Chronic Pain - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

CHRONIC PAIN A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

ii

ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2003 by ICON Group International, Inc. Copyright ©2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Chronic Pain: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83820-8 1. Chronic Pain-Popular works. I. Title.

iii

Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

iv

Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on chronic pain. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

v

About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

vi

About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

vii

Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CHRONIC PAIN ......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Chronic Pain ................................................................................. 5 E-Journals: PubMed Central ....................................................................................................... 69 The National Library of Medicine: PubMed ................................................................................ 70 CHAPTER 2. NUTRITION AND CHRONIC PAIN ............................................................................. 113 Overview.................................................................................................................................... 113 Finding Nutrition Studies on Chronic Pain.............................................................................. 113 Federal Resources on Nutrition ................................................................................................. 115 Additional Web Resources ......................................................................................................... 116 CHAPTER 3. ALTERNATIVE MEDICINE AND CHRONIC PAIN ....................................................... 117 Overview.................................................................................................................................... 117 The Combined Health Information Database............................................................................. 117 National Center for Complementary and Alternative Medicine................................................ 118 Additional Web Resources ......................................................................................................... 126 General References ..................................................................................................................... 131 CHAPTER 4. DISSERTATIONS ON CHRONIC PAIN ......................................................................... 133 Overview.................................................................................................................................... 133 Dissertations on Chronic Pain................................................................................................... 133 Keeping Current ........................................................................................................................ 139 CHAPTER 5. CLINICAL TRIALS AND CHRONIC PAIN .................................................................... 141 Overview.................................................................................................................................... 141 Recent Trials on Chronic Pain................................................................................................... 141 Keeping Current on Clinical Trials ........................................................................................... 143 CHAPTER 6. PATENTS ON CHRONIC PAIN .................................................................................... 145 Overview.................................................................................................................................... 145 Patents on Chronic Pain ............................................................................................................ 145 Patent Applications on Chronic Pain ........................................................................................ 169 Keeping Current ........................................................................................................................ 199 CHAPTER 7. BOOKS ON CHRONIC PAIN........................................................................................ 201 Overview.................................................................................................................................... 201 Book Summaries: Federal Agencies............................................................................................ 201 Book Summaries: Online Booksellers......................................................................................... 203 The National Library of Medicine Book Index ........................................................................... 210 Chapters on Chronic Pain.......................................................................................................... 212 CHAPTER 8. MULTIMEDIA ON CHRONIC PAIN ............................................................................. 213 Overview.................................................................................................................................... 213 Video Recordings ....................................................................................................................... 213 Bibliography: Multimedia on Chronic Pain............................................................................... 214 CHAPTER 9. PERIODICALS AND NEWS ON CHRONIC PAIN .......................................................... 217 Overview.................................................................................................................................... 217 News Services and Press Releases.............................................................................................. 217 Newsletter Articles .................................................................................................................... 220 Academic Periodicals covering Chronic Pain ............................................................................ 221 CHAPTER 10. RESEARCHING MEDICATIONS ................................................................................. 223 Overview.................................................................................................................................... 223 U.S. Pharmacopeia..................................................................................................................... 223 Commercial Databases ............................................................................................................... 224 Researching Orphan Drugs ....................................................................................................... 224

viii Contents

APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 229 Overview.................................................................................................................................... 229 NIH Guidelines.......................................................................................................................... 229 NIH Databases........................................................................................................................... 231 Other Commercial Databases..................................................................................................... 233 APPENDIX B. PATIENT RESOURCES ............................................................................................... 235 Overview.................................................................................................................................... 235 Patient Guideline Sources.......................................................................................................... 235 Associations and Chronic Pain .................................................................................................. 240 Finding Associations.................................................................................................................. 241 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 243 Overview.................................................................................................................................... 243 Preparation................................................................................................................................. 243 Finding a Local Medical Library................................................................................................ 243 Medical Libraries in the U.S. and Canada ................................................................................. 243 ONLINE GLOSSARIES................................................................................................................ 249 Online Dictionary Directories ................................................................................................... 250 CHRONIC PAIN DICTIONARY................................................................................................ 251 INDEX .............................................................................................................................................. 339

1

FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with chronic pain is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about chronic pain, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to chronic pain, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on chronic pain. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to chronic pain, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on chronic pain. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

3

CHAPTER 1. STUDIES ON CHRONIC PAIN Overview In this chapter, we will show you how to locate peer-reviewed references and studies on chronic pain.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and chronic pain, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “chronic pain” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Clinical Associations Between Tinnitus and Chronic Pain Source: Otolaryngology-Head and Neck Surgery. 2003;128:706-10. Contact: Send requests to:. Summary: In this article the authors report on a prospective nonrandomized study in which a survey and the Tinnitus Handicap Inventory (THI) were distributed to 72 patients (50 women and 22 men) attending a tertiary chronic pain clinic, to determine the prevalence and severity of tinnitus inpatients with chronic pain. The research findings suggest a high incidence of tinnitus in people suffering with chronic pain.

•

Use of Aromatherapy as a Complementary Treatment for Chronic Pain Source: Alternative Therapies in Health and Medicine. 5(5): 42-51. September 1999.

4

Chronic Pain

Summary: This article discusses the use of aromatherapy as a complementary treatment for chronic pain. First, it defines aromatherapy, reviews the effects of aroma on the body, and describes methods of using aromatherapy with and without touch. Then, it summarizes human studies on the use of aromatherapy in the treatment of pain, including aromatherapy for children, lavender for pain and coping, chamomile for pain in cancer, marigold for pain in hyperkeratotic plantar lesions, peppermint for headache and arthritic pain, and rose for pain in cancer with bone metastases. Finally, it reviews animal studies, and discusses the potential for untoward effects. It includes a list of essential oils with analgesic properties that are safe to use. The article has 4 tables and 96 references. •

Effective Ways to Manage Chronic Pain Source: Patient Care. 30(11):154-155,159-162,164-167,171-172; June 1996. Summary: This journal article addresses the various diagnostic and treatment considerations for patients with chronic pain. The authors explain that the keys to controlling pain and restoring function are understanding the multidimensional character of pain syndromes and engaging the full dimension of the doctor-patient relationship in the search for solutions. Both of these areas are examined, as well as the selection of a drug regimen, exercise, the use of a pain diary, and considerations when recruiting a caregiver team for case management. Nondrug therapies such as meditation and relaxation, hypnosis, cognitive therapy, biofeedback, and manipulation are also addressed, along with the invasive therapies of acupuncture, trigger- point injections, nerve blocks and ablation, and opioid reservoirs and pumps. The article concludes with a brief discussion on therapeutic objectives and follow-up. 1 reference.

