Acute pain management

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Acute Pain Management

This textbook is written as a comprehensive overview of acute pain management. It is designed to guide clinicians through the impressive array of different options available to them and to patients. Since the late 1990s, there has been a flurry of interest in the extent to which acute pain can become chronic pain and how we might reduce the incidence of such chronicity. This overview covers topics related to a wide range of treatments for pain management, including the anatomy of pain pathways, the pathophysiology of severe pain, pain assessment, therapeutic guidelines, analgesic options, organization of pain services, and the role of anesthesiologists, surgeons, pharmacists, and nurses in providing optimal care. It also discusses the use of patient-controlled analgesia and how this may or may not be effective and useful. Dr. Raymond S. Sinatra currently serves as Professor of Anesthesiology at Yale University School of Medicine. He received his MD as well as a PhD in neuroscience at SUNY Downstate School of Medicine and completed his anesthesiology residency at the Brigham & Women’s Hospital, Harvard Medical School. Dr. Sinatra joined the faculty at Yale in 1985 and organized one of the first anesthesiology-based pain management services in the United States. In addition to directing the service, he has served as principal investigator for dozens of clinical protocols evaluating novel analgesics and analgesic delivery systems. Dr. Sinatra has authored more than 130 scientific papers, review articles, and textbook chapters on pain management and obstetrical anaesthesiology and was senior editor of an earlier textbook titled Acute Pain: Mechanisms and Management. Dr. Sinatra annually presents papers and lectures at both national and international meetings and serves as a reviewer for several anaesthesiology and pain management journals. Dr. Oscar A. de Leon-Casasola is Professor of Anesthesiology and Chief of Pain Medicine in the Department of Anesthesiology of the Roswell Park Cancer Institute. His research interests include advances in analgesic therapy, physiology and pharmacology of epidural opioids, perioperative surgical outcomes, thoracic and cardiac anesthesia, acute pain control, and chronic cancer pain. He is a member of the American Society of Regional Anesthesia, American Society of Anesthesiologists, New York State Society of Anesthesiologists, American Pain Society, and Eastern Pain

Association. Dr. de Leon-Casasola has authored or coauthored 115 journal articles, abstracts, and book chapters. He serves as an associate editor for the Latin American Journal of Pain, the Argentinian Journal of Anesthesiology, the Journal of the Spanish Society of Pain, and the Clinical Journal of Pain. He also is editor-in-chief of Techniques in Regional Anesthesia and Pain Management and was listed as an exceptional practitioner by Good Housekeeping magazine in 2003. Dr. Brian Ginsberg is Professor of Anesthesiology and Medical Director of the Division of Acute Pain Therapy in the Department of Anesthesiology of Duke University School of Medicine. Dr. Eugene R. Viscusi is Director of Acute Pain Management and Regional Anesthesia in the Department of Anesthesiology at Thomas Jefferson University in Philadelphia, Pennsylvania, and Associate Professor of Anesthesiology. After receiving a medical degree from Jefferson Medical College, Dr. Viscusi completed a residency in anesthesiology at the University of Pennsylvania in Philadelphia. His research interests include the development of new pain management techniques, outcome studies with pain management, and the development of novel agents and delivery systems for pain management. He developed a novel “nursedriven” model for delivering acute pain management with specially trained nurses that has served as a model for other institutions. Dr. Viscusi also has been a primary investigator for many emerging technologies in the perioperative arena. Dr. Viscusi is a member of numerous professional associations, including the American Society of Anesthesiologists, the American Society of Regional Anesthesiology, and the International Anesthesia Research Society and serves on numerous society committees. Dr. Viscusi has lectured extensively both nationally and internationally, has authored more than 100 book chapters and abstracts, and has authored more than 50 peerreviewed articles in journals including Journal of the American Medical Association, Anesthesiology, Anesthesia & Analgesia, and Regional Anesthesia and Pain Medicine. Dr. Viscusi currently serves on the editorial board of the Clinical Journal of Pain and regularly reviews for many journals. He also has appeared in articles in major media including, Newsweek, the Wall Street Journal, USA Today, and has appeared nationally on televised interviews.

Acute Pain Management Edited by

Raymond S. Sinatra Yale University

Oscar A. de Leon-Casasola Roswell Park Cancer Institute

Brian Ginsberg Duke University

Eugene R. Viscusi Thomas Jefferson University

Foreword

Henry McQuay

CAMBRIDGE UNIVERSITY PRESS

Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo 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/9780521874915 © Raymond S. Sinatra, Oscar A. de Leon-Casasola, Brian Ginsberg, Eugene R. Viscusi 2009 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

978-0-511-51806-5

eBook (NetLibrary)

ISBN-13

978-0-521-87491-5

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 fromerror, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Contents

Contributors

vii

Acknowledgments Foreword: Historical Perspective, Unmet Needs, and Incidence Henry McQuay

xiii

SECTION II: CLINICAL ANALGESIA

11. Qualitative and Quantitative Assessment of Pain Cynthia M. Welchek, Lisa Mastrangelo, Raymond S. Sinatra, and Richard Martinez

xv

SECTION I: PAIN PHYSIOLOGY AND PHARMACOLOGY

1. Pain Pathways and Acute Pain Processing Nalini Vadivelu, Christian J. Whitney, and Raymond S. Sinatra 2. Pathophysiology of Acute Pain M. Khurram Ghori, Yu-Fan (Robert) Zhang, and Raymond S. Sinatra 3. Patient Variables Influencing Acute Pain Management Joshua Wellington and Yuan-Yi Chia 4. Acute Pain: A Psychosocial Perspective Francis J. Keefe

3

21

33

5. Nonsteroidal Anti-Inflammatory Drugs and Acetaminophen: Pharmacology for the Future Jon McCormack and Ian Power

53

6. Local Anesthetics in Regional Anesthesia and Acute Pain Management John Butterworth

70

7. Pharmacology of Novel Non-NSAID Analgesics P. M. Lavand’homme and M. F. De Kock

102

9. Transitions from Acute to Chronic Pain Frederick M. Perkins

109

10. Molecular Basis and Clinical Implications of Opioid Tolerance and Opioid-Induced Hyperalgesia Larry F. Chu, David Clark, and Martin S. Angst

172

13. Oral and Parenteral Opioid Analgesics for Acute Pain Management Raymond S. Sinatra

188

14. Intravenous Patient-Controlled Analgesia Pamela E. Macintyre and Julia Coldrey

204

15. Clinical Applications of Epidural Analgesia Daniel B. Maalouf and Spencer S. Liu

221

17. Regional Anesthesia James Benonis, Jennifer Fortney, David Hardman, and Gavin Martin 18. Regional Anesthesia for Acute Pain Management in the Outpatient Setting Holly Evans, Karen C. Nielsen, Marcy S. Tucker, and Stephen M. Klein

82

8. Pharmacokinetics of Epidural Opioids Bradley Urie and Oscar A. de Leon-Casasola

12. The Role of Preventive Multimodal Analgesia and Impact on Patient Outcome Scott S. Reuben and Asokumar Buvanendran

16. Neuraxial Analgesia with Hydromorphone, Morphine, and Fentanyl: Dosing and Safety Guidelines Susan Dabu-Bondoc, Samantha A. Franco, and Raymond S. Sinatra

41

19. Patient-Controlled Analgesia Devices and Analgesic Infusion Pumps Benjamin Sherman, Ikay Enu, and Raymond S. Sinatra 20. Novel Analgesic Drug Delivery Systems for Acute Pain Management James W. Heitz and Eugene R. Viscusi

114

v

147

230

245

287

302

323

vi

Contents

21. Nonselective Nonsteroidal Anti-Inflammatory Drugs, COX-2 Inhibitors, and Acetaminophen in Acute Perioperative Pain Jonathan S. Jahr, Kofi N. Donkor, and Raymond S. Sinatra

332

22. Perioperative Ketamine for Better Postoperative Pain Outcome Manzo Suzuki

366

33. Acute Pain Management in Sickle Cell Disease Patients Jaya L. Varadarajan and Steven J. Weisman

550

34. Acute Pain Management in Patients with Opioid Dependence and Substance Abuse Sukanya Mitra and Raymond S. Sinatra

564

SECTION IV: SPECIALIST MANAGED PAIN

583

377

35. Pain Management Following Colectomy: A Surgeon’s Perspective Theodore J. Saclarides

24. Nonpharmacological Approaches for Acute Pain Management Stefan Erceg and Keun Sam Chung

589

391

36. Acute Pain Management in the Emergency Department Knox H. Todd and James R. Miner

25. Opioid-Related Adverse Effects and Treatment Options Kok-Yuen Ho and Tong J. Gan

406

26. Respiratory Depression: Incidence, Diagnosis, and Treatment Dermot R. Fitzgibbon

416

23. Clinical Application of Glucocorticoids, Antineuropathics, and Other Analgesic Adjuvants for Acute Pain Management Johan Raeder and Vegard Dahl

SECTION III: ACUTE PAIN MANAGEMENT IN SPECIAL PATIENT POPULATIONS

433

28. Acute Pain Management in the Community Hospital Setting Brian E. Harrington and Joseph Marino

455

29. Ambulatory Surgical Pain: Economic Aspects and Optimal Analgesic Management Tariq M. Malik and Raymond S. Sinatra

476

31. Acute Pain Management for Elderly High-Risk and Cognitively Impaired Patients: Rationale for Regional Analgesia Thomas M. Halaszynski, Nousheh Saidi, and Javier Lopez 32. Postcesarean Analgesia Kate Miller and Ferne Braveman

38. Role of the Pharmacist in Acute Pain Management Leslie N. Schechter

597

607

SECTION V: PAIN MANAGEMENT AND PATIENT OUTCOMES

27. The Acute Pain Management Service: Organization and Implementation Issues Paul Willoughby

30. Pediatric Acute Pain Management Giorgio Ivani, Valeria Mossetti, and Simona Italiano

37. The Nurse’s Perspective on Acute Pain Management Chris Pasero, Nancy Eksterowicz, and Margo McCaffery

487

514

39. Economics and Costs: A Primer for Acute Pain Management Specialists Amr E. Abouleish and Govindaraj Ranganathan 40. Evidence-Based Medicine Tee Yong Tan and Stephan A. Schug 41. Effect of Epidural Analgesia on Postoperative Outcomes Marie N. Hanna, Spencer S. Liu, and Christopher L. Wu 42. Research in Acute Pain Management Craig T. Hartrick and Garen Manvelian 43. Quality Improvement Approaches in Acute Pain Management Christine Miaskowski

623 630

637

646

655

44. The Future of Acute Pain Management Brian Durkin and Peter S. A. Glass

670

Index

679

537

Contributors

Chapter 1

Chapter 3

Nalini Vadivelu, MD CA-3 Resident in Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT

Joshua Wellington, MD, MS Assistant Professor of Clinical Anesthesia and Physical Medicine and Rehabilitation Department of Anesthesia Indiana University Medical Center Indianapolis, IN

Christian J. Whitney, MD Associate Professor of Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT

Yuan-Yi Chia, MD Associate Professor of Anesthesiology Kaohsiung Veterans General Hospital National Yang-Ming University, School of Medicine, and Institute of Health Care Management National Sun Yatsen University Kaohsiung, Taiwan

Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT

Chapter 4 Francis J. Keefe, PhD Pain Prevention and Treatment Research Program Duke University Medical Center Durham, NC

Chapter 2 M. Khurram Ghori, MD Assistant Professor of Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT

Chapter 5

Yu-Fan (Robert) Zhang, MD CA-3 Resident in Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT

Jon McCormack, MBChB, FRCA, MRCP Clinical and Surgical Sciences Anaesthesia Critical Care and Pain Medicine University of Edinburgh Royal Infirmary Little France Edinburgh, UK

Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT

Ian Power, MD Clinical and Surgical Sciences Anaesthesia Critical Care and Pain Medicine University of Edinburgh Royal Infirmary Little France Edinburgh, UK vii

viii

Contributors

Chapter 6

Chapter 11

John Butterworth, MD Robert K. Stoelting Professor and Chairman Department of Anesthesia Indiana University School of Medicine Indianapolis, IN

Cynthia M. Welchek, RPh, MS Clinical Pharmacist Department of Pharmacy Service Yale New Haven Hospital New Haven, CT

Chapter 7

Lisa Mastrangelo, RN, BC, MS Nurse Coordinator Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT

