modafinil, for depression, 471 Monamine oxidase inhibitors, 471 RIMAs, 471 Monoamine systems, in pain transmission, 13 Monoclonal antibody therapy, 413–414 toxicities with, 414 Mononeuropathy, tumor-related, 70 Mood, assessment of, 96 Mood disorders, differentiation from major depression, 459–460 Morphine, 12–14 administration routes for, 203, 204 in children, 440 clonidine v., 293–294

635

dosing for, 201 for elderly, 449 genetic variations for, 187–188 for moderate to severe pain, 199–205 for OIN management, 241–242 oral, 199–202 oxycodone v., 202 pharmacokinetics of, 168 pharmacology of, 168–172 rectal administration of, 202–203, 204 side effects of, 200 spinal actions of, 12 spinal administration of, 202–203, 289 subcutaneous administration of, 202–203 MPAC. See Memorial Pain Assessment Card MPI. See Multidimensional Pain Inventory MSAS. See Memorial Symptom Assessment Scale Mucositis, 58 epidemiology of, 58 grading systems for, 58 pathophysiology of, 58 from radiotherapy, 60 Multidimensional Pain Inventory (MPI), 97 Multifocal bone pain, 62 Multifocal myoclonus, opioid-induced, 177 Multimodal pain therapy, 147 Muscles, chronic pain in, 65 Music, in pain rehabilitation, 372 Myalgia, 59 immunotherapy and, 60 Myelopathy, postradiation pain from, 73 Myelotomy, 332–333 complications from, 332–333 indications for, 332–333 technique for, 332 Myoclonus, from OIN, 240 Nalbuphine, 172 Naloxone for OIN, 243 for opioid-induced constipation, 235 for opioid-induced respiratory depression, 237 National Comprehensive Cancer Network (NCCN), 154–155 Nausea and vomiting, opioid-induced, 176, 235–236 management of, 236 after spinal administration, 290 NCCN. See National Comprehensive Cancer Network Needle biopsies, acute pain from, 56 bone marrow, 56 for prostate, 56 Neostigmine, as nonopioid analgesic, 296 Nerve blocks, for cancer pain, 319 with epidural steroid injections, 319 Nerve damage Brown-S´equard syndrome, 152 NMDA receptor activation and, 8–10 opioid effectiveness after, 13 from radiotherapy, 152–153 Nerve growth factor (NGF), 30

Nerve injury. See Neuropathic pain Neural blockade, for cancer pain, 315–326 classification of, 315–317 intensity of, 315 with intraspinal analgesia, 317–319 with nerve blocks, 319 with neurolytic blocks, 319–325 pathophysiology of, 315–316 peripheral neurolysis in, 325 temporal aspects of, 316–317 Neuraxial analgesia, 287–303 with combinations of agents, 297–298 with IDDS, 297 with intracerebroventricular opioids, 291–292 with local anesthetic agents, 292–293 toxicity of, 292 with nonspinal opioids, 293–296 ␥ -Aminobutyric acid agonists, 294 NMDA agonists as, 294–295 spinal administration of, 293–296 spinal delivery systems for, 299–303 with catheters, 300–301 complications from, 301 with infusion pumps, 301 mechanical issues with, 302–303 with spinal opioids, 288–291 efficacy of, 288–289 pharmacodynamics of, 288–289 side effects of, 290–291 Neuroleptics, for neuropathic pain, 500 Neurolytic blocks, for cancer pain, 319–325 of celiac plexus, 319–320 complications of, 320–321 efficacy of, 321–323 new perspectives of, 323 of ganglion impar, 324–325 complications of, 324 efficacy of, 324–325 neurolysis summary for, 325 of superior hypogastric plexus, 323–324 complications of, 323 efficacy of, 323–324 for visceral pain, 319 Neuropathic pain, 6–7, 54, 478–501 adjuvant analgesics for, 274, 497–499 animal models of, 16 antidepressants for, 274, 493–495 axonal sprouting with, 7 in bone pain, 518 from cancer, 61 central, 479 characteristics of, 112 from chemotherapy, 485–487 toxicity from, 58–59 in children, 434 CIPN and, 153–154 classification of, 478–479 clinical overview of, 479 CRPS and, 487–488 definition of, 479 development of, 6–7 diagnosis of, 482–483 DRG and, 6–7

index

636

Neuropathic pain (cont.) in elderly, 450 herpes zoster and, 489–490 PHN and, 489–490 malignant plexopathy and, 484 management of, 490–501 with adjuvant analgesics, 274, 497–499 with anticonvulsants, 491 with antidepressants, 274, 493–495 with anti-inflammatory drugs, 499 with bone metabolism modulators, 499 with cannabinoids, 500 with intraspinal therapy, 496–497 with local anesthetics, 495–496 with neuroleptics, 500 with nonopioids, 294, 497–499 with opioids, 12–13, 492–493 with rehabilitation, 358 with topical analgesics, 500–501 neohumoral changes secondary to neural injury and, 482 cytokines in, 482 ion channel upregulation in, 482 neurotrophic factors in, 482 pathologic changes in cell bodies in, 482 sensory neuron signaling in, 482 neurosurgical procedures and, 329 nociceptive sensory information for, 8 nonopioids for, 294, 497–499 opioids for, 12–13, 492–493 palliative radiotherapy for, with bone metastases, 389–390 paraneoplastic syndromes and, 488 pathophysiology of, 479–482 ion channels, 480–482 receptors in, 480 peripheral, 479 disease-related, 484 phantom pain and, 488–489 physical examination for, 482–483 post-cerebral infarct pain and, 489 postmastectomy pain syndrome and, 484 postradiation plexopathy and, 484 QOL and, 483–484 from radiotherapy, 152–153 secondary syndromes with, 485 somatosensory abnormalities with, 483 spinal cord compression and, 484 from spinal delivery systems, 302 treatment-induced, 146–147 tricyclic antidepressants for, 275 tumor-related syndromes, 67–70 cranial neuralgias, 68 leptomeningeal metastases, 67–68 malignant painful plexopathy, 68–70 malignant painful radiculopathy, 68 mononeuropathy, 70 paraneoplastic painful peripheral neuropathy, 70 paraneoplastic sensory neuropathy, 70 venlafaxine for, 276 Neurosurgical procedures, 329–337 ablative, 329–334 cordotomy, 331–332