•

Effective Management of Chronic Pain. The Analgesic Dilemma Source: Postgraduate Medicine. 100(3):281-284,287- 290,293,296; September 1996. Summary: This journal article for health professionals discusses the effective management of chronic pain by using prescription analgesics. The goals of chronic pain management are identified, and barriers to achieving them are highlighted. Prescription medications that can be used as analgesics for chronic pain are described, focusing on nonsteroidal anti-inflammatory drugs, opioids, and tramadol hydrochloride. Opioid use is discussed in terms of limiting factors, patient selection, and goals. Adjuvant medications that may be used in the management of selected chronic pain states are also highlighted, including antidepressants, antiarrhythmics, anticonvulsants, calcium channel blockers, antiadrenergics, and topical agents. 27 references, 1 figure, and 5 tables. (AA-M).

•

Chronic Pain: Primary Care Treatment of the Older Patient Source: Geriatrics. 54(1): 23-28,33-34,37. January 1999. Summary: This journal article provides health professionals with information on a practical, office based approach to managing older patients who have chronic pain. The prevalence of chronic diseases associated with pain increases with age, and pain prevalence appears to increase with the level of functional dependence. Chronic pain in older patients is associated with sleep disorders, impaired physical and social function, and increased health care utilization. Symptoms of pain, anxiety, and depression are often associated and may intensify one another. There is no biological marker for pain, so it is usually assessed by self report. Pain assessment tools include visual analog scales that measure pain intensity. Multidimensional assessments that offer pain descriptors

Studies

5

may provide important diagnostic clues to the underlying pathogenic process. Reports from caregivers should also be sought. Comprehensive pain assessment includes a medical history and a physical examination, as well as a psychosocial evaluation for anxiety and depression and for cognitive status and available support systems. Because a complete resolution of chronic pain is unlikely, it is important to establish early in therapy the level of pain that the patient would find acceptable. The goal of therapy is to treat chronic pain while minimizing side effects and optimizing the functional status of the patient. Pain can be managed pharmacologically with nonsteroidal antiinflammatory drugs, cyclooxygenase inhibitors, and opioids. Nonpharmacologic treatments include patient education, cognitive behavioral therapies, physical therapy, and exercise. The article uses a sample patient to illustrate important principles of diagnosing pain and prescribing pharmacologic and nonpharmacologic therapies. 4 tables and 26 references. (AA-M).

Federally Funded Research on Chronic Pain The U.S. Government supports a variety of research studies relating to chronic pain. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to chronic pain. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore chronic pain. The following is typical of the type of information found when searching the CRISP database for chronic pain: •

Project Title: A NOVEL RF TENS DEVICE FOR ACUTE PAIN MANAGEMENT Principal Investigator & Institution: Andrasik, Frank; Cyclotec Advanced Medical Technologies 4871 Nw 65Th Ave Lauderhill, Fl 33319 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Cyclotec AMT, Inc. is developing 'non-invasive' transcutaneous electrical stimulators (TENS) that may prove to be viable adjuncts to or alternatives for drugs for management of recent onset "acute" pain. TENS has long been used for "chronic" pain management. The device complexities have made them prohibitive for short-term 'acute' applications; an application for which the technology promises to be well suited for. Cyclotec's 'novel' developments for acute indications include: miniaturization, wireless operation, remote control activation, multiple pulsing features, durability, simplification of operation, extended battery life, and the capability of placement virtually anywhere on the body. The remote control (RF) features allow the stimulation devices now in development to be easily controlled by the patient - without

2

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

6

Chronic Pain

the extension wires necessary on all other TENS units - no matter where the units are placed on the body, e.g., back, neck, shoulder, hip, and etc. Upon completion of development of 12 functional prototype units, initial pilot investigations at various clinical sites will be performed to establish efficacy in conjunction with medication and with the absence of medication in a double-blinded study to determine effectiveness in treatment of acute pain. Should TENS prove as effective, simple and comfortable to wear by patients as the company hopes they will be, Cyclotec AMT devices will find a significant market niche as TENS has few cautions or warnings while drugs are well known to have long-term moderate to severe side effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIONS OF PROINFLAMMATORY CYTOKINES ON SENSORY NEURONS Principal Investigator & Institution: Nicol, Grant D.; Professor; Pharmacology and Toxicology; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2001; Project Start 10-JUN-1999; Project End 31-MAR-2003 Summary: (applicant's abstract): Increasing evidence suggests that activation of various components of the immune system contribute to chronic pain and inflammation. A number of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1-beta (IL-1beta), and interleukin-6 (IL-6) are synthesized and released at sites of trauma and produce hyperalgesia in animal models of pain. One mechanism for cytokine-induced augmentation of pain perception could involve their direct actions on nociceptive sensory neurons to enhance excitability and/or sensitize them to physical or chemical stimuli. Despite abundant evidence that TNF-alpha, IL-1beta, and IL-6 produce hyperalgesia and inflammation, there is little information regarding their capacity to modulate intracellular signaling pathways that regulate sensory neuron function. The hypothesis of this proposal is that pro-inflammatory cytokines act directly on sensory neurons to enhance their excitability and sensitize these cells to noxious mechanical and chemical stimuli and, in turn, augment the release of neuroactive substances from these neurons. The proposed studies will utilize two approaches: patch-clamp electrophysiology to assess cytokine-induced alterations in membrane excitability in rat sensory neurons grown in culture and biochemical measurements of neuropeptide release in isolated sensory neurons grown in culture and an in vitro preparation of rat spinal cord slices. The aims of this proposal are: 1) to determine whether acute or chronic exposure to TNF-alpha, IL-1beta, or 1L-6 alters membrane excitability and/or sensitizes isolated sensory neurons to electrical or chemical stimuli, 2) to determine whether these pro-inflammatory cytokines stimulate and/or sensitize the release of SP and CGRP from rat sensory neurons grown in culture or from rat spinal cord slices; and 3) to determine the effects of pro-inflammatory cytokines on sphingolipid second messengers and diacylglycerol in sensory neurons and to establish causal relationships between changes in second messenger systems and cytokine-induced alterations in excitability and peptide release. Overall, the knowledge gained from these studies is critical for understanding the etiology of chronic pain and could eventually aid in designing interventions to alleviate the pain. The results of this work can increase the understanding of the cellular mechanisms mediating the interaction between the nervous system and the immune system and thus be applicable to other areas of neurobiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