P. M. Lavand’homme, MD, PhD Department of Anesthesiology St Luc Hospital Universit´e Catholique de Louvain Brussels, Belgium M. F. De Kock, MD, PhD Department of Anesthesiology St Luc Hospital Universit´e Catholique de Louvain Brussels, Belgium Chapter 8 Bradley Urie, MD Fellow, Pain Management Department of Anesthesiology University at Buffalo, School of Medicine Buffalo, NY Oscar A. de Leon-Casasola, MD Professor and Vice-Chair for Clinical Affairs Department of Anesthesiology University at Buffalo, School of Medicine Chief, Pain Medicine and Professor of Oncology Roswell Park Cancer Institute Buffalo, NY Chapter 9 Frederick M. Perkins, MD Chief of Anesthesia Veterans Administration Medical Center White River Junction, VT Chapter 10 Larry F. Chu, MD, MS (BCHM), MS (Epidemiology) Assistant Professor Department of Anesthesia Stanford University School of Medicine Palo Alto, CA David Clark, MD, PhD Professor Department of Anesthesia and Pain Management Veterans Affairs Palo Alto Health Care System Palo Alto, CA Martin S. Angst, MD Associate Professor Department of Anesthesia Stanford University School of Medicine Palo Alto, CA

Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT Richard Martinez, MD CA-3 Resident in Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT Chapter 12 Scott S. Reuben, MD Director of Acute Pain Service Department of Anesthesiology Baystate Medical Center Springfield, MA and Professor of Anesthesiology and Pain Medicine Tufts University School of Medicine Boston, MA Asokumar Buvanendran, MD Associate Professor of Anesthesiology Department of Anesthesiology Director of Orthopedic Anesthesia Rush University Medical Center Chicago, IL Chapter 13 Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT Chapter 14 Pamela E. Macintyre, BMedSc, MBBS, MHA, FANZCA, FFPMANZCA Director of Acute Pain Service Consultant Anaesthetist Department of Anaesthesia, Pain Medicine and Hyperbaric Medicine Royal Adelaide Hospital and University of Adelaide Adelaide, Australia

Contributors

Julia Coldrey, MBBS(Hons), FANZCA Consultant Anaesthetist Department of Anaesthesia, Pain Medicine and Hyperbaric Medicine Royal Adelaide Hospital and University of Adelaide Adelaide, Australia

David Hardman, MD Assistant Professor of Anesthesiology Division of Orthopedic, Plastic and Regional Anesthesia Department of Anesthesiology Duke University Health System Durham, NC

Chapter 15 Daniel B. Maalouf, MD, MPH Instructor in Anesthesiology Department of Anesthesia Hospital for Special Surgery The Weill Medical College of Cornell University New York, NY Spencer S. Liu, MD Clinical Professor of Anesthesiology, Director of Acute Pain Service Department of Anesthesia Hospital for Special Surgery The Weill Medical College of Cornell University New York, NY

Gavin Martin, MB, ChB, FRCA Associate Professor of Anesthesiology Division of Orthopedic, Plastic and Regional Anesthesia Department of Anesthesiology Duke University Health System Durham, NC Chapter 18 Holly Evans, MD, FRCPC Assistant Professor Department of Anesthesiology University of Ottawa Ottawa, Ontario, Canada

Chapter 16 Susan Dabu-Bondoc, MD Assistant Professor of Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT Samantha A. Franco, MD CA-3 Resident in Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT

Karen C. Nielsen, MD Assistant Professor Division of Ambulatory Anesthesiology Department of Anesthesiology Duke University Medical Center Durham, NC Marcy S. Tucker, MD, PhD Assistant Professor Division of Ambulatory Anesthesiology Department of Anesthesiology Duke University Medical Center Durham, NC Stephen M. Klein, MD Associate Professor Department of Anesthesiology Duke University Medical Center Durham, NC

Chapter 17 James Benonis, MD Assistant Professor of Anesthesiology Division of Orthopedic, Plastic and Regional Anesthesia Department of Anesthesiology Duke University Health System Durham, NC Jennifer Fortney, MD Assistant Professor of Anesthesiology Division of Orthopedic, Plastic and Regional Anesthesia Department of Anesthesiology Duke University Health System Durham, NC

Chapter 19 Benjamin Sherman, MD CA-3 Resident in Anesthesiology Department of Anesthesiology Acute Pain Management Section Yale University School of Medicine New Haven, CT Ikay Enu, MD CA-3 Resident in Anesthesiology Department of Anesthesiology Acute Pain Management Section Yale University School of Medicine New Haven, CT

ix

x

Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT Chapter 20 James W. Heitz, MD Assistant Professor of Anesthesiology and Medicine Jefferson Medical College Thomas Jefferson University Philadelphia, PA Eugene R. Viscusi, MD Jefferson Medical College Thomas Jefferson University Philadelphia, PA Chapter 21 Jonathan S. Jahr, MD Professor of Clinical Anesthesiology David Geffen School of Medicine at UCLA Los Angeles, CA Kofi N. Donkor, PharmD Staff Pharmacist Department of Pharmaceutical Services UCLA Medical Center Los Angeles, CA Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Section Department of Anesthesiology Yale University School of Medicine New Haven, CT Chapter 22 Manzo Suzuki, MD Instructor Department of Anesthesiology Second Hospital Nippon Medical School Kanagawa, Japan Chapter 23 Johan Raeder, MD, PhD Professor in Anesthesiology Chairman of Ambulatory Anesthesia Medical Faculty University of Oslo Ullevaal University Hospital Oslo, Norway Vegard Dahl, MD, PhD Head Department of Anaesthesia and Intensive Care Professor in Anesthesiology University of Oslo Asker and Baerum Hospital Rud, Norway

Contributors

Chapter 24 Stefan Erceg, MD CA-3 Resident in Anesthesiology Department of Anesthesiology Pain Management Service Yale University School of Medicine New Haven, CT Keun Sam Chung, MD Associate Professor of Anesthesiology Department of Anesthesiology Pain Management Service Yale University School of Medicine New Haven, CT Chapter 25 Kok-Yuen Ho, MBBS, MMed, FIPP, DAAPM Department of Anaesthesia and Surgical Intensive Care Singapore General Hospital Singapore, Singapore Tong J. Gan, MB, FRCA, FFARCSI Department of Anesthesiology Duke University Medical Center Durham, NC Chapter 26 Dermot R. Fitzgibbon, MD Associate Professor of Anesthesiology Adjunct Associate Professor of Medicine University of Washington School of Medicine Seattle, WA Chapter 27 Paul Willoughby, MD Associate Professor Department of Anesthesiology Stony Brook Health Sciences Center Stony Brook, NY Chapter 28 Brian E. Harrington, MD Staff Anesthesiologist Billings Clinic Billings, MT Joseph Marino, MD Attending Anesthesiologist Director of Acute Pain Management Service Huntington Hospital Huntington, NY Chapter 29 Tariq M. Malik, MD Assistant Professor of Anesthesiology University of Chicago School of Medicine Department of Anesthesia and Critical Care Chicago, IL

Contributors

Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT Chapter 30

Chapter 33 Jaya L. Varadarajan, MD Attending Physician Children’s Hospital of Wisconsin Assistant Professor of Anesthesiology Medical College of Wisconsin Milwaukee, WI

Giorgio Ivani, MD Professor Chairman, Department for the Ladies Staff Doctors Department of Pediatric Anesthesiology and Intensive Care Regina Margherita Children’s Hospital Turin, Italy

Steven J. Weisman, MD Jane B. Pettit Chair in Pain Management Children’s Hospital of Wisconsin Professor of Anesthesiology and Pediatrics Medical College of Wisconsin Milwaukee, WI

Valeria Mossetti, MD Department of Pediatric Anesthesiology and Intensive Care Regina Margherita Children’s Hospital Turin, Italy

Sukanya Mitra, MD Reader Department of Anaesthesia and Intensive Care Government Medical College & Hospital Chandigarh, India

Simona Italiano, MD Department of Pediatric Anesthesiology and Intensive Care Regina Margherita Children’s Hospital Turin, Italy

Raymond S. Sinatra, MD, PhD Professor of Anesthesiology Director of Acute Pain Management Service Department of Anesthesiology Yale University School of Medicine New Haven, CT

Chapter 34

Chapter 31 Thomas M. Halaszynski, DMD, MD, MBA Associate Professor of Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT Nousheh Saidi, MD Assistant Professor of Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT Javier Lopez, MD CA-3 Resident in Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT Chapter 32 Kate Miller, MD Chief Resident in Anesthesiology Department of Anesthesiology Yale University School of Medicine New Haven, CT Ferne Braveman, MD Professor Department of Anesthesiology Yale University School of Medicine New Haven, CT

Chapter 35 Theodore J. Saclarides, MD Professor of Surgery Head of the Section of Colon and Rectal Surgery Department of General Surgery Rush University Medical Center Chicago, IL Chapter 36 Knox H. Todd, MD, MPH Professor of Emergency Medicine Albert Einstein College of Medicine Director of the Pain and Emergency Medicine Institute Department of Emergency Medicine Beth Israel Medical Center New York, NY James R. Miner, MD, FACEP Associate Professor of Emergency Medicine University of Minnesota Medical School Department of Emergency Medicine Hennepin County Medical Center Minneapolis, MN Chapter 37 Chris Pasero, MS, RN-BC, FAAN Pain Management Educator and Clinical Consultant El Dorado Hills, CA

xi

xii

Contributors

Nancy Eksterowicz, MSN, RN-BC, APN Advanced Practice Nurse in Pain Services University of Virginia Health System Charlottesville, VA Margo McCaffery, MS, RN-BC, FAAN Consultant in the Care of Patients with Pain Los Angeles, CA Chapter 38 Leslie N. Schechter, PharmD Advanced Practice Pharmacist Thomas Jefferson University Hospital Philadelphia, PA Chapter 39 Amr E. Abouleish, MD, MBA Professor Department of Anesthesiology University of Texas Medical Branch Galveston, TX Govindaraj Ranganathan, MD, FRCA Assistant Professor Department of Anesthesiology University of Texas Medical Branch Galveston, TX Chapter 40 Tee Yong Tan, MBBS, M Med (Anesthesiology) Department of Anaesthesia Alexandra Hospital Singapore, Singapore Stephan A. Schug, MD, FANZCA, FFPMANZCA Department of Anaesthesia and Pain Medicine Royal Perth Hospital Perth, Australia Chapter 41 Marie N. Hanna, MD Associate Professor Department of Anesthesiology and Critical Care Medicine The Johns Hopkins University Baltimore, MD

Spencer S. Liu, MD Clinical Professor Department of Anesthesia Hospital for Special Surgery The Weill Medical College of Cornell University New York, NY Christopher L. Wu, MD Associate Professor Department of Anesthesiology and Critical Care Medicine The Johns Hopkins University Baltimore, MD Chapter 42 Craig T. Hartrick, MD, DABPM, FIPP Anesthesiology Research William Beaumont Hospital Royal Oak, MI Garen Manvelian, MD Independent Pharmaceutical and Biotechnology Industry Consultant San Diego, CA Chapter 43 Christine Miaskowski, RN, PhD, FAAN Professor and Associate Dean for Academic Affairs Department of Physiological Nursing University of California San Francisco, CA Chapter 44 Brian Durkin, DO Director of Acute Pain Service Assistant Professor of Clinical Anesthesiology Department of Anesthesiology Stony Brook University Medical Center Stony Brook, NY Peter S. A. Glass, MB, ChB Professor and Chairman Department of Anesthesiology Stony Brook University Medical Center Stony Brook, NY