of DREZ, 330–331 intracranial, 333–334 myelotomy, 332–333 peripheral, 329–330 intrathecal drug delivery with, 334–337 complications from, 336–337 for pain treatment, 334–337 pump technique in, 335 neuropathic pain and, 329 nociceptive pain and, 329 NGF. See Nerve growth factor NMDA agonists, as nonopioid agonists, 294–295 NMDA receptors activation of, nerve damage and, 8–10 as adjuvant analgesics, 280–281 functional modulation of, 8–9 in methadone, 170 OIN and, 240–241 in opioid analgesics, 114 structure of, 8 Nociception, 3–18 in bone metastases, 516–517 mechanisms of pain and, 3–4 Nociceptive pain, 54, 61 neurosurgical procedures and, 329 Nociceptive-specific (NS) neurons, 4 Noncardiogenic peripheral edema, opioid-induced, from epidural, 291 Noncardiogenic pulmonary edema, opioid-induced, 238 management of, 238 with adjuvant analgesics, 238 Noninferiority clinical trials, 576–577 Nonmaleficence, principle of, 554 Nonopioid analgesics. See also Antipyretic analgesics ␥ -Aminobutyric acid agonists, 294 for breakthrough pain, 509–510, 511–512 for elderly, 448 for neuropathic pain, 294, 497–499 NMDA agonists as, 294–295 spinal administration of, 293–296 Nonopioid signaling systems, 185–186 catecholamines in, 185 interleukins in, 186 melanocortin in, 185–186 Nonsteroidal anti-inflammatory drugs (NSAIDs) antipyretic analgesics and, 255–256 arachidonic acid conversion and, 5–6 aspirin as, 261 for bone pain, 520 COX-1 inhibitors and, 5 COX-2 inhibitors and, 5–6 with high potency and long elimination half-life, 261 with high potency and short elimination half-life, 259 with intermediate potency and intermediate elimination half-life, 259–261 with low potency and short elimination half-life, 259

sedation from, 231 No-treatment-controlled trials, 571 NRS. See Numerical rating scales NSAIDs. See Nonsteroidal anti-inflammatory drugs NS neurons. See Nociceptive-specific neurons Numerical rating scales (NRS), 91, 139 Occipital condyle syndrome, 64 Octreotide, for bowel obstruction pain, 283 Odontoid fractures, 62 OIH. See Opioid-induced hyperalgesia OIN. See Opioid-induced neurotoxicity OPG. See Osteoprotegerin Opioid analgesics, 169–170 acute pain from, 57 OIH and, 57, 195 addiction to, 177–178 adjuvant analgesics with, 114 ␣2 -Adrenergic agonists, 279 anticonvulsant, 276–279 antidepressants, 274–276 for bone pain, 281–282 for bowel obstruction, 282–283 for cancer-related neuropathic pain, 274 cannabinoids, 281 classification of, 272–283 co-analgesic v., 272 corticosteroids, 273–274 definition of, 272 GABAergic drugs, 279 multipurpose, 273 NMDA receptor agonists, 280–281 for noncardiogenic pulmonary edema, 238 pain assessment with, 114 administration routes for, 172–175 buccal, 173 changing of, 174–175 continuous infusion, 173–174 continuous subcutaneous infusion, 174 epidural, 174 intramuscular, 173 intrathecal, 174 intravenous bolus, 173–174 oral, 172, 195 patient-controlled, 173–174 rectal, 174 transdermal, 172–173 transmucosal, 173 adverse effects of, 175–177 constipation as, 176 multifocal myoclonus as, 177 nausea as, 176 OIH as, 177 respiratory depression, 175–176 sedation as, 176 tolerance development as, 177 urinary retention as, 176–177 vomiting as, 176 agonist-antagonist analgesics, 172 buprenorphine, 172 butorphanol, 172

index nalbuphine, 172 pentazocine, 172 for bone pain, 519, 520 cancer pain assessment with, 113, 114 absorption routes for, 113 dose calculations for, 114 hyperalgesia from, 114 myths and misconceptions about, 113 tolerance levels in, 113–114 toxicity from, 113 central inhibitory systems and, influence on, 10–14 for children, 439–440, 441 classification of, 167–168 cloning of, 10–12 coadministration of, 215–216 codeine, 197 for delirium, 107 dependence on, 177–178 physical, 177–178 psychological, 177 drug combinations with, for enhancement of, 175 for elderly, 448–451 tolerance levels for, 448–449 federal laws and regulations for, 585–586 hypogonadism from, 245 individualized dosage for, 167 isolation of, 10–12 for mild to moderate pain, 196–199 for moderate to severe pain, 199–205 morphine-like agonists, 168–172 fentanyl, 171 hydromorphone, 170 levorphanol, 171 meperidine, 171–172 methadone, 12, 170–171 oxycodone, 171 oxymorphone, 171 pharmacokinetics of, 168 pharmacology of, 168–172 after nerve damage, 13 for neuropathic pain, 12–13, 492–493 NMDA receptors and, 114 opioid receptors and, 167–168 pharmacokinetics of, 172 pharmacology of, 195–218 intraindividual variability with, 195 plasma half-life values for, 171 receptor subtypes, 10–11, 12 adenosine receptor system, 13 GABA, 13 monoamine systems, 13 response to intraindividual variation with, 195 schedule for, 175 sexual dysfunction from, 245 side effects of, 230, 246 constipation as, 233–235 on endocrine system, 245–246 on immune system, 245 nausea and vomiting as, 235–236 noncardiogenic pulmonary edema as, 238 OIN as, 238–245