7

Project Title: ACUPUNCTURE TREATMENT OF PAIN IN PANCREATIC CANCER Principal Investigator & Institution: Cassileth, Barrie R.; Chief; Sloan-Kettering Institute for Cancer Res New York, Ny 10021 Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-AUG-2003 Summary: (provided by applicant): BACKGROUND: Pancreatic cancer affects approximately 28,000 Americans a year. Approximately 85-90 percent of these patients are first diagnosed when their disease already is locally advanced or metastatic. AT this point, median survival is three to six months. Treatment of pancreatic cancer is predominantly palliative in nature. Pain control is often the most serious challenge: the pancreas has an extensive blood, lymphatic and nerve supply and is surrounded by numerous other abdominal organs. More than 90 percent of patients with advanced pancreatic cancer experience moderate to severe pain. Several surgical and nonoperative procedures are used to palliate pancreatic pain, including blocking afferent pain fibers from the pancreas. Data on the efficacy of these approaches are limited and these interventions tend to be used only in select cases. Oncologic management with gemcitabine chemotherapy or radiotherapy reduces pain in a minority of patients. Most patients require opiates for pain control, and the high doses needed often cause undesirable sedation. Basic and clinical research supports acupuncture for the treatment of pain. A randomized trial found that acupuncture helps relieve non-malignant pancreatic pain, suggesting that an early phase trial of acupuncture for pancreatic cancer pain would be warranted. Objectives: To assess the effects of an acupuncture/acupressure intervention on pain, sedation and opiate medication in patients with pancreatic cancer experiencing moderate to severe pain to: i) determine whether controlled trials are warranted and ii) provide data to aid design of further warranted studies. Methods: Initially, a small number of pancreatic cancer patients reporting either high levels of pain or high levels of sedation will be treated in order to finalize the acupuncture prescription and the data collection procedures. We will then accrue patients in a standard two-stage, Phase II design. Patients will receive four sessions of a standardized acupuncture treatment with intervening acupressure over 10 days. Pain, opiate medication and sedation will be assessed for three days at baseline and post-treatment. Patients will be considered to have responded to treatment if they report a pre-specified level of improvement in either pain or sedation. Ten patients will be recruited. If less than two experience responses, the trial will be terminated. Otherwise, an additional 19 patients will be accrued. A Phase III trial will be deemed warranted if there are 6 or more responses in total; this is consistent with a 30 percent response rate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: AFFERENT PLASTICITY UNDERLYING URETHRAL AND PELVIC PA Principal Investigator & Institution: Yoshimura, Naoki; Associate Professor; Pharmacology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2003 Summary: Patients with painful bladder syndromes such as interstitial cystitis (IC) characterized by urinary frequency, urgency, and bladder pain often exhibit urethral or pelvic pain. It is also documented that peripheral nerve injury in the pelvis may contribute to the emergence of bladder and/or pelvic pain because surgical manipulation of visceral organs is known to be a risk factor for the IC, and also often

8

Chronic Pain

leads to aggravation of existing symptoms or onset of new symptoms in patients with pelvic pain. The urethra, urethral sphincter muscles and the pelvic floor are innervated by a subset of visceral (pelvic and hypogastric) and somatic (pudendal) afferent fibers which are a more diverse population (C, Asigma and Abeta-fibers; possibly Aalphafibers) than those innervating the urinary bladder (C and Asigma-fibers). However, little is known about their functional characteristics and changes under chronic pathological conditions including tissue inflammation or nerve injury that may result in chronic urethral or pelvic pain. Thus, in this research project, electrophysiologic, pharmacologic, molecular and neurochemical techniques will be used to examine the characteristics of urethral afferent neurons and somatic afferent neurons in the pudendal nerve. We are particularly interested in characterizing membrane properties of these afferent neurons, and also in identifying how the chemical mediators or pathology alter ion channel and receptor properties, leading to neuronal hyperexcitability. Several hypotheses will be tested: (1) Multiple subtypes of afferent neurons can be identified based on their functional and morphological properties including tetrodotoxin-resistant Na+ channels, slow-inactivating transient K+ channels, vanilloid receptors (VR1) sensitive to capsaicin, and immunoreactivity against specific cellular markers such as neurofilament or isolectin-B4, (2) Chronic inflammation of the urethra/pelvic floor or direct injury to the pudendal nerve alters the expression of ion channels or neurotransmitter mechanisms in afferent neurons, resulting in hyperexcitability of these neurons. These changes might be different from those that we have been recently identified in bladder afferent neurons, (3) Functional changes in urethral afferent neurons or pudendal afferent neurons under chronic pathological conditions can induce bladder and/or urethral hyperactivities by reorganizing viscerosomatic reflex activities. The long-term objectives of the research program are to understand the mechanisms by which irritating or nerve-injuring stimuli in pelvic organs induce phenotypic changes in their afferent pathways and thereby trigger chronic pain in the pelvis. If a specific relation is found between different pathology and alteration in ion channel or receptor properties/expression, it is possible to identify new molecular target of drug therapy for chronic bladder and/or pelvic pain associated with painful bladder syndromes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALTERNATIVES TO OPIOIDS FOR CHRONIC PAIN -PART III Principal Investigator & Institution: Deleo, Joyce A.; Associate Professor; Anesthesiology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2001; Project Start 15-JUL-1997; Project End 31-MAY-2005 Summary: The pain that follows nerve injury is chronic and consistently refractory to available analgesics. These neuropathic pain syndromes include deafferentation pain, diabetic, cancer and ischemic neuropathies, phantom limb pain, trigeminal neuralgia, postherpetic neuralgias and nerve injury caused by surgery or trauma. Neuropathic pain is not only chronic and intractable, it is debilitating and causes extreme physical, psychological and social distress. The broad, long- term objective pf our research is to elucidate spinal neuroimmune mechanisms responsible for the generation and maintenance of neuropathic pain. This knowledge will enable development of new medications to treat neuropathic pain without the added liability of drug abuse. Research completed in the previous funding period provides substantial data to support the role of central nervous system (CNC) cytokines in persistent neuropathic pain states. We propose to extend our studies to address the unifying hypothesis that chronic pain following peripheral nerve injury is maintained by central neuroimmune/neuroinflammatory mechanisms. The central hypothesis is that