Acknowledgments

To my wife Linda and daughters Kristin, Lauren, and Elizabeth who have encouraged and supported me during my academic career. Raymond S. Sinatra To my family for all the support throughout life. Oscar A. de Leon-Casasola To my wife Brenda and my children Nicki, Terri and Aaron. Thanks for your support and help. Brian Ginsberg To my children, Christina and Andrew, my wife, Beverly, and my parents who have supported me throughout my career. Eugene R. Viscusi

xiii

Foreword: Historical Perspective, Unmet Needs, and Incidence Henry McQuay

It is a delight and an honor to be asked to write the foreword for this text on acute pain management. We have an impressive array of different options for acute pain management (Figure F.1), and not all of them were available in the late 1970s. As a simple example of the improvement in knowledge, compare the analgesic efficacy work of Moertel and colleagues1 with that available to us now (Figure F.2). We can use these league tables of relative efficacy to say with some authority how well on average the different analgesics compare. This leaves us, of course, with the real-world issues of, for example, how the individual patient will react, prior experience, and drug-drug interactions. Yet, we have the continued embarrassment of surveys that show that a substantial number of patients still endure severe pain after their surgery or trauma. This “unmet need” is a mixture of our failure to implement effective analgesic strategies and the inadequacy of those strategies. Acute pain teams date back to the early 1980s, and their policies and education of both patients and caregivers have made a difference. There is little excuse now for the failure to provide adequate analgesia for straightforward cases, but we need to acknowledge that there are also difficult cases. Many of the patients whose care causes problems for the teams seem, locally for us at least, to be the patients with chronic pain problems who are already on substantial analgesic therapy (e.g., chronic gastrointestinal disease) or substance abusers. Things the teams can do well include the education and patient advocacy roles within the institution. Things they may struggle with include changing behavior and provision of seamless care across nights and weekends. Since the late 1990s there has been a flurry of interest in the extent to which acute pain can become chronic pain and how we might reduce the incidence of such chronicity. Perhaps the most important thing this foreword points out is the sheer scale of the problem. From the chronic pain perspective, it appears now that surgery may be the most common cause of nerve damage pain and should perhaps be something that patients are warned about as a possibility in the consenting process. Mechanistically, one can ask what happens to cause

this surgical pain to become chronic. I have always been skeptical that there is some psychological factor, pejoratively some weakness, that causes some patients to have the problem and others not. As an example, take a patient who had an inguinal herniorrhaphy 3 years ago: the procedure was performed perfectly and result was perfect. This year he had the other side done, and the same procedure was performed by the same surgeon. The patient described very severe postoperative pain, qualitatively and quantitatively quite different from the first operation, and this severe pain persisted. Something happened to cause the pain, and one cannot invoke a psychological explanation because of the perfect result the first time. What can we do about this? We still have no strong evidence that analgesia delivered before the pain does anything radically different from the same analgesia given after the pain, let alone that it preempts the development of this type of chronicity. It may be that unexpected severe pain is a red flag, but that is not easy to spot given the huge variations in pain intensity experienced after a given procedure. But it might be something we could pursue. Teasing apart precisely what happens during surgery would be another approach. The measurement of the analgesic efficacy of preemptive strategies is another of the outstanding methodological issues in acute pain management. Our current methods allow us to measure the relative change in pain intensity. If the patient has no pain initially, then the method is invalid. This is the conundrum in measurement of the analgesic efficacy of preemptive strategies, because we have no idea whether the patient would have had no pain without the intervention. We claim that the patient had no pain because of the intervention, but they may not have had any pain without it. A second cause of methodological angst is the use of patientcontrolled analgesia (PCA) as an outcome measure. Many of the current crop of studies – for instance, those studying prophylactic antiepileptic drugs – use PCA in this way and report reduced PCA opioid consumption compared with controls. Unfortunately, this difference in consumption is not reported at valid equivalence in pain scores in the two groups. The control groups

xv

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Foreword

Remove the cause of pain

Medication

Surgery, splinting

Non-opioid aspirin & other NSAIDs, acetaminophen combinations

Regional analgesia

High-tech epidural infusion, local anaesthetic ± opioid

Opioid aspirin & other NSAIDs, acetaminophen combinations

Physical methods

Low-tech nerve blocks, local anaesthetic ± opioid

Psychological approaches

Relaxation, psychoprophylaxis, hypnosis

Physiotherapy, manipulation, TENS, acupuncture, ice

Figure F.2: Relative analgesic efficacy of analgesics in postoperative pain: number-needed-to-treat (NNT) for at least 50% pain relief over 6 hours compared with placebo in single-dose trials of acute pain.

Figure F.1: The different options for acute pain management.

commonly fail to use the PCA to lower their pain scores to the same level as is seen in the “active” group. Unless the pain scores are equivalent, it is very difficult to interpret the difference in PCA consumption. We need urgently to establish the validity of PCA as an outcome measure. The editors and the authors of this book are to be congratulated on keeping academic and practical attention focused on acute pain, because there is room to both improve our current

practice by learning from the best and try to answer some of the important outstanding issues. Henry McQuay Nuffield Professor of Clinical Anaesthetics University of Oxford REFERENCE 1.

Moertel CG, Ahmann DL, Taylor WF, Schwartau N. Relief of pain by oral medications. JAMA. 1974;229:55–59.

Acute Pain Management

SECTION I

Pain Physiology and Pharmacology

1 Pain Pathways and Acute Pain Processing Nalini Vadivelu, Christian J. Whitney, and Raymond S. Sinatra

Understanding the anatomical pathways and neurochemical mediators involved in noxious transmission and pain perception is key to optimizing the management of acute and chronic pain. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Although acute pain and associated responses can be unpleasant and often debilitating, they serve important adaptive purposes. They identify and localize noxious stimuli, initiate withdrawal responses that limit tissue injury, inhibit mobility thereby enhancing wound healing, and initiate motivational and affective responses that modify future behavior. Nevertheless, intense and prolonged pain transmission,1 as well as analgesic undermedication, can increase postsurgical/traumatic morbidity, delay recovery, and lead to development of chronic pain (see also Chapter 11, Transitions from acute to persistent pain). This chapter focuses on the anatomy and neurophysiology of pain transmission and pain processing. Particular emphasis is directed to mediators and receptors responsible for noxious facilitation, as well as to factors underlying the transition from acute to persistent pain.

With regard to a more recent classification, pain states may be characterized as physiologic, inflammatory (nociceptive), or neuropathic. Physiologic pain defines rapidly perceived nontraumatic discomfort of very short duration. Physiologic pain alerts the individual to the presence of a potentially injurious environmental stimulus, such as a hot object, and initiates withdrawal reflexes that prevent or minimize tissue injury. Nociceptive pain is defined as noxious perception resulting from cellular damage following surgical, traumatic, or disease-related injuries. Nociceptive pain has also been termed inflammatory 6 because peripheral inflammation and inflammatory mediators play major roles in its initiation and development. In general, the intensity of nociceptive pain is proportional to the magnitude of tissue damage and release of inflammatory mediators. Somatic nociceptive pain is well localized and generally follows a dermatomal pattern. It is usually described as sharp, crushing, or tearing in character. Visceral nociceptive pain defines discomfort associated with peritoneal irritation as well as dilation of smooth muscle surrounding viscus or tubular passages.7 It is generally poorly localized and nondermatomal and is described as cramping or colicky. Moderate to severe visceral pain is observed in patients presenting with bowel or ureteral obstructions, as well as peritonitis and appendicitis. Visceral pain radiating in a somatic dermatomal pattern is described as referred pain. Referred pain8 may be explained by convergence of noxious input from visceral afferents activating second-order cells that are normally responsive to somatic sensation. Because of convergence, pain emanating from deep visceral structures may be perceived as well-delineated somatic discomfort at sites either adjacent to or distant from internal sites of irritation or injury. The process of neural sensitization and the clinical term hyperalgesia9 describe an exacerbation of acute nociceptive pain, as well as discomfort in response to sensations that normally would not be perceived as painful. These changes, termed hyperpathia10 and allodynia,11 although common following severe or extensive injuries, are most pronounced in patients developing persistent and neuropathic pain. Hyperalgesia can be

C L A S S I F I C AT I O N O F PA I N

Pain can be categorized according to several variables, including its duration (acute, convalescent, chronic), its pathophysiologic mechanisms (physiologic, nociceptive, neuropathic),2 and its clinical context (eg, postsurgical, malignancy related, neuropathic, degenerative). Acute pain3 follows traumatic tissue injuries, is generally limited in duration, and is associated with temporal reductions in intensity. Chronic pain4 may be defined as discomfort persisting 3–6 months beyond the expected period of healing. In some chronic pain conditions, symptomatology, underlying disease states, and other factors may be of greater clinical importance than definitions based on duration of discomfort.5 Clinical differentiation between acute and chronic pain is outlined in Table 1.1. 3

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Nalini Vadivelu, Christian J. Whitney, and Raymond S. Sinatra

Table 1.1: Clinical Differentiations between Acute and Chronic Pain

Table 1.2: Characteristics of Hyperalgesia

Acute Pain

Chronic Pain

Hyperalgesia

1. Usually obvious tissue damage

1. Multiple causes (malignancy, benign)

2. Distinct onset

2. Gradual or distinct onset.

3. Short, well characterized duration

3. Persists after 3–6 mo of healing

4. Resolves with healing

4. Can be a symptom or diagnosis.

Defines a state of increased pain sensitivity and enhanced perception following acute injury that may persist chronically. The hyperalgesic region may extend to dermatomes above and below the area of injury and is associated with ipsilateral (and occasionally contralateral) muscular spasm/immobility. (Hyperalgesia is may be observed following incision, crush, amputation, and blunt trauma.) Primary hyperalgesia

5. Serves a protective function

5. Serves no adaptive purpose

Increased pain sensitivity at the injury site

6. Effective therapy is available

6. May be refractory to treatment

Related to peripheral release of intracellular or humoral noxious mediators

classified into primary and secondary forms (Table 1.2). Primary hyperalgesia12 reflects sensitization of peripheral nociceptors and is characterized by exaggerated responses to thermal stimulation at or in regions immediately adjacent to the site of injury. Secondary hyperalgesia13 involves sensitization within the spinal cord and central nervous system (CNS) and includes increased reactivity to mechanical stimulation and spread of the hyperalgesic area.13 Enhanced pain sensitivity extends to uninjured regions several dermatomes above and below the initial site of injury. The stimulus response associated with primary and secondary hyperalgesia is outlined in Figure 1.1. Neuropathic pain is defined by the International Association for the Study of Pain as “pain initiated or caused by a pathologic lesion or dysfunction” in peripheral nerves and CNS. Some authorities have suggested that any chronic pain state associated with structural remodeling or “plasticity” changes should be characterized as neuropathic.1 Disease states associated with classic neuropathic sysmptoms include infection (eg, herpes zoster), metabolic derangements (eg, diabetic neuropathy), toxicity (eg, chemotherapy), and Wallerian degeneration secondary to trauma or nerve compression. Neuropathic pain is usually constant and described as burning, electrical, lancinating, and shooting. Differences between the pathophysiologic aspects of physiologic, nociceptive, and neuropathic pain are outlined in Table 1.3. A common characteristic of neuropathic pain is the paradoxical coexistence of sensory deficits in the setting of increased noxious sensation.14 By convention, symptoms related to peripheral lesions are termed neuropathic, whereas symptoms related to spinal cord injuries are termed myelopathic.15 Causalgia or Worst Pain

“Hyperalgesia”

No Pain

Normal Response

Allodynia

Increasing Stimulus Intensity

Figure 1.1: Stimulus response alteration observed with hyperalgesia.

Secondary hyperalgesia Increased pain sensitivity at adjacent, uninjured sites Related to changes in excitability of spinal and supraspinal neurons Abnormal sensations associated with hyperalgesia Hyperpathia (increased or exaggerated pain intensity with minor stimulation) Allodynia (nonnoxious sensory stimulation is perceived as painful) Dysesthesia (unpleasant sensation at rest or movement) Paresthesia [unpleasant often shock-like or electrical sensation precipitated by touch or pressure (CRPS-II causalgia)]

chronic regional pain syndrome II16 describes pain following injury to sensory nerves, whereas discomfort associated with injury or abnormal activity of sympathetic fibers is termed reflex sympathetic dystrophy or chronic regional pain syndrome I.17 Finally, it is well recognized that certain acute traumatic and chronic pain conditions are associated with a mixture of nociceptive and neuropathic pain. Symptoms are proportional to the extent of neural versus nonneural tissue injuries. Clinical appreciation of the qualitative factors of the pain complaint helps guide the caregiver in differentiating between pain categories (Table 1.4). PA I N P E RC E P T I O N

A number of theories have been formulated to explain noxious perception.18 One of the earliest ideas, termed the specificity theory, was proposed by Descartes.19 The theory suggested that specific pain fibers carry specific coding that discriminates between different forms of noxious and nonnoxious sensation. The intensity theory, proposed by Sydenham,20 suggested that the intensity of the peripheral stimulus determines which sensation is perceived. More recently, Melzack and Wall21 proposed the gate control theory and suggested that sensory fibers of differing specificity stimulate second-order spinal neurons (dorsal horn transmission cell or wide dynamic range [WDR] neuron) that, depending on their degree of facilitation or inhibition, fire at varying intensity. Both large- and small-diameter afferents can activate “transmission” cells in dorsal horn; however, large sensory fibers also activate inhibitory substantia gelatinosa (SG) cells.22 Indeed, it is the neurons and circuitry within the substantia gelatinosa that determine whether the “gate” is opened

Pain Pathways and Acute Pain Processing

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Table 1.3: Pathophysiologic Representation of Pain Category

Cause

Symptom

Examples

Physiologic

Brief exposure to a noxious stimulus

Rapid yet brief pain perception

Touching a pin or hot object

Nociceptive/inflammatory

Somatic or visceral tissue injury with mediators having an impact on intact nervous tissue Damage or dysfunction of peripheral nerves or CNS

Moderate to severe pain, described as crushing or stabbing

Surgical pain, traumatic pain, sickle cell crisis

Severe lancinating, burning or electrical shock like pain

Neuropathy, CRPS. Postherpetic Neuralgia

Combined somatic and nervous tissue injury

Combinations of symptoms; soft tissue plus radicular pain

Low back pain, back surgery pain

Neuropathic Mixed

Table 1.4: Qualitative Aspects of Pain Perception 1. Temporal: onset (when was it first noticed?) and duration (eg, acute, subacute, chronic) 2. Variability: constant, effort dependent (incident pain), waxing and waning, episodic “flare” 3. Intensity: average pain, worst pain, least pain, pain with activity of living 4. Topography: focal, dermatomal, diffuse, referred, superficial, deep 5. Character: sharp, aching, cramping, stabbing, burning, shooting 6. Exacerbating/Relieving: worse at rest, with movement or no difference; incident pain is worse with movement (stretching and tearing of injured tissue); intensity changes with touch, pressure, temperature 7. Quality of life: interfere with movement, coughing, ambulation, daily life tasks, work, etc.