637

pruritus as, 237 respiratory depression as, 236–237 sedation as, 230–233 urinary retention as, 237–238 at supraspinal sites, 13 switching of, in treatment therapies, 196, 210, 216–217 Opioid-induced hyperalgesia (OIH), 57, 177, 195 pharmacogenetics and, 186 Opioid-induced neurotoxicity (OIN), 238–245 cognitive failure from, 238–240 delirium from, 240 hallucinosis from, 240 hyperalgesia from, 240–241 management of, 241, 243, 244–245 with circadian modulation, 242 with dose reduction, 242 with hydration, 242–243 with opioid rotation, 241–242 myoclonus from, 240 NMDA receptors and, 240–241 prevention of, 243–244, 245 of dose escalation, 243 of psychological distress, 243–244 of substance abuse, 244 risk factors for, 238 sedation and, 238 seizures from, 240 tolerance levels influenced by, 240–241 Opioid metabolism, in pharmacogenetics, 182–183 Opioid receptors, 10–12 adenosine, 13 GABA, 13 monoamine systems, 13 opioid analgesics and, 167–168 pharmacogenetics for, 183–184 Opioid signaling systems, 186 ␤-Arrestin-2, 186 STAT6, 186 Opioid transport, pharmacogenetics for, 184–185 Oral administration route, for opioid analgesics, 172, 195 for hydromorphone, 209–210 for oxycodone, 210–211 Oral methadone, 205–209 Oral morphine, 199–202 adverse effects of, 200 Oral transmucosal fentanyl citrate (OTFC), 213–214 Orbital syndrome, 64 Organ obstruction or perforation, acute pain from, 55 Orthopedic surgery, for bone pain, 526–527 Orthoses, for pain rehabilitation, 365–366 Osteoblasts, 25–26 Osteoclasts, 28 bisphosphonates and, 28 OPG and, 28–29 Osteonecrosis of the jaw, 523 Osteoporosis, 154–155

from antiandrogen therapy, 71 pain management for, 357–358 Osteoprotegerin (OPG), 28–29 Osteoradionecrosis, 74 Otalgia. See Primary otalgia; Secondary otalgia OTFC. See Oral transmucosal fentanyl citrate Oucher Scale, 141 Outcome measurement, for clinical trials, 573–574 Oxaliplatin, neuropathic pain from, 485, 486–487 Oxcarbazepine, for neuropathic pain, 278 Oxycodone (OxyContin), 171 administration studies with, 211 for elderly, 449 genetic variations for, 188 morphine v., 202 oral administration of, 210–211 pharmacology of, 210–212 Oxymorphone, 171 for elderly, 450 pharmacology of, 215 Oxytrex, 216 Paclitaxel for CIPN, 154 neuropathic pain from, 486 Pain, 3–4. See also Cancer pain, neural blockade for; Inflammatory pain; Neuropathic pain; Opioid analgesics anatomy and physiology of, 3–4 afferent fibers in, 3–4 spinal neurons in, 4 animal models of, 15–18 for carrageenan-induced inflammation, 16 for central pain, 17 development of, 17–18 of diabetic neuropathy, 17 for formalin-induced inflammation, 15–16 of neuropathic pain, 16 of partial denervation of hindpaw, 16–17 bone cancer and, mechanisms of, 15 CIBP, 15 mechanisms of, 15 WDR neurons in, 15 central inhibitory systems of, 10–12 opioids’ influence on, 10–14 central mechanisms of, 7–8 definition of, 37 dimensions of, 105 excitatory transmission of, 8–10 NMDA receptors in, 8–10 as experience, steps in, 105 inflammatory, 5–6 arachidonic acid and, 5–6 bradykinin and, 6 hydrogen ions and, 6 mast cells and, 6 serotonin and, 6 sumatriptan and, 6

index

638

Pain (cont.) intrathecal drug delivery for, during neurosurgical procedures, 334–337 multidimensional concept of, 457 neuropathic, 6–7 axonal sprouting with, 7 development of, 6–7 DRG and, 6–7 gabapentin for, 7–8 nociceptive sensory information for, 8 opioids for, 12–13 pregabalin for, 7–8 peripheral mechanisms of, 4–7 events in, 4–5 pharmacogenetic considerations for, 180–189, 190 pharmacology of transmission of, 4–15 psychological factors for, 457–458 psychological interventions for, 341–352 challenges of, 343–344 with CST, 344–345 with guided imagery, 348 with hypnosis, 347–348 partner-assisted, 345–347 skills rehearsal for, 351 supervision and treatment monitoring in, 350 therapist training for, 349–350 treatment fidelity in, 350 with yoga, 348–349 respiratory depression and, 237 visceral mechanisms of, 14–15 serotonins and, 15 symptoms in, 15 transmission of, 14 Pain and suffering, of patients, 558 Pain assessment, 53–54, 89–100 barriers to, 95–96 for cancer stages, 110–112 in cancer survivors, 156 characteristics in, 94–95 quality of, 95 in response to prior treatment, 95 spatial, 94 temporal patterns, 94–95 in children, 97, 130–142, 435 behavioral factors in, 131–132 through behaviors, 435 clinical interviews for, 133–134, 135 clinical practice recommendations in, 136–141 cognitive factors in, 131 developmental considerations in, 132–133 emotional factors in, 132 interviews for, 137 pain scores in, 135–136 psychometric considerations in, 135–136 QOL and, 141 quantitative pain scales in, 133–135 questionnaires for, 135–136, 137 through symbolic expression, 435 validity considerations in, 135–136