Studies

9

peripheral nerve injury causes an inappropriate CNS expression of Major Histocompatibility Complex (MHC) Class II and cellular adhesion molecules which leads to an imbalance of proinflammatory cytokines and immune mediators that manifests as persistent neuropathic pain. This hypothesis will be tested using the following Specific Aims: 1) Assess the role of spinal MHC Class II and cellular adhesion molecule expression in nerve injury and acute inflammatory animal models; 2) Determine whether activated T-cells or macrophages are recruited into the CNS in response to a peripheral nerve injury; 3) Continue to evaluate the potential for global or specific immunosuppressive therapy yo alter sensory nociceptive processing; 4) Determine the effect of the above immunosuppressive therapy on spinal proinflammatory cytokines, MHC Class II and CAM expression. Immunocytochemistry, in situ hybridiazation, ELISA, RNS protection assays, specific pharmacological agents and noncieptive behavioral assays will be used to resolve these specific aims. When completed, these studies will provide: a) Information o the kinetics of spinal MHC class II and CAM expression following peripheral nerve injury and acute intraplantar inflammation, b) Data on the recruitment of immune cells into the CNS in response to nerve injury; c) Preliminary data to support new pharmacological approaches to the treatment of clinical neuropathic pain; d) a foundation for further understanding the neuroimmune response of nerve injury and the relationship to other central nervous systems inflammatory disease states e) Data to guide future studies that evaluate the role of cytokines and neuroimmune activation in chronic pain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AMPA RECEPTOR BLOCKING PEPTIDES FOR CHRONIC PAIN Principal Investigator & Institution: Harty, Patrick T.; Cognetix, Inc. 421 Wakara Way, Ste 201 Salt Lake City, Ut 84108 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2003 Summary: (provided by applicant): We propose to isolate and identify novel AMPA receptor blocking conopeptides from marine cone snail venom for chronic pain intervention. Conopeptides are bioactive peptides from marine cone snail venom, and AMPA (a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are nonNMDA glutamate type receptors, which mediate fast signal transmission in nociceptive pathways. AMPA receptor blocking conopeptides will be isolated from the venom and sequenced for their amino acid composition. AMPA receptor blocking drugs for the treatment of chronic pain exist, but are limited in use by a high incidence of unwanted side effects, and lack of specificity for only the AMPA type glutamate receptor. AMPA receptor involvement in chronic pain transmission occurs in the dorsal root ganglia, dorsal horn and spinal cord. Novel conopeptides that are selective for blocking AMPA receptors will provide analgesia in the treatment of chronic pain. In Phase I we will: 1) establish biologically active AMPA receptor blocking venom fractions, 2) purify identified venom fractions and sequence the individual peptides that block AMPA receptors, 3) determine the specific AMPA receptor subunits acted on by the AMPA blocking peptides. In Phase II we will determine the analgesic activity of AMPA receptor blocking conopeptides in vivo rodent models of chronic pain. PROPOSED COMMERCIAL APPLICATION: The treatment and management of chronic pain afflicts approximately 34 million Americans resulting in costs of $40 billion annually. The incidence of chronic pain is predicted to increase due to a rise in the aging population. In many instances chronic pain is not well managed through current therapies, especially due to the addictive nature of narcotics used to treat chronic pain.

10

Chronic Pain

Therefore, an increasing demand for non-opioid analgesics could be met by effective conopeptide analgesics in this market. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEURALGIA

ANALGESIA

IN

HERPES

ZOSTER

AND

POSTHERPETIC

Principal Investigator & Institution: Dworkin, Robert H.; Professor; Anesthesiology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Herpes zoster is a common and painful neurological disease that is caused by reactivation of the varicella-zoster virus. Herpes zoster pain that persists after healing of the acute infection is termed postherpetic neuralgia (PHN), a chronic pain syndrome that is often refractory to all treatment. The prevalence of PHN is expected to increase substantially in the coming decades because the incidence of herpes zoster and the risk of PHN will both increase as the population ages. Although research to improve treatment is continuing, as many as half of all patients do not currently obtain relief. For this reason, the development of interventions that prevent PHN would lead to major reductions in disability, distress, and use of health care resources. On the basis of the results of research on risk factors for PHN and its pathophysiologic mechanisms, it can be hypothesized that combined antiviral and analgesic treatment begun as soon as possible after the -onset of herpes zoster will reduce the risk of PHN. The specific aim of this planning grant is to develop the protocol and procedures for a clinical trial to test this hypothesis. The proposed trial will have the following major objectives: The primary aim will be to test the hypothesis that the risk of PHN is reduced by half in herpes zoster patients treated with an antiviral agent and an opioid analgesic compared with patients treated with the antiviral agent and matching placebo. Support for this hypothesis would have a major impact on the treatment of patients with herpes zoster and lead to a substantial reduction in the prevalence of PHN. A second major aim that will be accomplished by the proposed trial is determining whether the initiation of central mechanisms of chronic neuropathic pain can be prevented by attenuating acute pain. The answer to this question will provide important information about mechanisms of prolonged pain and have major implications for its prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALGESIC EFFECTS OF ADRENAL CHROMAFFIN CELL TRANSPLANTS Principal Investigator & Institution: Pappas, George D.; Professor; Anatomy and Cell Biology; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Transplantation of same species (allogeneic) chromaffin cells from the adrenal gland to the central nervous system has been widely shown to produce profound analgesia. This was first demonstrated in rats, but the technique has also successfully alleviated pain in more than 35 cancer patients. After spinal transplant, these patients show a distinct increase in spinal fluid levels of endogenous opioids and catecholamines, with a robust analgesic effect. The effects last many months and are accompanied by a definite inhibition in the development of tolerance to exogenous opiate analgesic drugs, a common problem with these patients. Thus transplantation of allogeneic chromaffin cell graft clearly shows potential as a