or closed.23 Substantia gelatinosa cells close the gate by directly suppressing transmission cells. In contrast, increased activity in small-diameter fibers decreases the suppressive effect of SG cells and opens the gate. Peripheral nerve injuries also open the gate by increasing small fiber activity and reducing large fiber inhibition.24 Finally, descending inhibition from higher CNS centers and other inhibitory interneurons can also suppress transmission cells and close the gate. Some aspects of the gate control theory have fallen out of favor; nevertheless, pain processing in dorsal horn and, ultimately, pain perception are dependent on the degree of noxious stimulation, local and descending inhibition, and responses of second-order transmission cells. A schematic representation of the gate control system is presented in Figure 1.2. Woolf and coworkers have proposed a new theory to explain pain processing.27 They suggest that primary and secondary hyperalgesia as well as qualitative differences among physiologic, inflammatory, and neuropathic pain reflect sensitization of both peripheral nociceptors and spinal neurons (Figure 1.3). Noxious perception is the result of several distinct processes that begin in the periphery, extend up the neuraxis, and terminate at supraspinal regions responsible for interpretation and reaction. The process includes nociceptor activation, neural conduction, spinal transmission, noxious modulation, limbic and frontal-cortical perception, and spinal and supraspinal responses. The process of central sensitization, particularly

within the SG, appears to be the key that unlocks the dorsal horn gate, thereby facilitating pain transmission. Identifying mediators that increase or diminish spinal sensitization and help close the gate will be important targets for treating pain in the near future.23 The anatomic pathways mediating pain perception are outlined in Figure 1.4. TRANSDUCTION

Transduction27 defines responses of peripheral nociceptors to traumatic or potentially damaging chemical, thermal, or mechanical stimulation. Noxious stimuli are converted into a calcium ion– (Ca2+ ) mediated electrical depolarization within the distal fingerlike nociceptor endings. Peripheral noxious mediators are either released from cells damaged during injury or as a result of humoral and neural responses to the injury. Cellular damage in skin, fascia, muscle, bone, and ligaments is associated with the release of intracellular hydrogen (H+ ) and potassium (K+ ) ions, as well as arachadonic acid (AA) from lysed cell membranes. Accumulations of AA stimulate and upregulate the cyclooxygenase 2 enzyme isoform (COX-2) that converts AA into biologically active metabolites, including prostaglandin E2 (PGE2 ), prostaglandin G2 (PGG2 ), and, later, prostaglandin H2 (PGH2 ). Prostaglandins28 and intracellular H+ and K+ ions play key roles as primary activators of peripheral nociceptors. They also initiate inflammatory responses and peripheral sensitization that increase tissue swelling and pain at the site of injury.

Central Control

Descending Modulation

Large fibers

-

+ Input

SG

Small fibers

-

+ T

-

Ascending Action System

- +

Dorsal Horn “Gate”

Figure 1.2: The gate control theory of pain processing. T = Secondorder transmission cell; SG = substantia gelatinosa cell. (Modified from Melzack R and Wall PD, Science. 1965;150(699):971–979.).21

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Nalini Vadivelu, Christian J. Whitney, and Raymond S. Sinatra

Low intensity Stimulation

Low threshold Aβ fiber

PNS

Low intensity stimulation

High intensity Stimulation

Low threshold mechanoreceptor Aβ

Sensitized nociceptor Aδ and C fibers

PNS

High threshold Aδ and c fiber nociceptors

CNS

CNS Dorsal Horn Cells

Hyperexcitable dorsal horn neuron Innocuous sensation

Pain

Brief Pain

(b)

(a)

Figure 1.3: (a) The sensitization theory of pain perception suggests that brief high-intensity noxious stimulation in the absence of tissue injury activates the nociceptive endings of unmyelinated or thinly myelinated (high-threshold) fibers, resulting in physiologic pain perception of short duration. Other low-threshold sensory modalities (pressure, vibration, touch) are carried by larger-caliber (low-threshold) fibers. Large and small fibers make contact with second-order neurons in the dorsal horn. (b) Following tissue injuries and release of noxious mediators, peripheral nociceptors become sensitized and fire repeatedly. Peripheral sensitization occurs in the presence of inflammatory mediators, which in turn increases the sensitivity of high-threshold nociceptors as well as the peripheral terminals of other sensory neurons. This increase in nociceptor sensitivity, lowering of the pain threshold, and exaggerated response to painful and nonpainful stimuli is termed primary hyperalgesia. The ongoing barrage of noxious impulses sensitizes second-order transmission neurons in dorsal horn via a process termed wind-up. Central sensitization results in secondary hyperalgesia and spread of the hyperalgesic area to nearby uninjured tissues. Inhibitory interneurons and descending inhibitory fibers modulate and suppress spinal sensitization, whereas analgesic under medication and poorly controlled pain favors sensitization. In certain settings central sensitization may then lead to neurochemical/neuroanatomical changes (plasticity), prolonged neuronal discharge and sensitivity (long-term potentiation), and the development of chronic pain. (Modified from Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765–1769.)1

Limbic Cortex Sensory Cortex

Thalamus Trauma Descending Pathway Nociceptor Noxious Fiber

Ascending Pathways Central grey Mid Brain

Dorsal Horn

Motor Efferent

Spinal Cord R Sinatra, 2007

Figure 1.4: An anatomical overview of pain pathways. Noxious information is conveyed from peripheral nociceptors to the dorsal horn via unmeylinated and myelinated noxious fibers. Second-order spinal neurons send impulses rostrally via two distinct pathways, the neospinothalamic and paleospinothalamic tracts. These cells also activate motor and sympathetic efferents within the spinal cord. Ascending tracts make contacts in the brainstem and midbrain, central gray, and thalamus. Projections are then made with the frontal and limbic cortex. Descending fibers emanating from cortex, hypothalamus, and brainstem project to the spinal cord to modulate pain transmission.

In addition to PGEs, leukotrienes,29 5-hydroxytryptamine (5-HT),30 bradykinin (BK),31 and histamine32 released following tissue injury are powerful primary and secondary noxious sensitizers. 5-hydroxytryptamine released after thermal injury sensitizes primary afferent neurons and produces mechanical allodynia and thermal hyperalgesia via peripheral 5-HT2a receptors.33 Bradykinin’s role in peripheral sensitization is mediated by Gprotein-coupled receptors,1 B1 and B2, that are expressed by the primary nociceptors. When activated by BK and kallidin, the receptor-G-protein complex strengthens inward Na+ flux, whereas it weakens outward K+ currents, thereby increasing nociceptor excitability. These locally released substances increase vascular permeability, initiate neurogenic edema, increase nociceptor irritability, and activate adjacent nociceptor endings. The resulting state of peripheral sensitization is termed primary hyperalgesia. In addition to locally released and humoral noxious mediators, neural responses play an important role in maintaining both peripheral sensitization and primary hyperalgesia. Bradykinin, 5-HT, and other primary mediators stimulate orthodromic transmission in sensitized nerve endings and stimulate the release of peptides and neurokinins, including calcitonin gene-related protein (CGRP),34 substance P (sP),35 and cholocystokinin (CCK),36 in and around the site of injury. Substance P, via a feedback loop mechanism, enhances peripheral sensitization by facilitating further release of bradykinin, histamine from mast cells, and 5-HT. Calcitonin gene-related protein is a 37-amino-acid peptide found in the peripheral and central terminals of more than 50% of C fibers and 35% of Aδ fibers.37

Pain Pathways and Acute Pain Processing

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Nociceptive Ending (Primary Afferent Fiber)

“Noxious Soup”

Na+

Ca++ Peptides- TRP sP, CCK, CGRP Local & Vascular Mediators- Traumatic Bradykinin, MediatorsCytokines K+, H+, Histamine, PGE 5HT ATP TRP Neural MediatorsEpinephrine, Norepinephrine

Action Potential

Ca++

Generator Potential R Sinatra 2007

Figure 1.5: Pain is detected by unmyelinated nerve endings, termed nociceptors, that innervate skin, bone, muscle, and visceral tissues. Nociceptor activation initiates a depolarizing Ca2+ current or generator potential. Generator potentials depolarize the distal axonal segment and initiate an inward Na+ current and self-propagating action potential. Following tissue injury, cellular mediators (potassium, hydrogen ions, and prostaglandin released from damaged cells, as well as bradykinin [BK] released from damaged vessels) activate the terminal endings (nociceptors) of sensory afferent fibers. Prostaglandin (PGE), synthesized by cyclooxygenase 2, is responsible for nociceptor sensitization and plays a key role in peripheral inflammation. Orthodromic transmission in sensitized afferents leads to the release of peptides (substance P (sP), cholycystokinin (CCK), and calcitonin gene-related peptide (CGRP) in and around the site of injury. Substance P is responsible for further release of BK and also stimulates release of histamine from mast cells and 5HT from platelets, which further increases vascular permeability (neurogenic edema) and nociceptor irritability. The release of these mediators and others, such as serotonin (5HT) and cytokines, creates a “noxious soup” that exacerbates the inflammatory response, recruits adjacent nociceptors, and results in primary hyperalgesia. Reflex sympathetic efferent responses may further sensitize nociceptors by releasing noradrenaline and, indirectly, by stimulating further release of BK and sP and leading to peripheral vasoconstriction and trophic changes.

Like sP, CGRP38 is produced in the cell bodies of primary nociceptors located in the dorsal root ganglion. Following axonal transport to peripheral and central terminals, these substances initiate mechanical and thermal hyperalgesia. When released at peripheral endings, CGRP enhances PGE39 and histamineinduced vasodilation and inflammatory extravasation. It also prolongs the effect of sP by inhibiting its peripheral metabolic breakdown.40 Finally, reflex-sympathetic efferent responses also sensitize nociceptors by releasing norepinephrine, which produces peripheral vasoconstriction at the site of injury. Norepinephrine also stimulates release of BK and sP and leads to atrophic changes in bone and muscle. Peripheral sensitization is also associated with release of nerve growth factor, which alters intracellular signaling pathways and initiated posttranslational regulatory changes, including phosphorylation of tyrosine kinase and G proteins. These alterations markedly increase the sensitivity and excitability of distal nociceptor terminals.41 For example, nociceptors are activated at lower temperatures (< 40◦ C) and in response to lower concentrations of PGE2 and other primary mediators. Acute tissue injury results in an increased synthesis and extravasation of humoral proinflammatory cytokines, such as interleukin- (IL) 1β and IL-6. These cytokines play an important role in exacerbating edematous and irritative components of inflammatory pain.42 Studies have shown that elevated levels

of IL-1β result in allodynia and the development of persistent pain,42 whereas effective postoperative analgesia decreases proinflammatory cytokines levels.43,44 According to Bessler et al,42 genetic polymorphisms influence production of proinflammatory cytokines and may contribute to observed interindividual differences in postoperative pain intensity scores and variations in morphine consumption. The inflammatory mediators and proinflammatory cytokines described above activate transducer molecules such as the transient receptor potential (TRP) ion channel.1 At least 8 different TRP ion channels have been identified and respond differentially to thermal, traumatic, and chemical 14 evoked mediators within the microenvironment. The TRP-VI/capsaicin ion channel has been well described. This 4-unit receptor contains a central ion channel that permits inward Ca2+ and Na+ currents following stimulation by H+ ions, heat, and direct application of capsaicin,45 the active chemical compound found in hot pepper. The inward flux of Ca2+ via TRP ion channels is responsible for the generator potential.31 Generator potentials summate and depolarize the distal axonal segment and the resulting action potential is then conducted centrally to terminals in the dorsal horn. The “noxious soup” of local humoral and neural mediators released following acute tissue injury as well as the nociceptor response to peripheral injury are summarized in Figure 1.5.