through verbal expression, 435 coping in, 117–118 in elderly, 98–100, 445–446 in hospice care, 538–539 inadequate, 89 innovative trends in, 100 with IVR, 100 through medical evaluation, 90 through neurological evaluation, 90 opioid analgesic use and, 113, 114 absorption routes for, 113 dose calculations for, 114 hyperalgesia from, 114 myths and misconceptions about, 113 tolerance levels in, 113–114 toxicity from, 113 of pain impact, 96–97 concurrent symptoms and, 97 with FACT, 96 on mood, 96 on QOL, 96 on social support, 96–97 physical function in, 115–116 psychiatric disorders and, 119–121 in adjustment, 120–121 of adjustment, 120–121 with anxiety, 120–121 chemical coping and, 120 depression, 120–121 personality disorders, 121 somatization, 119–120 psychosocial distress in, 116–117, 119 somatic symptoms in, 116 spiritual distress and, 118–119 suffering in, 117–118 QOL of patients and, 89 for quality assurance, 100 severity in, 90–94 intensity levels and, 91–94 with questionnaires, 91 scales of, 38, 90–91 spiritual distress in, 117, 118–119 suffering in, 117–118 Pain flares, 382 breakthrough pain and, 510 dexamethasone for, 382 Pain impact, assessment of, 96–97 concurrent symptoms and, 97 with FACT, 96 on mood, 96 on QOL, 96 on social support, 96–97 Pain management barriers to, 95–96 prior, response to, 95 rehabilitation and, 357 from muscular imbalance, 359 of neuropathic pain, 358 from shortened muscles, 359 of skeletal pain, 357–358 of soft tissue, 358 with TENS, 357 of trigger points, 358–359 Pain mechanisms

in bone cancer, 15 of breakthrough pain, 112–113 of incident pain, 112 of neuropathic pain, 112 nociception and, 3–4 of visceral pain, 14–15 Pain questionnaires, 91 for children, 135–136, 137 Pain scores, in children, 135–136 behavioral, 137–139 self-report scales and, 139–141 facial scales, 141 NRS, 139 under VAS, 135 Pain severity assessment of cancer pain and, 90–94 intensity levels and, 91–94 treatment guidelines as result of, 94 from questionnaires, 91 Adolescent Barriers Questionnaire, 95 Barriers Questionnaire, 95 BPI, 91, 115, 404 MPAC, 91 SF-MPQ, 91 scales of, with cancer, 38 NRS, 91 VAS, 90–91 VDS, 90 Pain syndromes, 53–74 acute, 54–61 after analgesic interventions, 57 from cancer, 54–55 with chemotherapy, 57–59 from diagnostic interventions, 56 after hormonal therapy, 59–60 from infections, 55 with radiotherapy, 60–61 with therapeutic interventions, 56–57 with vascular events, 55–56 with bone pain, 518 continuous pain, 518 incident pain, 518 mixed bone and neuropathic pain, 518 mixed bone and visceral pain, 518 in cancer survivors, 145–158 assessment of pain in, 156 CIPN, 153–154 osteoporosis as, 154–155 radiation-induced, 152–153 research on, 145 surgically-induced, 147–152 treatment-related, 146–147 chronic, 61–74 from base-of-skull metastases, 64–65 from cancer therapies, 61–74, 147 in chest wall, 65 ear pain, 65 from epidural spinal cord compression, 62–64 eye pain, 65 from headache syndromes, 65 from hip metastases, 64 in muscles, 65 from paraneoplastic syndromes, 65–66

index from pelvic metastases, 64 in soft tissues, 65 tumor-related, 62, 66–70 vertebral bone pain, 62 management issues with, 53 prevalence of, 53 Pain transmission acute v. chronic, 53 assessment of, 53–54 with bone cancer, 24–25, 645 through sensory neurons, 24 chronic, acute v., 53 classification of, 53–54 acute v. chronic, 53 neuropathic, 54 nociceptive, 54, 61 syndromic, 54 Palliative care, for pain, 105–121 access to, as ethical issue, 562 activity level in, 115–116 for chemically dependent patients, 425–426 patient selection for opioid therapy, 426 risk factors for, 425–426 with chemotherapy, 114–115 cognitive status and, 107 for delirium, 107 with complementary therapies, 115 for constipation, 108 in developing world, 608–623 goal of, 107 in hospices, 535–551 addiction and, 539–540 analgesic trials in, 544–545 barriers to referral for, 537–538 caregiver reports in, 544 case studies for, 537, 540 cognitive awareness in, 539 cultural and psychosocial issues and, 540 depression and, treatment for, 549–551 development of, 535–537 emotional suffering and, treatment of, 548–549 evaluation of pain in patients, 538–539 financial reimbursement for, 536–537 levels of care under, 536 medication administration for dying patients in, 540–542 medication administration routes in, 545–548 medication diversion and, 541–542 nonverbal patient evaluation in, 542–544 overmedication in, 540 pain assessment in, 538–539 statistics for cancer patients in, 538 treatment barriers in, 539–540 pain characteristics and, 112–113 for breakthrough pain, 112–113 for incident pain, 112 for neuropathic pain, 112 physical function in, 115–116 predictors of difficulty in, 110–112 for psychosocial distress, 116–119