Studies

11

means of treating chronic, intractable pain. Unfortunately, transplantation of allogeneic chromaffin cells has limitations similar to other transplants, e.g., the availability of suitable human tissue. To meet this challenge, xenogeneic (cross-species) transplants have demonstrated clear analgesic effects in rodents. However, there are significant roadblocks in transferring this method to humans. Earlier work indicates that purification of bovine or porcine cells minimizes rejection potential in rats. Preliminary work also indicates that embedding cells in a collagen matrix may improve their viability and analgesic potential. However, prior to attempting cross-species transplants in humans, it is critical to examine these effects in detail in species that are much closer to man immunologically and neurophysiologically, namely nonhuman primates. Thus, the work proposed here entails investigations designed to optimize the analgesic potential of xenogeneic chromaffin cells when transplanted into primates. The experiments will determine, in vitro, the effects of seeding cells in collagen matrices on the viability, integrity, and rejection potential of purified chromaffin cells. In vivo experiments will take these preparations to monkeys, investigating cell-dose dependence and collagen matrix effects on the analgesic efficacy of xenogeneic transplants. In this way, we hope to move much closer to the capability of treating patients with severe chronic pain with a novel treatment that is long-lasting and not only does not precipitate tolerance, but also appears to impede its development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALGESICS FOR CHRONIC PAIN TREATMENT IN THE ELDERLY Principal Investigator & Institution: Narducy, Kenneth W.; St Charles Pharmaceuticals 478 Broadway St New Orleans, La 70118 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-DEC-2001 Summary: adapted from applicant's abstract): Acetaminophen, a nonsteroidal antiinflammatory drug (NSAID), is widely used for treatment of pain and/or fever in the elderly. This dual action is sometimes contraindicated. In many instances pain needs to be controlled without masking the symptomatic fever (e.g., postoperative period). Acetaminophen can also cause hepatotoxicity, particularly after ingestion of large doses or chronic use of smaller doses (especially in the elderly or when liver function is affected) that can lead to death. Therefore, there is a need for new more selective compounds with greater pharmacological potency and devoid of hepatotoxic or antipyretic effect. We are exploring a series of new proprietary derivatives of acetaminophen. In preliminary studies, one of these compounds (SCP-1) demonstrated high analgesic activity free from antipyretic activity and hepatotoxicity. In this STTR project we propose to further characterize SCP-1 and compare biological properties with acetaminophen. We will also explore combinations of SCP-1 with morphine (and with other pain relievers) to confirm preliminary studies indicating a synergistic effect of this combination. The Phase I experiments will help us ascertain the legitimacy of SCP-1 as a lead candidate drug worthy of further development and testing in Phase II for the treatment of chronic and post-operative pain in the elderly. PROPOSED COMMERCIAL APPLICATION: The market for pain relievers in the US is estimated to be $4 billion annually. Acetaminophen (marketed under the name Tylenol(TM) and other brand names) represents about 40% of that market. Although widely used, acetaminophen is not without some serious side effects. There is a clear unmet medical need for pain relievers that are effective but have a better safety profile than acetaminophen. The research proposed in this grant application is directed at developing a pain reliever that is as effective as acetaminophen but with fewer side effects. This drug would be targeted at those patients most at risk from acetaminophen toxicity, the elderly, particularly those

12

Chronic Pain

who must take pain relievers on a chronic basis, and those experiencing post-operative pin where masking the symptomatic fever could delay the diagnosis of infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRIEF FOCUSED TREATMENT FOR TMD: MECHANISMS OF ACTION Principal Investigator & Institution: Litt, Mark D.; Behav Scis & Community Health; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 31-MAR-2008 Summary: (provided by applicant): TMD is a widespread chronic pain condition. Successful psychosocial treatments for TMD have been developed, but the mechanisms by which these treatments achieve their effects are not well known. The goal of this project is to evaluate the possible mechanisms responsible for treatment gains in TMD treatment. Men and women (N=106) with complaints of chronic facial pain for at least 3 months' duration will be recruited from the University Dental Clinics and from the community via advertisements and randomly assigned to either a Standard Conservative Treatment (STD) employing an intraoral splint plus anti-inflammatory agents, or to a Standard Treatment + Cognitive-Behavioral Treatment Program (STD+CBT), that will include standard treatment but also focus on changing self-efficacy and decreasing catastrophization. Both treatments will entail 6 clinic visits. Dispositional and situational variables derived from a comprehensive model of pain coping will be measured before and after treatment. The situational variables, including coping responses, mood states, situational appraisals and self-efficacy, will be measured in an experience sampling paradigm four times daily using a hand-held computer. This will be done to minimize retrospective biases that may have hampered earlier studies of treatment process. Dependent variables will be self-report measures of distress, pain, and interference with activities, as well as blood plasma levels of cortisol and selected cytokines, measured at the end of the 6-week treatment period, and at follow-up points thereafter up to a 12-month follow-up. It is expected that the STD+CBT treatment will result in measurable changes in constructs such as self-efficacy and catastrophization, and that these changes will be related to improved outcomes compared to the STD controls. It is also expected that outcome differences between groups will be associated with changes in inflammatory mediators (cytokine levels). Finally, it is suggested that changes in situational treatment process variables will be associated with changes in cytokine levels. The results may indicate the true active mechanisms of successful TMD treatment, if these mechanisms can be successfully identified it would have important implications for the development of more effective treatment programs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CAPSAICIN RECEPTOR SUBTYPES IN PAIN TRANSDUCTION Principal Investigator & Institution: Schumacher, Mark A.; Anesthesia and Perioperative Care; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2006 Summary: (provided by applicant) Despite intense efforts to effectively treat acute and chronic pain, current therapies are still associated with significant side effects including central nervous system depression, development of tolerance and risk of addiction. Since the majority of acute and chronic pain is maintained by the persistent activation of specialized sensory neurons, the selective blockade of pain sensing nerve terminals could represent a novel way to treat pain with fewer unwanted side effects. Recent