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Table 1.5: Classification of Primary Afferent Nerve Fibers Characteristic

Aβ

Aδ

C fibers

Diameter size

Largest

Small

Very small

Degree of myelination

Myelinated

Thinly myelinated

Unmyelinated

Conduction velocity

Very Fast

Fast

Slow

30–50 m/s

5–25 m/s

G mutation being the most common, might be associated with the clinical effects of opioid analgesics.59,61 In vitro, the binding of endorphin to the receptor of a homozygous G allele has been shown to be tighter by 3-fold compared with its binding to a homozygous A allele.62 Moreover, a recent report suggested that cancer patients who were homozygous for the G118 variant required higher doses of oral morphine for long-term treatment of pain.60 Romberg et al63,64 studied the pharmacokinetics and pharmacodynamics of morphine6-glucuronide (M6G), a μ-opioid agonist, and observed that A118G mutation of the human μ-opioid receptor gene also reduced analgesic responses to M6G. This genetic variation of the μ-opioid receptor was also associated with the different response of surgical pain to intravenous PCA morphine therapy. It might be warranted to extend these results to other ethnic groups.65,66 In an recent review on the evidence for genetic modulation of analgesic response, L¨otsch and Geisslinger67 described that the 118A > G mutation of the μ-opioid receptor affected up to 17% of subjects in their response to alfentanil,68 morphine,69 M6G,63,64 and levomethadone.70 The polymorphism of the human catechol-O-methyltransferase (COMT) gene has been found to influence the morphine requirements in cancer pain patients.71 Dopamine, epinephrine, and norepinephrine are inactivated in the nervous system by COMT. Enzyme activity of COMT may vary 3- to 4-fold because of a common functional polymorphism (Val158Met). Patients with the Val/Val genotype needed more

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morphine in comparison to the Val/Met genotype and Met/Met genotype groups. Mogil and coworkers72 found that polymorphism of the melanocortin-1-receptor (MC1R) may also affect morphine requirements in a small subset of patients. MC1R mutations may also affect pentazocine analgesic efficacy in women only.73 Morphine requirements may also be affected by an SNP of 3435C>T in the ABCB1 (P-glycoprotein) gene.74 The cytochrome P450 2D6 (CYP2D6) is known to metabolize many drugs. The activity of CYP2D6 ranges from complete deficiency to ultrafast metabolism, depending on at least 16 different known alleles.75 This may account for variation in metabolism for dextromethorphan, tramadol, and codeine, among other medications. PAT I E N T S W I T H H I S TO R I E S O F S U B S TA N C E ABUSE OR OPIOID DEPENDENCIES

Patients abusing heroin or diverted opioid analgesics experience the same intensity of acute postsurgical pain as nondependent individuals. Nevertheless caregivers tend to limit opioid administration in these patients. PCA is often withheld from these individuals, and neural blockade or epidural analgesic techniques are substituted because self-administered IV boluses may reinforce drug-seeking behavior.39 More recent practice guidelines permit well-supervised PCA therapy for use by patients having a history of alcohol, cocaine, and heroin abuse. Opioid-dependent patients with a history of chronic pain and tolerance development also require increased amounts of opioids to compensate for both baseline requirements as well as that needed to control pain following surgery (see also Chapter 34, Acute Pain Management in Patients with Opioid Dependence and Substance Abuse.) PAT I E N T S W I T H O R G A N I M PA I R M E N T O R FA I LU R E

Declines in cardiac, hepatic, and renal function are often associated with alterations in the volume of distribution, clearance, and excretion of most analgesic agents. For analgesics having high hepatic uptake and clearance, reductions in hepatic blood flow are accompanied by proportional decrements in the overall extraction rate and prolonged pharmacological effects.76–80 The patient with organ compromise or failure may present with unique considerations, depending on the analgesic to be administered. These patients may include those who have renal or hepatic impairment or failure or others recovering from nephrectomy and hepatic lobectomy. Analgesic efficacy may be altered not only by impaired clearance of the medication but also through the production and potential accumulation of metabolites which may be toxic. A classic example is accumulation of meperidine’s renally cleared metabolite, normeperidine, which can precipitate CNS toxicity. A recent review of the impact of concurrent renal or hepatic disease on the pharmacology of the patient requiring acute pain management found specific differences in safety of the pharmacological profile among pain medications.76,77 These differences are presented in Table 3.3. According to this table, there are a number of safer medications that can be used in patients with renal impairment as these drugs typically do not have a significantly prolonged clearance or deliver a high active metabolite load. Other medications may be used with caution wherein

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Joshua Wellington and Yuan-Yi Chia

Table 3.3: Pharmacological Safety Profile with Renal or Hepatic Impairment Safest

Require Precaution (ie, dose reduction)

Avoid

Renal impairment/failure Acetaminophen Alfentanil Buprenorphine Fentanyl Ketamine Remifentanil Sufentanil

Amitriptyline Bupivacaine Clonidine Gabapentin Hydromorphone Levobupivacaine Lidocaine Methadone Mexilitine Morphine Oxycodone Tramadol

Aspirin Dextropropoxyphene Meperidine NSAIDs

As methadone has a very long half-life, it is contraindicated in patients with severe liver disease. Dextropropoxyphene has also been implicated in several cases of hepatotoxicity.82 To prevent cumulative increases in levels of analgesics,82 but maintain therapeutic plasma concentrations, it is essential that the dose of drugs that undergo hepatic biotransformation or are eliminated by the kidneys be reduced. This can be accomplished by either decreasing the amount of each dose while maintaining the normal dosing schedule or by increasing the interval between doses while administering the standard size dose. Dosage adjustment is of critical importance if renal function is less than 50% of normal and the agent to be administered is to a great degree (>50%) excreted unchanged or has active metabolites that are primarily eliminated by the kidney.39,77–79 Patients suffering congestive heart failure experience greater reductions in hepatic and renal perfusion than blood flow directed to the heart, lungs, and central nervous system. As would be expected both hepatic clearance/biotransformation and renal elimination of drug will be compromised, whereas delivery of free drug to the nervous system and heart may be increased.

Hepatic impairment/failure Remifentanil

Other opioids

Amitriptyline Carbamazepine Dextropropoxyphene Meperidine Valproate

dose reduction is usually necessitated. Some drugs should not be used because of the high risk of toxicity. Although morphine remains primarily unaffected by renal failure, accumulation of morphine-6-glucuronide (an active metabolite that may induce CNS irritability) and morphine-3-glucuronide (inactive metabolite) have been reported.78 Buprenorphine may provide analgesic efficacy in patients with renal failure requiring intermittent hemodialysis. Filitz and coworkers79 recently found that buprenorphine and its metabolite norbuprenorphine were not elevated in plasma levels in chronic pain patients with endstage renal disease. Additionally, hemodialysis did not affect buprenorphine plasma levels, allowing for stable analgesia. When using pain medications in the patient with hepatic impairment, consideration must be given to the impaired clearance and increased oral bioavailability caused by a reduced first-pass metabolism. The primary metabolic pathway for most opioids is oxidation, which may be decreased in patients with hepatic cirrhosis. Morphine and buprenorphine are exceptions that primarily undergo glucuronidation. Although glucuronidation is thought to be less affected in hepatic cirrhosis, morphine clearance is still decreased and oral bioavailability increased.80 Remifentanil is least subject to alteration because of its clearance by ester hydrolysis; however, its practicality in the acute pain setting may be limited. As fentanyl is more often used in the acute pain setting, consideration must be given for its metabolism by the P450 enzyme CYP3A4.81 In patients with hepatic impairment or failure, elevated plasma fentanyl levels will occur. The analgesic activity of codeine is dependent on the P450 enzyme CYP2D6 to transform into the active metabolite of morphine. The analgesic efficacy of codeine will be decreased accordingly in patients with hepatic impairment. The use of other opioids, such as hydromorphone and oxymorphone, may be considered with close patient monitoring.

C O N C LU S I O N

Patient variables clearly influence analgesic dose requirements and analgesic response. Factors associated with the greatest reduction in analgesic requirement as well as potential toxicity include increasing patient age and hepatorenal dysfunction. Variables responsible for increased analgesic requirement and less effective pain control include opioid tolerance, more extensive surgery, and cultural influences. Cognitive deficits lead to reductions in both analgesic requirement as well as ineffective pain control. It seems likely that understanding and utilizing genetic polymorphisms that mediate receptor efficacy and drug metabolism will have clinical usefulness by either increasing analgesic sensitivity or diminishing toxicity. In the near future, oral and intravenous analgesic dosing and selection of optimal compounds may be facilitated by presurgical analysis of genetic markers. At present, elderly patients and those presenting with multiorgan failure have the most to gain from advances in neuraxial analgesic therapy and continuous neural blockade. Such therapy provides highly effective pain control and reduction in stress responses to pain, whereas at the same time reducing opioid burden and the deleterious effects of opioids on the CNS.

REFERENCES 1. Glasson JC, Sawyer WT, Lindley CM, Ginsberg B. Patient-specific factors affecting patient-controlled analgesia dosing. J Pain Palliat Care Pharmacother. 2002;16:5–21. 2. Tamsen A, Hartvig P, Fagerlund C, Dahlstrom B. Patient-controlled analgesic therapy. II. Individual analgesic demand and analgesic plasma concentrations of pethidine in postoperative pain. Clin Pharmacokinet. 1982;7:164–175. 3. Bellville JW, Forrest WH Jr, Miller E, Brown BW Jr. Influence of age on pain relief from analgesics: a study of postoperative patients. JAMA. 1971;217:1835–1841. 4. Burns JW, Hodsman NB, McLintock TT, et al. The influence of patient characteristics on the requirements for postoperative analgesia: a reassessment using patient-controlled analgesia. Anaesthesia. 1989;44:2–6.

Patient Variables Influencing Acute Pain Management 5. Kaiko RF. Age and morphine analgesia in cancer patients with postoperative pain. Clin Pharmacol Ther. 1980;28:823–826. 6. Austin KL, Stapleton JV, Mather LE. Relationship between blood meperidine concentrations and analgesic response: a preliminary report. Anesthesiology. 1980;53:460–466. 7. Gagliese L, Jackson M, Ritvo P, et al. Age is not an impediment to effective use of patient-controlled analgesia by surgical patients. Anesthesiology. 2000;93:601–610. 8. Gagliese L, Weizblit N, Ellis W, Chan VW. The measurement of postoperative pain: a comparison of intensity scales in younger and older surgical patients. Pain. 2005;117:412–420. 9. Gagliese L, Katz J. Age differences in postoperative pain are scale dependent: a comparison of measures of pain intensity and quality in younger and older surgical patients. Pain. 2003;103:11–20. 10. Aubrun F, Monsel S, Langeron O, et al. Postoperative titration of intravenous morphine in the elderly patient. Anesthesiology. 2002;96:17–23. 11. Ready LB, Chadwick HS, Ross B. Age predicts effective epidural morphine dose after abdominal hysterectomy. Anesth Analg. 1987;66:1215–1218. 12. Portenoy RK, Kanner RM. Patterns of analgesic prescription and consumption in a university-affiliated community hospital. Arch Intern Med. 1985;145:439–441. 13. Faherty BS, Grier MR. Analgesic medication for elderly people post-surgery. Nurs Res. 1984;33:369–372. 14. Monk TG, Barker RK, White PF. Use of PCA in geriatric patientseffect of aging on the postoperative analgesic requirement. Anesth Analg. 1990;70:S272. 15. Ruggiero A, Barone G, Liotti L, et al. Safety and efficacy of fentanyl administered by patient controlled analgesia in children with cancer pain. Support Care Cancer. 2007;15:569–573. 16. Marchetti G, Calbi G, Vallani A. PCA in the control of acute and chronic pain in children. Pediatr Med Chir. 2000;22:9–13. 17. Collins JJ, Geake J, Grier He, Berde CB, et al. Patient-controlled analgesia for mucositis pain in children: a three-period crossover study comparing morphine and hydromorphone. J Pediatr. 1996;129:722–728. 18. Anghelescu DL, Burgoyne LL, Oakes LL, Wallace DA. The safety of patient-controlled analgesia by proxy in pediatric oncology patients. Anesth Analg. 2005;101:1623–1627. 19. Streltzer J, Wade TC. The influence of cultural group on the undertreatment of postoperative pain. Psychosom Med. 1981;43:397– 403. 20. Parker RK, Perry F, Holtman B, et al. Demographic factors influencing the PCA morphine requirement. Anesthesiology. 1990;73:A818. 21. Ng B, Dimsdale JE, Rollnik JD, Shapiro H. The effect of ethnicity on prescriptions for patient-controlled analgesia for postoperative pain. Pain. 1996;66:9–12. 22. Tamayo-Sarver JH, Hinze SW, Cydulka RK, Baker DW. Racial and ethnic disparity in emergency department analgesic prescription. Am J Public Health. 2003;93:2067–2073. 23. Todd KH, Samaroo N, Hoffman JR. Ethnicity as a risk for inadequate emergency department analgesia. JAMA. 1993;269:1537– 1539. 24. Todd KH, Deaton C, D’Adamo AP, Goe L. Ethnicity and analgesic practice. Ann Emerg Med. 2000;35:11–16. 25. Yen K, Kim M, Stremski ES, Gorelick MH. Effect of ethnicity and race on the use of pain medications in children with long bone fractures in the emergency department. Ann Emerg Med. 2003;42:41–47. 26. Fuentes EF, Kohn MA, Neighbor ML. Lack of association between patient ethnicity or race and fracture analgesia. Acad Emerg Med. 2002;9:910–915. 27. VanderBeek BL, Mehlman CT, Foad SL, et al. The use of conscious sedation for pain control during forearm fracture reduc-