639

for QOL, 105–107 with radiotherapy, 114–115 with somatization, 119–120 symptom assessment tools in, 108–110 Palliative Care Outcome Scale, 38 Palliative chemotherapy, for children, 434 Palliative Performance Scale (PPS), 115 Palliative radiotherapy, 379–394 with bisphosphonates, 388–389 for bone metastases, 382–385, 388 complications of, 385–388 impending fractures with, 385–387 with neuropathic pain, 389–390 for pathological fractures, 382, 387 postoperative, 387–388 risk prediction with, 385–386, 387 with chemotherapy, 389 clinical considerations for, 379, 380–381 with EBRT, 379 for neuropathic pain, 389–390 principles of, 379–381 with radiopharmaceuticals, 388 reirradiation and, 389, 392–394 of bone metastases, 393–394 of brain metastases, 394 clinical indications for, 392–393 rules for, 381 side effects of, 381–382 bone fractures as, 382 hematologic, 381–382 pain flares as, 382 with surgery, 386, 388 PVP, 388 toxicity with, 384 visceral pain and, 390–392 for brain metastases, 390 general, 390 for liver, 391 for lungs, 390–391 for pelvic masses, 391–392 for recurrent masses, 391–392 for skin, 392 Palliative sedation therapy (PST), 559 as euthanasia, 559 Palliative systemic antineoplastic therapy, 399–415 age and, 402 basic principles of, 406–408 clinical trials of, 408–410 determination of palliation as goal and, 399–400 duration of, for responding patient, 410–411 future of, 415 goals of, 403–404 hormonal therapy as, 411–413 for breast cancer, 411–412 for prostate cancer, 412–413 toxicity of, 409, 413 impact of prior therapy and, 401–402 DFIs and, 402 monoclonal antibody therapy as, 413–414 toxicities with, 414 patient evaluation for, 408

patient preferences and, 405–406 performance status as predictor of prognosis and outcome and, 400–401, 404, 405 with ECOG scale, 400 under Karnofsky Performance Status scale, 239, 400 response categories for, 399, 400 small molecule inhibitors and, 414–415 for stable or progressive disease, 411 symptom assessment for, 404–405 variation in response among metastatic disease sites and, 401, 402 Palmar-planted erythrodysesthesia syndrome, 59 Pamidronate, for bone pain, 281, 521 Pancreatic cancer, 66–67 Paracetamol, pharmacological and physiochemical data of, 262 Paraneoplastic painful peripheral neuropathy, 70 Paraneoplastic sensory neuropathy, 70 Paraneoplastic syndromes, 65–66 gynecomastia from, 66 hypertrophic pulmonary osteoarthropathy, 66 neuropathic pain and, 488 pemphigus, 66 Raynaud’s syndrome, 66 Parasellar syndrome, 64 Partial denervation of hindpaw, models of, 16–17 Partial sciatic tight ligation (PSTL) model, 17 Partner-assisted psychological interventions, for cancer pain, 345–347 Pathological fractures, acute pain from, 55 Patient-controlled administration routes, for opioid analgesics, 173–174 Patient-controlled analgesia (PCA), for neural blockade, 315 PCA. See Patient-controlled analgesia Pediatric Quality of Life Inventory-Cancer Module, 141 Pelvic floor pain, 72 Pelvic masses, palliative radiotherapy for, 391–392 Pelvic metastases, 64 in children, 434–435 Pemoline, for depression, 470 Pemphigus, 66 Pentazocine, 172 Percutaneous vertebroplasty (PVP), 388 Peripheral ablative neurosurgical procedures, 329–330 complications from, 329–330 in DRG, 329 indications for, 329–330 Peripheral neurolysis, 325 Peripheral neuropathy, 479 acute pain from, 58–59 after chemotherapy, 70–71 disease-related, 484 Peritoneal carcinomatosis, 67

index

640

Permanent intrathecal therapy, 318–319 Personality disorders, assessment of, 121 Phantom pain, 72 of limbs, after amputation, 72 neuropathic pain and, 488–489 Pharmacodynamics, in elderly, changes in, 445 Pharmacogenetics, for pain, 180–189, 190 adverse effects of, 186–187 for alfentanil, 188 for codeine, 187 for fentanyl, 188 for methadone, 188 for morphine, 187–188 OIH and, 186 opioid metabolism and, 182–183 opioid receptors and, 183–184 for opioid transport, 184–185 for oxycodone, 188 pain sensitivity in, variations of, 182 research considerations for, 188–189 ethnicity as, 188–189 population samples in, 189 statistics as, 189 signaling systems in, 185–186 nonopioid, 185–186 opioid, 186 SNPs in, 180–181 splice variants in, 181–182 tolerance levels and, 186 for tramadol, 187 variability of pain perception and, 180 Pharmacokinetics in elderly, changes in, 445 of methadone, 206–207 of morphine, 168 of opioid analgesics, 172 Phenazone, 256, 263 PHN. See Postherpetic neuralgia Physical dependence, on opioids, 177–178 Physical function, in pain assessment, 115–116 Physician-assisted suicide, 561–562 Physician Orders for Life-Sustaining Treatment (POLST) documents, 557–558 Pilates, for pain rehabilitation, 372 Placebo-controlled trials, 570 Plexopathy malignant, 484 postradiation, 484 radiation-induced, 60 PMNs. See Polymorphonuclear leukocytes PMPS. See Postmastectomy pain syndrome PMPs. See Prescription monitoring programs, state laws for POLST. See Physician Orders for Life-Sustaining Treatment documents Polymorphonuclear leukocytes (PMNs), 245 Postamputation pain, 151 Post-cerebral infarct pain, 489 Postherpetic neuralgia (PHN), 489–490 Postmastectomy pain syndrome (PMPS), 71, 148–149