Studies

13

advances have been made in the characterization of receptors and ion channels that function to detect painful noxious stimuli. Notably, the vanilloid (capsaicin) receptorVR1 has been isolated and is undergoing intense characterization to determine whether it can direct sensory nerve activation in response to painful stimuli. Because the response properties of sensory neurons are complex, we have investigated whether other related receptor / ion channels exist in sensory neurons. This effort has revealed the existence of vanilloid receptor splice variants. VR.5'sv is one such variant that we isolated that appears insensitive to capsaicin and other noxious stimuli. In this proposal, we are testing the hypothesis that VR.5'sv can block the activation of VR1 in response to noxious stimuli when both proteins are expressed together. Another vanilloid receptor splice variant originally identified in kidney by another laboratory was found to have mechano-sensitive properties and therefore is termed "stretch inactivated channel." SIC is activated by cell shrinkage, and based on its pattern of expression in sensory neurons, it may participate in the detection of noxious hypertonic conditions. Comparison of SIC to VR1 and VR.5'sv has revealed a unique structural feature that could help explain its ability to couple changes in cell shape into channel activation. We propose to study this feature in the hope to better understand how noxious mechanical stimuli are detected by sensory neurons. Although our understanding about VR1 and its splice variants have grown, little is known about what factors control their abundance in the sensory nerve terminals. Using genomic fragments isolated upstream from the vanilloid receptor gene and inserted into reporter plasmids, we will test the hypothesis that tissue derived growth factors positively regulate the amount of RNA encoding VR1 in sensory neurons through their effect on RNA transcription. Moreover, using this assay system, we hope to determine in general what factors regulate VR1, VR.5' sv and SIC. Determining bow these factors increase or decrease the transcription of VR subtypes will provide a potential means to modulate pain transduction and hyperalgesia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CGX-1160, A NON-OPIOID, BROAD-SPECTRUM ANALGESIC Principal Investigator & Institution: Wagstaff, John D.; Cognetix, Inc. 421 Wakara Way, Ste 201 Salt Lake City, Ut 84108 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-JUL-2002 Summary: (provided by applicant): The goal of this proposal is to establish the efficacy of contulakin-G (CGX-1160), a newly discovered analgesic conopeptide for the treatment of chronic pain. Currently chronic pain is treated with a variety of analgesic and adjuvant drugs including: opioids, tricyclic antidepressants, anticonvulsants, and local anesthetics. A significant number of patients, particularly those suffering from neuropathic pain, are refractory to all of the currently available drugs. Furthermore, all of these compounds have significant, dose- and treatment-limiting side effects. Preliminary data suggest that CGX-1160 is an extremely potent analgesic in animal models of persistent pain following intrathecal administration, with a wide separation between efficacy and toxicity, and may represent an alternative therapy for intractable pain. In phase I we will demonstrate the efficacy of CGX-1160 in a broad range of animal pain models including: acute, persistent inflammatory, chronic inflammatory, and neuropathic pain. A series of closely related analogs will be synthesized and compared to the native conopeptide for their in vivo efficacy, and resistance to endogenous peptidases. We will attempt to determine the specific mechanism of action through in vivo and in vitro pharmacological methods. We will also compare the toxicity profile of this compound with morphine. These studies will determine a behavioral therapeutic index for the compounds tested. This will determine which of the analogs will be further

14

Chronic Pain

characterized in formal toxicology testing. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHIMERIC PEPTIDES AS NOVEL ANALGESICS Principal Investigator & Institution: Kream, Richard M.; Professor of Pharmacology; Biochemistry; Suny Downstate Medical Center 450 Clarkson Ave New York, Ny 11203 Timing: Fiscal Year 2001; Project Start 15-JAN-2001; Project End 31-DEC-2004 Summary: (Adapted from applicant's abstract) Important medically-related issues exist as to why acute pain is perceived with high intensity despite the presence of extensive endogenous pain-modulating systems, and why chronic intractable pain arises from pathophysiological sequelae of nerve injury without consistency of symptomatology, etiological factors; and treatment strategies across patient populations. This necessitates an in depth understanding of how spinal excitatory systems, of which the tachykinin substance P (SP) represents a prototypic regulatory peptide, functionally interact with endogenous opioid systems to maintain functional homeostasis of nociceptive signaling and compensatory antinociceptive responsiveness at spinal and supra spinal levels. The foundation of present proposal is based on recent data obtained from in vivo pharmacological testing, and complementary biochemical analyses, of a chimeric peptide newly synthesized by our group: a heptapeptide consisting of overlapping NH2- and COOH-terminal functional domains of the opioid endomorphin-2(EM-2) and SP, respectively. The chimeric molecule YPFFGLM-NH2, designated ESP7, displays agonist activity at both the u-opioid (MOR) and SP (SPR) receptors. Administration of low concentrations of ESP7 by the intrathecal route produces long-lasting analgesia in the rat tail-flick text that is blocked by prior treatment with the opioid antagonist naltrexone. Repeated administration of ESP7 produces opioid-dependent analgesia without loss of potency over five days. In contrast, repeated administration of ESP7 in the presence of the selective SPR antagonist RP67580 results in a rapid loss of analgesic potency consistent with the development of opioid tolerance observed following administration of MOR-preferring opioids; post-hoc administration of ESP7 also effects partial rescue of opioid responsiveness in tolerant animals. We conclude that in vivo activation of SPR-expressing spinal neurons is functionally linked to inhibition of or delayed onset of opioid tolerance, and further hypothesize that coincident activation of MOR- and SPR-expressing systems mimics an ongoing state of reciprocal excitation and inhibition normally encountered in nociceptive processing. Our overall testable hypothesis is thus: chimeric peptides, composed oftwo independent but overlapping moieties contributed by an opioid peptide and substance P, are novel non-tolerance forming analgesics via their combined agonist action at functionally interactive classes of spinal and supra spinal receptors.Within this framework we propose the following three Specific Aims. 1. To evaluate chimeric peptides as novel analgesic agents through targeting of interactive spinal and supra spinal opioid and tachykinin neural systems, 2. To evaluate chimeric peptides in preclinical models of opioid tolerance and of acute and chronic pain, 3. To develop chimeric peptides with overlapping but distinct functional moieties derived from NH2-terminal domains of delta and kappa opioids and the COOH-terminal domain of SP as novel analgesics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CHRONIC LOW BACK PAIN AS A MODEL OF FIBROMYALGIA Principal Investigator & Institution: Clauw, Daniel J.; Associate Professor; Medicine; Georgetown University Washington, Dc 20057