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48. Sanchez B, Waxman K, Tatevossian R, et al. Local anesthetic infusion pumps improve postoperative pain after inguinal hernia repair: a randomized trial. Am Surg. 2004;70:1002–1006. 49. Morrison JE Jr, Jacobs VR. Reduction or elimination of postoperative pain medication after mastectomy through use of a temporarily placed local anesthetic pump vs. control group. Zentralbl Gynakol. 2003;125:17–22. 50. Aubrun F, Langeron O, Quesnel C, et al. Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology. 2003;98:1415–1421. 51. Austin KL, Stapleton JV, Mather LE. Multiple intramuscular injections: a source of variability in analgesic response to meperidine. Pain. 1980;8:47–62. 52. Gil KM. Psychologic aspects of acute pain. Anesthesiol Rep. 1990;2:246–255. 53. Tamsen A, Hartvig P, Dahlstrom B, et al. PCA therapy in the early postoperative period. Acta Anaesthesial Scand. 1979;23:462–470. 54. Macintyre PE, Jarvis DA. Age is the best predictor of postoperative morphine requirements. Pain. 1995;64:357–364. 55. Rosenquist RW, Rosenberg J, United States Veterans Administration. Postoperative pain guidelines. Reg Anesth Pain Med. 2003;28:279–288. 56. Ferrante FM, Orav EJ, Rocco AG, Gallo J. A statistical model for pain in patient-controlled anesthesia and conventional intramuscular opioid regimens. Anesth Analg. 1988;67:457–461. 57. Dahlstrom B, Tamsen A, Paalzow L, et al. Patient-controlled analgesic therapy. IV. Pharmacokinetics and analgesic plasma concentrations of morphine. Clin Pharmacokinet. 7:266–279. 58. Gear RW, Miaskowski C, Gordon NC, et al. The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain. 1999;83:339–345. 59. L¨otsch J, Geisslinger G. Are mu-opioid receptor polymorphisms important for clinical opioid therapy? Trends Mol Med. 2005;11:82–89. 60. Klepstad P, Rakvag TT, Kaasa S, et al. The 118 A > G polymorphism in the human micro-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand. 2004;48:1232–1239. 61. Mantione KJ, Goumon Y, Esch T, Stefano GB. Morphine 6beta glucuronide: fortuitous morphine metabolite or preferred peripheral regulatory opiate? Med Sci Monit. 2005;11:MS43–MS46. 62. Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters betaendorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA. 1998;95:9608–9613. 63. Romberg R, Olofsen E, Sarton E, et al. Pharmacokineticpharmacodynamic modeling of morphine-6-glucuronide– induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology. 2004;100:120–133. 64. Romberg RR, Olofsen E, Bijl H, et al. Polymorphism of muopioid receptor gene (OPRM1:118A/G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology. 2005;102:522–530. 65. Chou WY, Wang CH, Liu PH, et al. The human opioid receptor A118G polymorphism affects intravenous patient-controlled

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4 Acute Pain: A Psychosocial Perspective Francis J. Keefe

Our understanding of the psychosocial aspects of pain has advanced considerably since the early 1980s. Much has been learned about psychosocial factors that influence pain and psychosocial interventions that can enhance pain control.1,2 Recently, there has been growing interest in applying the psychosocial perspective to enhance our understanding and ability to treat acute pain. This chapter focuses specifically on psychosocial aspects of acute pain. The chapter is divided into four sections. The first section provides a conceptual background on psychosocial aspects of acute pain. The second section highlights research on the role of psychosocial factors in acute pain. The third summarizes the results of recent studies testing the efficacy of psychosocial interventions for acute pain. The chapter concludes with a discussion of future directions for work in this important area.

in battlefield situations but also in civilian situations. In a study of 138 alert and oriented patients seen in an emergency room setting, Melzack et al4 found that 37% reported feeling no pain at the time of injury. Delays in the onset of pain ranged from 1 to 9 hours. Taken together, the results of these studies suggest that the relationship between injury and pain is not as simple and straightforward as assumed by the traditional biomedical model. Other limitations of the biomedical model include its failure to account for observations such as pain that returns and persists following neurosurgical lesions to pain pathways, variations in pain, or pain relief following the same treatments that occur in patients with very similar degrees of tissue pathology.2,5 The biomedical model also fails to address the effects that psychosocial factors can have on the pain experience. Growing recognition of the limitations of the traditional medical model, has spurred interest in alternative theories of pain. One of the most influential of these theories is Melzack and Wall’s gate control theory.6 The basic tenet of this theory is that there is a gating mechanism in the dorsal horn of the spinal cord that influences the transmission of noxious input from the periphery to the brain. Important from a psychosocial perspective is the notion that the action of the spinal gating mechanism is influenced, not only by peripheral input (ie, relative balance of large diameter and small diameter fiber input), but also by descending input from higher brain centers. The gate control theory proposes that, under certain circumstances (eg, exposure to danger, use of adaptive coping skills, or high levels of social support), neural processes in the brain can be activated in a way that closes the gate in the spinal cord and inhibits transmission of noxious signals to the brain. Under other circumstances (eg, when preoccupied with pain, depressed, or exposed to ongoing interpersonal stress), neural processes in the brain can be activated in a way that opens the gate and facilitates transmission of noxious signals to the brain. The gate control theory thus underscores that, through its influence on spinal gating mechanisms, the brain plays a crucial role in pain inhibition and facilitation. The gate control theory was important because it provided a way of integrating psychosocial variables into our understanding

C O N C E P T UA L B AC KG RO U N D

Traditionally, acute pain has been understood using a biomedical model.2 According to this model, acute pain is a warning signal that results from nociceptive input as a result of tissue damage or injury. In the biomedical approach, careful assessments are conducted to identify sources of tissue damage or injury that are causing pain. Medical and/or surgical interventions designed to correct or ameliorate underlying tissue damage or injury are then carried out to eliminate or reduce pain.2 In the biomedical model, psychosocial factors play a secondary role in that they are viewed simply as responses to pain itself. Although the biomedical model has been very influential in understanding and treating acute pain, its limitations have become increasingly clear since the late 1950s.2 One problem with this model is that acute pain is not always proportional to the amount of tissue damage or injury. A classic study conducted by Beecher3 at the Anzio beachhead found that 66% of wounded soldiers reported feeling no pain. Beecher reasoned that a psychological factor (e, the expectation that the wound would result in removal from the battlefield to a safe setting) tempered the experience of pain. Pain-free injuries have been noted not only 41

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and treatment of pain. In contrast to the traditional biomedical model, the gate control theory did not view psychosocial factors as simply responses to pain but rather as an integral component of pain processing.5 The gate control theory not only stimulated laboratory and clinical research on the psychology of pain, it also led to heightened interest in the role that psychological interventions might play in managing acute and persistent clinical pain.1 More recently, Melzack5,7 has proposed the neuromatrix theory of pain, a theory that builds on and extends concepts introduced in the gate control theory. Melzack had studied persons with total spinal sections who experienced phantom body pains (ie, pains that persisted despite a lack of clear-cut peripheral tissue pathology).5 To account for such phenomena, he proposed that pain is produced by a “body-self neuromatrix,” reflecting input from a network of widely distributed brain neurons. The neuromatrix consists of a network made up of neurons that loop between the thalamus and the cortex and the cortex and limbic systems. The neuromatrix theory states that the composition of the neuromatrix is initially determined by genetic background, but that it is subsequently modified by a person’s sensory experiences. Although this theory recognizes sensory input as an important factor influencing pain, it maintains that sensory input represents only one of three major sources of neural inputs that affect the neuromatrix. The other two inputs reflect the activity of cognitive-evaluative factors (eg, tonic brain inputs resulting from learning and personality, phasic inputs resulting from attention and mood) and motivationalaffective factors (eg, the hypothalamic-pituitary-adrenal system, immune system, and endogenous opiates). The neuromatrix theory also identifies three important neural outputs of the pain neuromatrix that can themselves influence pain. These outputs include brain programs responsible for perception (cognitiveevaluation, sensory-discriminative, and motivational affective dimensions of pain perception), action (involuntary and voluntary pain responses, coping strategies, and social communications of pain), and stress regulation (immune system activity, levels of cortisol, noradrenaline, cytokines, and endorphins). According to this theory, the loops of the neuromatrix network diverge (to allow parallel processing in cognitive-evaluation, sensory-discriminative, and motivational-affective inputs) and converge to allow interactions between the outputs of this parallel processing (ie, the perceptual, action, and stress-regulation programs).7 The repetitive cyclical processing and synthesis of neural signals produces a characteristic pattern that is experienced by the individual as pain. A major contribution of the neuromatrix theory is its emphasis on the role that stress and stress regulation systems play in the pain experience. Pain is not only a sensory phenomenon, but also a major stressor.7 When pain is severe or prolonged it can alter homeostasis and trigger stress regulation responses designed to reinstate homeostasis (eg, release of cortisol, cytokines) that can heighten pain. Not surprisingly, the neuromatrix theory has provided a conceptual foundation for the growing emphasis on the use of skills that enhance control over stress in psychosocial protocols for managing pain. In summary, although the biomedical model remains influential in the assessment and treatment of acute pain, there is growing recognition of its limitations. Since the mid-1960s, influential theories of pain have emerged (eg, the gate control theory and neuromatrix theory) that highlight the role that psychosocial factors can play in the acute pain experience.

P S YC H O S O C I A L FAC TO R S A N D AC U T E PA I N

Converging lines of evidence suggest that psychosocial factors play an important role in the experience of acute pain. In this section, we consider four psychosocial factors that are among the most intensively studied in the context of acute clinical pain: anxiety, pain-related anxiety and fear, pain catastrophizing, and the social context.

Anxiety Pain can be influenced by and, in turn, influence negative affect (eg, anxiety, depression, and anger).1 Of the negative affects associated with acute pain, there is growing evidence that anxiety is the most important. Feeney,8 for example, conducted a crosssectional study examining the relationship of negative affect to acute pain in older adults. Participants in this study were 100 older patients (mean age = 79 years) who were recently (within 5 days) admitted to a rehabilitation unit after orthopedic surgery (e.g., hip or knee replacements). All participants completed a measure of pain along with five measures of negative affect (ie, measures of state anxiety, trait anxiety, depression, state anger, and trait anger). Multiple regression analysis was performed to examine the relative contribution of the five measures of negative affect in predicting pain. The results of the regression analysis revealed that state anxiety (i.e., transitory or situational anxiety) was the only variable that significantly contributed to the prediction of pain. State anxiety accounted for 27% of the variance in pain, whereas the combination of the other variables accounted for only 3.8% of the variance. Taken together, this cross-sectional study suggests that state anxiety may be the most significant contributor to acute postoperative pain in older adults recovering from orthopedic surgery. One limitation of the Feeney study8 was that it was cross sectional in nature (i.e., it assessed anxiety and pain at the same time). This makes it difficult to test the hypothesis that anxiety is a risk factor for acute pain. To rigorously test this hypothesis, one needs to conduct longitudinal research in which anxiety is assessed at the time of a baseline pain-free period and participants are then followed to assess their pain status after an event that is likely to cause pain (eg, surgery). Several recent longitudinal studies have examined the relative importance of anxiety as a risk factor that might predict postoperative pain. For example, Carr et al9 conducted a study that examined the influence of presurgical anxiety and depression on acute pain following major gynecological surgery. In this study, 85 women having gynecological surgery completed measures of anxiety and depression prior to surgery and were then followed to assess their pain status 2 days, 4 days, and 10 days following surgery. Data analyses revealed that 44.7% of the sample reported a high level of anxiety (score > 7) prior to surgery and that patients with high anxiety were significantly more likely to report high levels of pain on days 2, 4, and 10 following surgery. Only 11.8% of patients reported a high level of depression (score > 7) prior to surgery and patients with high depression were significantly more likely to report high levels of pain on only one of the postsurgical days examined (day 4). Taken together, these findings suggest that anxiety is common in patients undergoing major gynecological surgery and that anxiety measured prior to surgery shows a strong relationship to the subsequent development of postoperative pain.

Acute Pain: A Psychosocial Perspective

Katz et al conducted a longitudinal study that examined how well presurgical anxiety and other emotional factors predicted acute pain following breast cancer surgery.10 Prior to surgery, 109 women having breast cancer completed demographic measures and assessments of emotional functioning (state anxiety, depression, somatic preoccupation, and illness behavior). Two days after surgery measures of pain were collected. Data analyses revealed that state anxiety (ie, transitory or situational anxiety) was the only risk factor significantly (P = .003) associated with the risk of developing acute pain following surgery. The results of this study suggest that, when compared to other emotional factors, presurgical state anxiety is a very important risk factor for postoperative pain following breast cancer surgery. Taken together, the studies reviewed in this section underscore the importance of anxiety in understanding acute pain. Anxiety is not only correlated with acute pain when both are assessed simultaneously but also an important risk factor for the subsequent development of acute pain. Anxiety is more strongly associated with the risk of developing acute pain than other negative affects (eg, depression or anger) or other emotional factors (eg, somatic preoccupation and illness behaviors). Finally, these studies suggest that state anxiety (ie, anxiety that is situational or transitory in nature) seems to be more important in understanding acute pain than trait anxiety (ie, anxiety that reflects a disposition or personality trait).