neuropathic pain and, 484 preventive strategies for, 149 risk factors for, 148–149 Post-neck dissection pain, 150–151 Postoperative pain, 56 Postradiation plexopathy, neuropathic pain and, 484 Post-radical neck dissection pain, 71 Post-therapy lymphedema, 151–152 after breast cancer, 151 Post-thoracotomy syndrome, 149 PPS. See Palliative Performance Scale Prayer, in pain rehabilitation, 373 Pregabalin for neuropathic pain, 7–8, 276–278, 491–492 for surgically-induced pain syndromes, 148 Prescription drug abuse, 430 Prescription monitoring programs (PMPs), state laws for, 589–590 Primary Care Evaluation of Mental Disorders (PRIME-MD), 462 Primary otalgia, 65 Primary tumor sites, prevalence of pain at, 45, 46 PRIME-MD. See Primary Care Evaluation of Mental Disorders Proctitis, 73, 153 Prophylactic palliation, 404 Prostaglandins, 29 COX-1 inhibitors and, 29 COX-2 inhibitors and, 29 Prostate biopsies, 56 Prostate cancer flare syndromes in, 59–60 hormonal therapy for, palliative, 412–413 Proteinase-activated receptor-2, 480 Pruritus, opioid-induced, 237 management of, 237 after spinal administration, 290 PST. See Palliative sedation therapy PSTL model. See Partial sciatic tight ligation model Psychiatric disorders, assessment of, 119–121 in adjustment, 120–121 with anxiety, 120–121 chemical coping and, 120 depression, 120–121 personality disorders, 121 somatization, 119–120 Psychological dependence, on opioids, 177 Psychological distress, 117, 120 from OIN, 243–244 Psychological interventions, with cancer pain, 341–352 challenges of cancer pain, 343–344 with CST, 344–345 with guided imagery, 348 with hypnosis, 347–348 partner-assisted, 345–347 skills rehearsal for, 351

supervision and treatment monitoring in, 350 therapist training for, 349–350 treatment fidelity in, 350 with yoga, 348–349 Psychosocial distress, assessment of, 116–117, 119 coping in, 117–118 somatic symptoms in, 116 spiritual distress and, 118–119 suffering in, 117–118 Psychostimulants for pain management with depression, 470–471 for sedation management, 232 Purine receptors, 480 PVP. See Percutaneous vertebroplasty Pyrazolinone derivatives, 263–264 Qi manipulation, 362 QOL. See Quality of life, for patients Quality of life (QOL), for patients, 89 for cancer survivors, 146 for children, 141, 438 for family caregivers, 600, 601 HRQOL and, 105 with neuropathic pain, 483–484 pain impact on, 96 palliative care for, 105–107 Quantitative pain scales, 133–135 Radioisotopes, for bone pain, 524, 525–526 Radionuclides, for bone pain, 282 Radiopharmaceuticals, 61 with palliative radiotherapy, 388 Radiopharmaceuticals, for bone pain, 525–526 Radiotherapy acute pain with, 60–61 acute plexopathy from, 60 enteritis from, 60, 73, 153 mucositis from, 60 from radiopharmaceuticals, 61 during spinal metastasis, 60 for bone pain, 524–525 clinical trials in, 520 clinical considerations with, 379–381 for epidural spinal cord compression, 63–64 neuropathy from, 152–153 pain syndromes in cancer survivors from, 152–153 from chronic headaches, 153 from chronic proctitis, 153 from nerve damage, 152–153 palliative, 379–394 with bisphosphonates, 388–389 for bone metastases, 382–385, 388 with chemotherapy, 389 clinical considerations for, 379, 380, 381 with EBRT, 379 for neuropathic pain, 389–390 principles of, 379–381 with radiopharmaceuticals, 388

index reirradiation and, 389, 392–394 rules for, 381 side effects of, 381–382 with surgery, 388 toxicity with, 384 visceral pain and, 390–392 palliative care with, 114–115 Randomized control trials (RCTs), 568. See also Clinical trials Rapid switching, to methadone, 208–209 Raynaud’s syndrome, 66, 71 Rectal administration routes, for opioids, 174 in hospice care, 545 for methadone, 206 of morphine, 202–203, 204 of tramadol, 199 Reflex sympathetic dystrophy (RSD), 487 Rehabilitation, 354–373 ambulatory aids for, 366 with bone pain, 526–527 for capsulitis, 359–360 compression in, 367–368 energy conservation as part of, 368 for hypertonia, 360 for ligamentous and tendinous injuries, 359–360 for lymphedema, 360 with CDP, 360 manual interventions in, 360–363 with acupuncture, 362 massage as, 361–362 with stretching, 360–361 with touch, 362–363 of trigger points, 360 meditation and prayer in, 373 mind-body techniques in, 372 modalities for, 363–365 superficial cold as, 363–364 superficial heat as, 363–364 ultrasound as, 364 water-based therapy as, 364–365 music in, 372 with orthoses, 365–366 pain management and, 357 from muscular imbalance, 359 of neuropathic pain, 358 from shortened muscles, 359 of skeletal pain, 357–358 of soft tissue, 358 of trigger points, 358–359 philosophy of, 354–356 self-maintenance as goal in, 356 relaxation with imagery in, 372 for somatic dysfunction, 359 for spasticity, 360 with TENS, 357, 365 therapeutic exercises for, 368–370 Pilates as, 372 Tai chi as, 370–372 yoga as, 372 Reirradiation, 389, 392–394 of bone metastases, 393–394 of brain metastases, 394 clinical indications for, 392–393