Studies

15

Timing: Fiscal Year 2001; Project Start 15-JUN-1999; Project End 31-MAY-2003 Summary: Fibromyalgia (FM) is defined by a history of widespread pain, and the finding of tender points on examination. Arguably the two most discriminating features of FM are: 1) a generalized disturbance in pain perception, and 2) elevated levels of pronociceptive neuropeptides in the cerebrospinal fluid. The first feature, pain induced by a normally non-painful stimuli, is not surprising since this is a defining feature of FM. But it is not certain how tenderness relates to pain, since population based studies have demonstrated that not all persons who are tender have pain, and vice versa. And it has recently become clear that tender points are a poor measure of a person's inherent tenderness. The meaning of these elevated levels of CSF neuropeptides is likewise unclear. These findings may not be specific for FM, and may be the cause of pain and/or tenderness, or may be the result of pain, tenderness, or some other process. Chronic lower back pain (CLBP) is among the most common medical problems in industrial societies. Despite this, little is actually known about the precise cause for most cases of CLBP. Anatomic and psychosocial factors have been demonstrated to predict only a small portion of the variance in the degree of pain or disability in CLBP. In preliminary studies in CLBP, we have demonstrated that tenderness predicts a significant percentage of the variance in both functional status and pain, more than either the severity of path-anatomical abnormality (i.e., X-ray/MRI),or by psychosocial factors. In a small pilot study of a subset of these patients tenderness was correlated with CSF levels of pro-nociceptive neuropeptides. There are 3 specific aims in the proposed study: 1) To confirm in a cross-sectional study of 200 CLBP patients that pain sensitivity predicts more variance in clinical outcome (e.g. functional status, pain level, Roland index) than either anatomic or psychological factors. Furthermore, we will demonstrate that pain sensitivity is an independent trait, and not a surrogate for psychological factors such as depression, anxiety, or work-related stressors. 2) To demonstrate that an individual's global pain sensitivity is determined primarily by physiologic factors (e.g. neurotransmitters in cerebrospinal fluid) and modified by psychosocial factors (e.g. cognitive and behavior influences on pain perception). We will measure the CSF concentrations of pro-nociceptive peptides such as Substance P and Nerve Growth Factor, and hypothesize that the levels of these substances largely determine an individual's global pain sensitivity. This testing will be done in patients with CLBP and FM, as well as sedentary and non-healthcare-seeking controls. 3) To use alternative methods of pain assessment that are much less influenced by psychological factors (e.g., scaling methods, Multiple Random Staircase), using both pressure and thermal stimuli, to examine the true meaning of tender points, and the relationship between these results, and the results of the above noted physiologic and psychologic parameters in individuals with FM and CLBP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC OPIOID SELF ADMINISTRATION IN THE PRESENCE OF NEUROPATHIC PAIN Principal Investigator & Institution: Martin, Thomas J.; Associate Professor; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: Extensive study of opioids has generated much information regarding the mechanisms of their analgesic and reinforcing properties. Distinct anatomical pathways have been elucidated for the antinociceptive and reinforcing properties of opioids using antagonists and neurotoxin- induced lesions of specific neuronal populations. However, these two important aspects of opioid pharmacology have largely been studied in