Pain-Related Anxiety and Fear Given evidence of the importance of state anxiety in acute pain, it is not surprising that researchers have begun to focus on more specific aspects of anxiety that might be particularly relevant to how persons respond to acute pain. One potentially salient source of anxiety for persons at risk for acute pain is anxiety or fear about pain itself (i.e., pain-related anxiety and fear). A number of recent studies have examined the role of pain-related anxiety and fear in acute pain. A good example of this research is a study by Aaron et al examining burn-specific pain anxiety (ie, anxiety regarding the anticipation of pain during or after medical procedures involved in the care for burns [eg, debridement]).11 In this study, 27 patients with acute burn injuries completed a measure of burnspecific pain anxiety along with two other standard anxiety measures (a state anxiety measure and a mood measure of anxiety). All three anxiety measures were found to significantly predict total pain medication taken over 24 hours. The burn-specific pain anxiety measure, however, was clearly the best predictor of acute pain experienced during debridement procedures. Burnspecific pain anxiety also was the best predictor of physical functioning. These results suggest that anxiety measures that are specific to fears of pain may add something over and above measures of general anxiety in predicting pain and functioning in burn survivors. To measure the range of anxiety symptoms specific to pain, McCracken, Zayfert, and Gross developed the Pain Anxiety Symptoms Scale (PASS).12 The PASS has four subscales assessing (1) fear (fearful thoughts about pain or its consequences), (2) cognitive anxiety (cognitive symptoms related to pain such as racing thoughts or excessive preoccupation), (3) somatic anxiety (somatic symptoms such as sweating or heart speeding), and (4) escape/avoidance (overt behavioral responses such as trying to avoid all activities). The PASS mainly has been used in studies

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of persons with persistent pain,12,13 where it has been found to predict higher levels of disability and interference due to pain. A recent study by Thomas and France suggests that painrelated anxiety as measured by the PASS might be useful in understanding recovery from an acute pain experience (ie, low back injury).14 In that study, a sample of 43 individuals who were within 3 weeks on an initial episode of low back pain completed the PASS at a baseline evaluation. At baseline and 3, 6, and 12 weeks later they also participated in an assessment session in which they completed a series of physical performance measures that involved reaching for three targets (high, middle, and low) at both high and low speeds. Data analyses revealed that participants with high levels of pain-related anxiety showed significantly smaller excursions of the lumbar spine during the reaches to all targets at 3 and 6 weeks. The authors observed that, when asked to perform reaches, participants with high painrelated anxiety adopted pain-avoidant postures that minimized motion of the lumbar spine. Their results suggest that anxiety about pain may alter movement patterns in a way that could impair recovery from an acute pain episode. Excessive and irrational fears of movement and injury/ reinjury (kinesiophobia) have been noted in persons experiencing pain.15 In studies of persistent pain conditions (eg, chronic low back pain), kinesiophobia has been linked to increased pain, psychological distress, and physical disability.15 Given that acute pain often occurs in the context of an injury, kinesiophobia may also be relevant to understanding adjustment in persons with acute pain. Several recent studies have examined this possibility. In a cross-sectional study of 615 acute low back pain patients seen in primary care settings, Swinkels-Meewisse et al16 found that individuals scoring high on a measure of kinesiophobia (the Tampa Scale of Kinesiophobia) had much higher levels of pain and physical disability. Buitenhuis et al19 conducted a prospective study of 590 individuals who developed neck pain symptoms following a whiplash injury caused by a car crash.17 All participants completed a measure of kinesiophobia at baseline and were followed up for assessments of their neck symptoms 6 and 12 months later. Data analyses revealed that those with higher baseline levels of kinesiophobia were much more likely to experience longer durations of neck symptoms such as pain. Swinkels-Meewisse et al18 also conducted a prospective study testing the predictive utility of kinesiophobia in explaining recovery from acute low back pain.18 In this study, 555 patients with acute low back pain (pain < 4 weeks) completed a baseline measure of kinesiophobia and underwent follow-up evaluations of their pain and functional status 6 weeks and 6 months later. Data analysis showed that the baseline measure of kinesiophobia was the strongest predictor of functional disability, even stronger than baseline pain severity. In sum, anxieties and fear about pain itself seem to be important in explaining the short- and long-term pain and disability experienced by persons having acute pain. The precise mechanisms underlying the effects of pain-related anxiety and fear on acute pain are not known. However, evidence suggests that persons with high pain-related anxiety or fear avoid movements and activities that are important to the process of recovering from acute pain14,19 When such avoidance patterns become entrenched, they can lead to disuse, deconditioning, and high levels of physical and psychological disability, all of which can increase the risk of persistent pain.15

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Pain Catastrophizing Pain catastrophizing has been found to be one of the most important psychosocial predictors of pain and adjustment to pain.20 Pain catastrophizing has been defined as the tendency to ruminate on and magnify pain sensations and to feel helpless when confronted with pain.20 Although there is a large and growing literature on pain catastrophizing, most of the research has been conducted in studies of chronic pain and experimental pain. In these studies, higher levels of pain catastrophizing have been associated with higher levels of pain, psychological distress, analgesic intake, pain behavior, and physical disability.20 Is catastrophizing relevant to acute clinical pain? Two recent studies have examined the predictive utility of pain catastrophizing in persons undergoing surgery. Pavlin et al21 tested whether pain catastrophizing could predict postsurgical pain in persons undergoing anterior cruciate ligament (ACL) repair. Participants, 48 surgical candidates, completed a pain-catastrophizing measure prior to undergoing ACL surgery. Measures of pain and analgesic intake were then collected 1, 2, and 7 days after surgery. Results demonstrated that pain catastrophizing was a significant predictor of postoperative pain. Patients who scored high on pain catastrophizing reported 33% to 74% higher levels of maximum pain and were significantly more likely to report pain on walking than those who scored low on pain catastrophizing. Strulov et al22 recently tested the relative importance of pain catastrophizing and responses to experimental pain stimuli in predicting pain after elective cesarean section. Participants, 47 women who were scheduled for elective cesarean sections, completed a pain catastrophizing measure and rated a series of painful experimental heat stimuli prior to surgery. Pain ratings and measures of analgesic intake were then collected from all participants on day 1 and day 2 following their surgery. Multiple regression analysis was conducted to examine the relative importance of pain catastrophizing and ratings of experimental pain in predicting postsurgical pain. These analyses revealed that preoperative ratings of experimental pain were a significant predictor of pain on day 1 after surgery and that pain catastrophizing was a significant predictor of pain on day 2 after surgery. Neither pain catastrophizing nor ratings of experimental pain predicted analgesic intake. Like pain-related fear, pain catastrophizing may be important in explaining disability resulting from acute pain conditions such as low back pain. Swinkels-Meewisse et al18 conducted a study of acute low back pain patients in which they examined the relative importance of pain catastrophizing and pain-related fear (kinesiophobia) in predicting physical performance and selfreported disability. Participants, 96 individuals with an acute episode of low back pain, completed a self-report measure of physical disability (the Roland Disability Questionnaire) and then were timed as they performed a dynamic lifting task (lifting a 7-kg bag from the floor to the table and then back to the floor). Regression analyses demonstrated that, even after controlling for demographic variables and pain intensity, both pain catastrophizing and pain-related fear were significant predictors of self-reported disability. Pain-related fear, however, was the only factor that was a significant predictor of actual physical performance during the lifting task. Physical examination is an important component in any assessment of acute pain. Can catastrophizing influence the results of a clinical examination? Although this possibility has

not been examined in the context of acute pain, a recent study by Turner et al23 tested it in the context of a chronic pain condition (pain related to temporamandibular disorders [TMD]). In this study, 338 patients with TMD completed a series of measures assessing pain, pain-related activity interference, health care use, and depression and underwent a clinical examination from an oral medicine specialist. Study results showed that pain catastrophizing was not related to clinical examination measures considered to be more objective (ie, measures of maximum assisted jaw opening or jaw joint sounds). Pain catastrophizing, however, was significantly related to clinical examination measures considered to have a more subjective component (ie, extraoral muscle site palpation pain severity and joint site palpation pain severity). What makes these findings regarding the effects of pain catastrophizing on clinical examination findings particularly impressive is that they were obtained even after controlling for demographic variables, pain duration, and depression severity. The studies reviewed above suggest that pain catastrophizing may be a risk factor for acute pain and may be related to selfreports of physical disability in persons suffering from acute pain. The findings of these studies also suggest that pain catastrophizing may show a stronger relationship to more subjective measures of adjustment to pain (eg, self-reports of pain/disability and physical exam findings based on self-report) than to more objective measures (eg, analgesic intake, physical performance, or physical exam findings that are less reliant on self-report). This raises the possibility that the effects of pain catastrophizing on acute pain may be related to the way that pain is processed, perceived, and responded to emotionally. Brain-imaging studies provide one way of examining this intriguing hypothesis. An example of the type of imaging study that could be conducted in acute pain conditions is a functional magnetic resonance imaging (fMRI) study conducted by Gracely et al.24 In this study, fMRI was used in 29 fibromyalgia patients to assess their brain responses to acute pain stimuli (blunt pressure stimuli). Results showed that high levels of pain catastrophizing were associated with increased activity in brain regions related to the anticipation of pain (eg, medial frontal cortex and cerebellum), attention to pain (eg, dorsal anterior cingulate cortex and dorsolateral prefrontal cortex), and emotional responses to pain (eg, claustrum and closely connected to the amygdala). These findings suggest that pain catastrophizing may alter perceptions of pain by modifying neural processes related to attention to pain, anticipation of pain, and increased emotional responding.

Social Context Acute pain occurs in a social context that often includes family, friends, and health care providers. There is growing evidence that pain not simply has an impact on those in the social context, but that it also can be influenced by its social context. Witnessing a loved one experiencing acute pain is a difficult and stressful experience. Facial expressions of pain, in particular, can have a powerful impact on others. Botvinick et al25 used fMRI to study the neural responses of pain-free observers to videotapes of persons experiencing moderate pain versus no pain. They found that when participants viewed facial expressions of moderate pain, they showed increased brain activity in areas known to be involved in the actual experience of pain (eg, anterior insula and anterior cingulate cortex). Thus, witnessing

Acute Pain: A Psychosocial Perspective

pain in another can produce an increase in neural activity in cortical areas related to the first-hand experience of pain. Saarela et al26 conducted an fMRI study in which they had pain-free observers view photographs of faces of chronic pain patients whose pain was transiently increased. After viewing each photo, the observers were asked to estimate the amount of pain the patient experienced. Analysis of the fMRI data showed that viewing the pain faces produced increases in observers’ levels of neural activity in regions of the brain involved in the pain experience (ie, the bilateral anterior insula, left anterior cingulate cortex, and left inferior parietal lobe.) In addition, the level of brain activation in the observer corresponded to their estimates of pain in the patient. Observers showed high levels of brain activation when they estimated the patients’ pain intensity as high and low levels of brain activation when they estimated the patients’ pain intensity as low. Finally, the observers ratings of their own emotional empathy were found to correlate with the strength of brain activations that occurred in response to viewing the pain faces (specifically in the left anterior insula and left inferior frontal gyrus). The results of these recent fMRI studies support the notion that there are sensory neural mirroring mechanisms that may support the understanding of other’s pain and suffering. From an evolutionary perspective, the ability to detect pain and respond appropriately to others in pain has survival value.27 Clinically, acute pain may elicit a variety of responses from others, including reassurance, sympathy, or encouragement to use pain-coping strategies. These responses, in turn, may influence the pain and distress experienced by the individual having acute pain. The vast majority of studies on the social context of acute pain have been conducted in children undergoing painful medical procedures. In these studies, child-parent or child-staff interactions have been directly observed and coded. Data analyses have then been conducted to determine how parental or staff behaviors relate to children’s distress. In a study of 77 preschool children undergoing immunizations, Frank et al28 found that maternal behaviors predicted 53% of the distress in children’s behavior. Interestingly, reassurance behaviors commonly used by parents (eg, “You can do this” and “Don’t worry”) were associated with much higher levels of child distress. Although this finding seems counterintuitive, the link between reassurance and higher levels of child distress has been reported in a number of studies.29 Three mechanisms have been proposed to explain the link between reassurance and increased pain/distress29 : (1) such responses serve as a warning that orients the person to pain or distress, (2) such responses reinforce apprehension and distress behaviors, and (3) such responses release the expression of negative emotions that otherwise might not be expressed. To date, the most rigorous observational study of the relationship of adult behavior to children’s coping during a painful medical procedure has been conducted by Blount et al.30 This study focused on 23 children (aged 5 to 13 years) having acute lymphocytic leukemia who were undergoing bone marrow aspirations and lumbar puncture procedures. Audiotapes were made during the procedures and written transcriptions made of the verbal interactions between the child and adults who were present (eg, parents, nurses, residents). These transcripts were then systematically coded by trained observers to assess both child and adult behaviors. Sequential lagged analyses were conducted to determine how behaviors exhibited by adults related to subsequent distress and coping behaviors on the part of the child. Findings showed that adults’ reassurance, apologizing,