641

Respiratory depression, opioid-induced, 175–176, 236–237 in elderly, 451 management of, 237 pain as agonist with, 237 from spinal administration, 290 Reversible inhibitors of monamine oxidase-A (RIMAs), 471 RIMAs. See Reversible inhibitors of monamine oxidase-A Rituximab, palliative, 413–414 Romania, palliative care in, 611–613 Ropivacaine, 293 Sacral syndrome, 62 SADS. See Schedule for Affective Disorders and Schizophrenia Schedule for Affective Disorders and Schizophrenia (SADS), 461–462 Schedule for Evaluation of Individual Quality of Life (SEIQoL), 110 SCID. See Structured Clinical Interview for DSM-IV SDS. See Symptom Distress Scale Secondary depression, 460 Secondary otalgia, 65 Sedation, opioid-induced, 176 from NSAIDs, 231 OIN and, 238 as side effect, 230–233 cholinergic pathways and, 232–233 management of, 231–233 psychostimulants for, 232 SEIQoL. See Schedule for Evaluation of Individual Quality of Life Seizures, from OIN, 240 Selective enrollment, in clinical trials, 577–578 Selective norepinephrine reuptake inhibitors (SNRIs), 275–276 for neuropathic pain, 494–495 for pain management with depression, 468 side effects of, 276 Selective serotonin reuptake inhibitors (SSRIs), 275–276 for neuropathic pain, 494 for pain management with depression, 467–468 Selective SNL model, 17 Self-efficacy, in coping, 118 Self-report measures, for assessment of depression, 462–463 Self-report pain scales, for children, 97, 139, 140–141 facial scales, 141 NRS, 139 Serotonin inflammatory pain and, 6 visceral pain and, 15 Severe pain, prevalence of, 45–47 Sexual dysfunction, opioid-induced, 245 SF-MPQ. See short form-McGill Pain Questionnaire

short form-McGill Pain Questionnaire (SF-MPQ), 91 Side effects, opioid-induced. See Constipation, opioid-induced; Nausea and vomiting, opioid-induced; Noncardiogenic pulmonary edema, opioid-induced; Opioid-induced neurotoxicity; Pruritus, opioid-induced; Respiratory depression, opioid-induced; Urinary retention, opioid-induced Single-blind clinical trials, 572 Single nucleotide polymorphisms (SNPs), 180–181 Skeletal pain, pain management for, 357–358 for osteoporosis, 357–358 skeletal remodeling, 24–25 Skin damage to, from vesicants, 409 palliative radiotherapy for, 392 Slow switching, to methadone, 208 SMART syndrome, 153 SNPs. See Single nucleotide polymorphisms SNRIs. See Selective norepinephrine reuptake inhibitors Social support, assessment of, 96–97 Sodium channel blockers, for neuropathic pain, 279–280 Soft tissues, chronic pain in, 65 management of, with rehabilitation, 358 Somatic dysfunction, rehabilitation for, 359 Somatic pain paraneoplastic syndromes as cause of, 65–66 psychosocial distress and, 116 Somatization, assessment of, 119–120 components of, 119 ethnocultural influences on, 119–120 Somatostatin, as nonopioid analgesic, 296 Spasticity, rehabilitation for, 360 Sphenoid sinus syndrome, 64–65 Spinal administration routes delivery systems for, 299–303 with catheters, 300–301 complications from, 301 with infusion pumps, 301 mechanical issues with, 302–303 for nonopioids, 293–296 for opioids, 288–291 efficacy of, 288–289 pharmacodynamics of, 288–289 pharmacokinetics of, 288 side effects of, 290–291 Spinal local anesthetic agents, 292–293 toxicity of, 292 Spinal metastasis, acute pain with, 60 Spinal neurons, 4 NS, 4 WDR, 4 Spiritual distress, assessment of, 117, 118–119 SSRIs. See Selective serotonin reuptake inhibitors Stanford Sleepiness Scale, 231

index

642

STAT6, in opioid signaling system, 186 State pain commissions, state laws for, 590 State-Trait Anxiety Inventory, 96 Steroid therapy bony complications of, 71 for epidural spinal cord compression, 63 perineal burning from, 59 Stretching, in pain rehabilitation, 360–361 Structured Clinical Interview for DSM-IV (SCID), 461 Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT), 406, 535. See also Hospice care ethical issues and, 553 Stump pain, 72. See also Postamputation pain Subcutaneous injections acute pain from, 57 in hospice care, 545, 546–548 Substance abuse. See Abuse of substances Sufentanil, spinal administration for, 290 Suffering, assessment of, 117–118 Sumatriptan, 6 Superficial cold, in pain rehabilitation, 363–364 Superficial heat, in pain rehabilitation, 363–364 Superior hypogastric plexus block, 323–324 complications of, 323 efficacy of, 323–324 Superior vena cava obstruction, acute pain with, 56 SUPPORT. See Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments Supportive care, for cancer survivors, 156–157 Support Team Assessment Schedule, 38 Suppositories, for opioid-induced constipation, 235 Surgically-induced pain syndromes, 147–149, 150–152 acetaminophen and, 148 anesthesia use and, 147–148 gabapentins for, 148 multimodal pain therapy for, 147 PMPS, 148–149 postamputation pain, 151 post-neck dissection pain, 150–151 post-therapy lymphedema, 151–152 post-thoracotomy syndrome, 149 pregabalin for, 148 Switching, to methadone, 208–209 rapid, 208–209 slow, 208 Symptom Distress Scale (SDS), 109 Syndromic classification, of pain, 54 T2-L1 syndrome, 62 Tai chi, for pain rehabilitation, 370–372 TARGET. See Therapeutic Arthritis Research and Gastrointestinal Event Trial