16

Chronic Pain

isolation. The analgesic effects of opioids are studied in the laboratory following passive administration, in which the animal does not control the dose or dosing interval. Similarly, the reinforcing effects of opiates are studied in the laboratory in the absence of pain, and little is known regarding the relevance of reinforcing mechanisms identified in this manner to the clinical use of opioids for pain relief. This project seeks to examine the pharmacology of opioids using a self-medication paradigm in rats with nerve injury. These studies will focus on the development of opioid tolerance in the presence of pain and exploration of the mechanisms of tolerance. Dosing will be accomplished through self-administration, in which the animal is allowed to determine the drug quantity necessary to achieve the desirable pharmacological effect. This technique has proven to be invaluable in the study of drug abuse, but is being applied in this project to the study of pain mechanisms and should provide equally invaluable information. Experiments are designed to determine receptor mechanisms related to the development of tolerance as well as to develop strategies for minimizing the development of tolerance and selfdetermined dose escalation through experiments using 24 hr self-administration. Preliminary data show that animals rapidly escalate opioid intake when given 24 hr access to self-administration, and that tolerance to the anti-allodynic effects of opioids results. Initial strategies include using drugs of differing efficacies and a dose-fading procedure to determine the optimum maintenance dose that minimized total dose escalation over time. Intrathecal agents will then be given as adjuvant analgesics as another strategy to inhibit or retard the development of tolerance to opioids and subsequent dose escalation. Parallel clinical studies are proposed to address these concerns in patients self-administering opioids. These studies will hopefully identify mechanisms of tolerance to opioids self- administered for pain relief and strategies to minimize such effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC PAIN IN THE 65+: EVALUATING FUNCTIONAL IMPACTS Principal Investigator & Institution: Rudy, Thomas E.; Professor and Director; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 15-SEP-2001; Project End 31-AUG-2006 Summary: Chronic pain plagues approximately 50 percent of community dwelling older adults, and may cause significant disruption of physical, psychosocial, and cognitive function. Despite the prevalence of this potentially devastating problem, well-controlled studies of chronic pain in older adults that use a comprehensive multidimensional model are lacking. Chronic low back pain (CLBP) is among the most common chronic pain conditions of older adults, affecting approximately 6 million individuals in the United States who are greater than or equal to age 65. CLBP offers a robust model with which to study the comprehensive functional effects of chronic pain in the older adult because of the reliable and valid measures of observed physical capacity, self-reported disability and pathology that have been developed specifically for patients with low back pain. The purpose of this investigation is to broaden our understanding of disability in the older adult with chronic pain. Specifically, we will explore (1) the magnitude of the effect of CLBP on physical, psychosocial, and cognitive functioning in 200 community dwelling older adults greater than or equal to age 65 as compared with 200 pain-free control subjects, (2) the impact of CLBP associated psychosocial and neuropsychological dysfunction on physical function, and (3) whether older adults with chronic pain can be classified using a multiaxial taxonomy that has been demonstrated

Studies

17

in younger chronic pain patients. The laboratory-based physical capacities testing protocol is designed to assess body mechanics, endurance and coordination using ergonomically relevant tasks (e.g., lifting, reaching). Other comprehensive multidimensional assessment measures will include those that have particular relevance to older adults, such as pain intensity, clinical measures of physical performance, disability, sleep, mood, self- efficacy, detailed measures of neuropsychological function, and self perceptions of health and well-being. This study represents the first wellcontrolled, comprehensive examination of the effects of chronic pain on individuals who may be most threatened by the risk of functional decline, that is, community dwelling older adults. Once the effects of chronic pain have been comprehensively described, only then can effective treatment programs be developed to help ameliorate the suffering of these older Americans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC PAIN MANAGEMENT IN PRIMARY CARE Principal Investigator & Institution: Von Korff, Michael R.; Senior Investigator; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JAN-1989; Project End 31-AUG-2004 Summary: This research seeks a more effective and cost-effective integration of medical care and self-care for chronic and recurrent pain in pr5imary care settings. Aim 1: Identify improved methods for analysis of automated health care and medicine use data for TMD pain, headache and back pain patients. Identify potentially modifiable determinants of long-term frequent use of health care and pain medications for these conditions. Study One: We will study determinants of health care and prescription medicine use for pain over a five-year time span. {{Methods for analysis of automated health care and medicine use data will be assessed to test more powerful and informative approaches. Using improved analytic methods,}} we will assess the ability of patient variables to predict and explain frequent use of health care, opioid medications and sedative- hypnotic medications for patients with TMD (n=391), back pain (n=833) and headache (n=869) over a five year time-span. Aim 2: Evaluate the effectiveness of Self-Care Group interventions guided by a stepped care model. Study Two: Data from two randomized controlled trials of Self- Care Groups (SCG) initiated in 1996-98) as part of the current Program Project will be used to identify factors influencing the long-term effectiveness of SCG (participation, baseline severity, self-care orientation, prognostic variables). Study Three: A new randomized controlled trial will evaluate Self-Care Groups fully integrated into primary care. This trial will evaluate the initial benefits and the long-term effectiveness of Self-Care Groups among actively recruited back pain patients (n=250). The intervention will target patients with enduring activity limitations and higher use of health care for back pain {{Patients with continuing activity limitations will receive more intensive intervention according to a stepped care protocol.}} Patients will be followed-up 2, 6, 12 and {{24}} months after randomization. The primary outcome will be activity limitations (Roland Disability Score with added items concerning occupational role disability). Aim 3: Assess the impact of Self-Care Groups (SCG) on long-term health care and prescription medication use. Determine the effect of SCG on health care costs. Study Four: Using automated health care and medicine use data and improved analytic methods, we will investigate the long-term effects of SCG on: (1) use of health care; (2) use of prescription pain medications; and (3) health care costs for back pain (total n from three SCG trials=731). Since the SCG interventions have been shown to reduce worry, enhance confidence in self-care, and

18

Chronic Pain

reduce activity limitations, this research will provide an experimental test of whether modifying these factors reduces subsequent use of health care. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHRONIC PAIN TIVR TO PREVENT PRESCRIPTION DRUG ABUSE Principal Investigator & Institution: Naylor, Magdalena R.; Psychiatry; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): This is an R21 application by a new investigator to utilize Interactive Voice Response (IVR) to develop a new strategy for preventing prescription drug abuse in patients with persistent pain. IVR is a computer-based, automated telephone that enables callers to respond to a recorded voice via the telephone keypad. Using this technology, we developed Therapeutic IVR (TIVR) as an intervention in patients using prescription medication for chronic pain. The TIVR reinforces group Coping Skills Training (CST) given in our pain clinic. It includes an automated daily diary for self monitoring, guided behavioral rehearsals of key CST coping skills, and monthly personalized feedback, all of which can be accessed by patients on demand. In our pilot test, ten subjects with severe, chronic musculoskeletal pain participated in 10 weeks of group CST followed by four months of TIVR. Subsequently, we recruited a second sample of eight patients as a comparison group who were given group CST but not the TIVR. Within subjects analysis (ANOVA) of the TIVR group showed that, compared to baseline values, the maximum mean positive change for nearly all outcome measures occurred at the post TIVR point. Several measures were significantly improved post TIVR despite lack of significance after CST. These included SF-36 Mental Health Composite Score (p