TENS. See Transcutaneous electrical nerve stimulation Terminal disease, prevalence of pain with, 43–44 Terminal sedation, for pain and suffering, 558–559 as euthanasia, 559 Thalamotomy, 333 Thalidomide, neuropathic pain from, 486 Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), 264 Therapeutic exercises, in pain rehabilitation, 368–370 Therapeutic interventions, acute pain with, 56–57 chemical pleurodesis, 57 for CIN, 56–57 from postoperative procedures, 56 Thoracotomy, postsurgical pain after, 71–72 post-thoracotomy syndrome, 149 Thrombosis, acute pain with, 55–56 Tiagabine, for neuropathic pain, 278–279 Tocainide, as adjuvant analgesic, 279 Tolerance levels, for opioid analgesics, 113–114 OIN influenced on, 240–241 pharmacogenetics influence on, 186 Topical analgesics, for neuropathic pain, 500–501 Topiramate, for neuropathic pain, 278 Total pain, 457 Touch, in rehabilitation, 362–363 Toxicity. See also Opioid-induced neurotoxicity agitation from, 113 from chemotherapy, 58–59 of hormonal therapy, palliative, 409, 413 of local anesthetic agents, 292 neuropathic pain from, 58–59 from opioid use, 113 agitation in, 113 of palliative radiotherapy, 384 from spinal delivery systems, 302 Tramadol for children, 441 for elderly, 449 for mild to moderate pain, 198–199 pharmacogenetics for, 187 Transcutaneous electrical nerve stimulation (TENS), 357, 365 Transdermal administration route, for opioids, 172–173 with ionsys, 173 Transient receptor potential vanilloid (TRPV1), 29 Transmucosal administration route, for opioid analgesics, 173 Trastuzumab, palliative, 414 Trazodone, 469 Treatment fidelity, in psychological interventions, 350 Treatment-induced neuropathic pain, 146–147

Treatment programs, 588 Tricyclic antidepressants as adjuvant analgesics, 275 for neuropathic pain, 275, 494 for pain management with depression, 469–470 Trigeminal neuralgia, 68 Trigger points, pain management of, 358–359. See also Acupuncture, in pain rehabilitation arthritides and, 359 manual intervention in, 360 TRPV1. See Transient receptor potential vanilloid Tumor-derived products, for bone cancer pain, 29–30 endothelins, 29–30 kinins, 30 NGF, 30 prostaglandins, 29 COX-1 inhibitors and, 29 COX-2 inhibitors and, 29 Tumor-related neuropathic pain syndromes, 67–70 cranial neuralgias, 68 glossopharyngeal, 68 trigeminal, 68 leptomeningeal metastases, 67–68 malignant painful plexopathy, 68–70 cervical, 68 lumbosacral, 69–70 malignant painful radiculopathy, 68 mononeuropathy, 70 paraneoplastic painful peripheral neuropathy, 70 paraneoplastic sensory neuropathy, 70 Tumor-related somatic pain, 62 Tumor-related visceral pain syndromes, 66–70 adrenal pain syndrome, 67 chronic intestinal obstruction, 67 hepatic distention syndrome, 66 malignant perineal pain, 67 midline retroperitoneal syndrome, 66–67 pancreatic cancer and, 66–67 peritoneal carcinomatosis, 67 ureteric obstruction, 67 Ultrasound, for pain rehabilitation, 364 Ureteric obstruction, 67 Urinary retention, opioid-induced, 176–177, 237–238 after spinal administration, 290 Urine toxicology screening, for chemically dependent patients, 427–428 Varni-Thompson Pediatric Pain Questionnaire, 97, 137 VAS. See Visual analogue scales Vascular events, acute pain with, 55–56 acute thrombosis, 55–56 superior vena cava obstruction, 56 VDS. See Verbal descriptor scales

index Venlafaxine (Effexor) for neuropathic pain, 276 for PMPS, 149 Ventilator withdrawal, 561 Verbal descriptor scales (VDS), 90 Vertebral bone pain syndromes, 62 atlantoaxial destruction in, 62 C7-T1 syndrome, 62 odontoid fractures in, 62 sacral syndrome, 62 T2-L1 syndrome, 62 Vertebroplasty, for bone pain, 527–528 Vincristine, neuropathic pain from, 486 Visceral pain in bone pain, 518 cancer-related syndromes, 61 mechanisms of, 14–15 serotonins and, 15 symptoms in, 15 transmission of, 14 with neurolytic blocks, 319 palliative radiotherapy and, 390–392 for brain metastases, 390

643

general pain, 390 for liver, 391 for lungs, 390–391 for pelvic masses, 391–392 for recurrent masses, 391–392 for skin, 392 tumor-related syndromes, 66–70 adrenal pain syndrome, 67 chronic intestinal obstruction, 67 hepatic distention syndrome, 66 malignant perineal pain, 67 midline retroperitoneal syndrome, 66–67 peritoneal carcinomatosis, 67 ureteric obstruction, 67 Visual analogue scales (VAS), 90–91 for children, 135 measurement of pain in, 436 Voltage-gated calcium channels, 480–482 Water-based therapy, for pain rehabilitation, 364–365 WBRT. See Whole-brain radiation therapy

WDR neurons. See Wide-dynamic range neurons WHO. See World Health Organization, pain ladder for Whole-brain radiation therapy (WBRT), 390 Wide-dynamic range (WDR) neurons, 4 in bone cancer pain, 15 Word-Graphic Rating Scale, 139 World Health Organization (WHO), pain ladder for, 438–439 Yoga for pain rehabilitation, 372 as psychological intervention, for pain, 348–349 Ziconotide as nonopioid analgesic, 295–296 spinal administration of, 7 Zidovudine (AZT), 578 Zoledronic acid, for bone pain, 281, 499 Zonisamide, for neuropathic pain, 279