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criticizing, and giving control to the child significantly increased the likelihood of childhood distress. In contrast, encouraging the child to use coping procedures, talking about unrelated topics, or directing humor to the child significantly increased the likelihood the child would engage in coping behaviors. These findings underscore the important role that adults can play in influencing children’s experiences during painful medical procedures. They also highlight the fact certain parental/staff responses commonly thought to be helpful to children (eg, reassurance, giving control to the child), in fact, can increase distress, whereas other responses (eg, humor, talking about other topics) can reduce distress. The results of a recent study by Lang et al31 suggests that similar phenomena may occur in adults undergoing invasive procedures. In this study, videotapes were made of 159 patients undergoing potentially painful procedures (eg, administration of local anesthetic, percutaneous puncture/catheter insertion, tract or vessel dilatation, and intravascular injection of contrast medium). All statements made by health care providers during the videotapes were transcribed and coded by trained observers. The observers coded two categories of behavior: (1) warning statements that the upcoming procedure would be painful or undesirable and (2) expressions of sympathy after a potentially painful procedure. Patients also provided ratings of their own pain and anxiety during and after the procedures on scales from 0 to 10. Data analyses revealed that when health care professionals warned the patient about pain, the patient experienced significantly higher levels of pain as compared to when they did not warn. When health care professionals sympathized with patients about their pain, the patient experienced higher levels of anxiety but not pain. Considered as a whole, the studies reviewed above reinforce the notion that, although acute pain is a private event, it does influence and is influenced by others. Witnessing acute pain in another activates empathic neural processes that likely play a key role in determining the responses of loved ones and health care providers to acute pain. Although certain empathic responses to acute pain (eg, reassurance) are common in patients’ significant others, they may paradoxically increase pain and distress. In contrast, other common responses (eg, distraction or humor) may actually help decrease distress in persons experiencing acute pain. P S YC H O LO G I C A L I N T E RV E N T I O N S F O R AC U T E PA I N

Evidence that psychosocial factors can influence pain has helped spur the development of a number of psychosocial protocols for managing acute pain. In this section, we highlight studies testing the efficacy of four psychosocial interventions for managing acute pain: (1) distraction, (2) cognitive-behavioral therapy, (3) hypnosis, and (4) virtual reality.

Distraction There is a growing consensus that distraction is one of the most important psychosocial strategies for managing pain. Distraction is believed to work because it uses up cognitive resources that otherwise might be devoted to pain.32 Distraction has been found to be particularly effective in children. Sparks,33 for example, tested the efficacy of two

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distraction techniques on the pain experienced by children undergoing a diptheria-tetanus-pertussis injection. A sample of 105 children ranging in age from 4 to 6 years was randomly assigned to one of two distraction conditions (touch or bubble blowing) or to a standard care control condition. Children in the touch condition were given light skin stroking near the injection site just before and after the injection. Children in the bubble blowing condition were encouraged to blow bubbles during the injection. Data analyses revealed that, when compared to the standard care condition, both touch and bubble blowing produced significant decreases in pain. This study shows that distraction interventions that are inexpensive, easy to use, and well accepted by young children can produce significant reductions in injection pain. In managing injection pain in children, are certain forms of distraction more effective than others? MacLaren and Cohen34 compared distraction that required an overt response (interactive toy) with a passive distraction (movie watching). Participants, 88 young children (aged 1 to 7 years), were randomly assigned to one of three conditions: (1) playing with one of two age-appropriate interactive toys (eg, a toy robot that made sounds, played music, and moved when buttons were pressed), (2) watching an age-appropriate movie (eg, Toy Story 2, The Little Mermaid) on a hand-held DVD player, or (3) standard care. Distress was measured using parent and nurse reports and direct observations of children’s level of distraction were made before, during, and after the injection. Results indicated that children in the passive condition not only appeared to be more distracted on observation, but also were rated as less distressed than children in the interactive condition. Children in the interactive toy condition were rated as showing no differences in distress from those in the standard care condition, although on observation they appeared to be significantly more distracted. These results are somewhat surprising in that one might expect that tasks requiring a response from a child would be more distracting and thus more effective in reducing distress during a painful procedure than those not involving such task demands. Nevertheless, this study underscores the potential of high-quality visual materials (eg, Hollywood-made movies) in distracting children from acute pain. As noted earlier, reassurance is a common behavior exhibited by parents responding to distress in children undergoing acutely painful medical procedures. Manimala, Blount, and Cohen conducted one of the few direct experimental comparisons of reassurance and distraction in the management of acute pain in children (ages 3 to 6).35 In this study, 82 parent-child dyads were assigned randomly to one of three conditions: reassurance, distraction, or attention control. Parents assigned to the reassurance condition were asked to provide reassurance in ways that they usually do with their child before, during, and after the injection. Parents assigned to the distraction condition were encouraged to play with their children with toys and to talk about nonmedical topics prior to the injection. They were also taught to encourage the child to use a party blower immediately before, during, and after the injection. Parents in the attention control condition spent time talking with an experimenter regarding the child’s medical history and how the child usually handles painful medical procedures. Data analyses revealed a number of significant between-group differences in the treatment conditions. First, children in the distraction condition exhibited the lowest level of distress. Second, children in the reassurance group were much more likely to need to be restrained during the

procedure than children in the distraction and control groups. Finally, parents in the reassurance group were significantly more distressed after the procedure than parents in the distraction or control groups. Taken together, these findings reinforce the notion that reassurance is not a very effective strategy for managing pain during injections in children and that distraction techniques can provide benefits for both children and their parents. How does distraction compare to the effects of topical anesthetics that are now being widely used in managing pain that occurs during injections of children? Cohen et al36 conducted a study in which they compared the effects of a nursedirected distraction intervention, an anesthetic (eutectic mixture of local anesthetics [EMLA]), and typical care. Participants, 39 fourth-grade children undergoing a series of immunizations were exposed to both experimental interventions using a within subjects design. The order of interventions was randomly determined. In the distraction intervention, a nurse assisted the child to select a movie to watch and encouraged the child to focus on the movie before, during, and after the immunization. Videotaped records of each immunization were taken and later coded for signs of child distress and coping behaviors. Data analyses revealed that the distraction intervention produced significant reductions in distress and increases in coping behavior. In contrast the EMLA intervention had no effects on children’s distress or coping behaviors. The authors conclude that a nurseassisted intervention can decrease child distress and increase coping behavior in children undergoing a painful medical procedure. Overall, the findings of the distraction studies reviewed above are in line with the results of two meta-analyses that have examined the effects of distraction on pain and distress in children undergoing painful medical procedures. The first metaanalysis included studies testing the effects of distraction in a range of painful medical procedures and reported that distraction had a mean effect size of 0.62 for pain and a mean effect size of 0.33 for distress.37 The second meta-analysis focused specifically on needle-related procedures and reported that distraction produced a mean effect size of 0.24 for pain.38

Cognitive-Behavioral Therapy The term cognitive-behavioral therapy (CBT) is used to describe multicomponent psychosocial interventions. CBT interventions for acute pain are more comprehensive than simple distraction interventions and rely on combinations of techniques such as distraction, relaxation training, positive self-talk, imagery, and reinforcement. A good example of a multicomponent CBT protocol is that used in a study by Manne et al.39 That study examined the efficacy of CBT in reducing child and parent distress during a venipuncture procedure in children having cancer who required multiple venipunctures. All children in this study had previously shown difficulty coping with acute venipuncture pain in that they had required physical restraint during a prior venipuncture. The CBT protocol tested combined four major components: distraction (slow blowing with a party blower), parental involvement, positive reinforcement (stickers of cartoon characters), and therapist coaching. Role playing with therapist coaching was used prior to the procedure and the therapist was present during the first venipuncture to systematically teach the parents and children how to best use the CBT techniques. Children in this study (N = 23, aged 3 to 9 years) and their parents

Acute Pain: A Psychosocial Perspective

were randomly assigned to the CBT protocol or an attention control intervention that encouraged parents to use whatever techniques they thought might help the child. Measures of child and parent distress and ratings of pain were obtained over the course of a series of three venipuncture procedures. Data analyses revealed that, when compared to attention control, the CBT protocol produced significant reductions in observations of children’s distress, parents’ ratings of the child’s distress, and parents’ ratings of their own distress. The CBT protocol also significantly reduced the use of physical restraint. The CBT protocol yielded no significant reductions in children’s reports of pain, however. The authors speculated that this was possibly because the party blower was not as potent a distractor as had been used in other studies (eg, watching movies.) Jay et al40 compared CBT to general anesthesia in reducing distress in children with leukemia who were undergoing painful bone marrow aspiration (BMA) procedures. All children were studied over the course of two BMAs. Prior to one BMA they received CBT and prior to the other they received a short-acting mask anesthesia. The order of these treatments was randomly determined and counterbalanced across subjects. The CBT protocol involved filmed modeling of coping skills (eg, coping self-statements, use of slow breathing, and imagery), rehearsal with breathing and imagery exercises, and positive reinforcement (eg, a small trophy). The anesthesia consisted of halothane adjusted as indicated to maintain light anesthesia and prevent movement. To assess treatment effects, the investigators collected direct observations of child and parent distress during the BMAs, as well as child ratings of pain and fear and parent ratings of anxiety and coping difficulty. The results indicated that the effects of CBT and general anesthesia were quite similar. Both interventions produced reductions in childrens’ ratings of pain and fear and parent ratings of their own anxiety and coping difficulties. Taken together, these results suggest that CBT and general anesthesia are both viable alternatives to managing pain and distress in children undergoing painful procedures. Liossi and Hatira41 conducted a study that compared the effects of CBT and hypnosis on acute pain. Participants, 30 children (aged 5 to 15 years) with leukemia who had to undergo two BMAs as part of their medical treatment protocol, were randomly assigned to receive a multicomponent CBT protocol, a hypnosis intervention, or standard treatment. At baseline and following treatment, the investigators collected measures of child reported pain and anxiety and nurse ratings of child behavioral distress. Data analyses revealed that the children who received either CBT or hypnosis reported significantly less pain and anxiety than children in the control condition. Although there were no significant differences in the effects of CBT and hypnosis on pain, hypnosis was more effective than CBT in reducing anxiety and distress. Taken together, these findings support the efficacy of CBT in managing pain and anxiety during BMA. They also suggest that, during BMA procedures, hypnosis may be even more effective than CBT in the control of anxiety and behavioral distress. The evidence reviewed above and from a recent metaanalysis by Uman et al38 suggest that CBT interventions for acute pain can be effective, particularly in reducing behavioral distress during BMAs. These interventions, however, are more time intensive than other psychosocial treatments (eg, simple distraction) and their effects may not be superior to those of other medical treatments (eg, general anesthesia) or psychosocial treatments (eg, hypnosis).

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Hypnosis The term hypnosis has been used to describe interactions in which an individual responds to suggestions from a therapist (hypnotist) in a way that alters perception, memory, or actions.42 Although hypnosis has been used for the relief of pain for over 100 years, early reports of its effects were primarily anecdotal and uncontrolled in nature. Rigorous controlled studies of the effects of hypnosis on acute clinical pain are a relatively recent development.42 Lang et al43 conducted a randomized clinical trial to test the effects of hypnosis in managing acute pain in patients undergoing percutaneous diagnostic and therapeutic vascular and renal procedures.43 Participants, 241 persons ranging in age from 18 to 92 years, were randomly assigned to one of three conditions: structured attention, structured attention plus hypnosis, or standard care control. For patients in the structured attention condition, a therapist was present during the procedure who engaged in interventions designed to structure the patient’s attention (eg, attentive listening, provision of the perception of control, encouragement, use of neutral descriptions, or avoiding negatively loaded suggestions). For patients in the structured attention and hypnosis condition, the therapist provided the same attentional structuring, but also guided the patient through a self-hypnosis script that included instructions in relaxation and imagery. The treatment protocols were well standardized and featured structured treatment manuals, systematic therapist training, and ongoing monitoring of fidelity of treatment administration. Patients in all three treatment groups had the same access to drugs that were delivered via patient-controlled analgesia (PCA). Data analyses revealed that although pain increased over the course of the procedure for patients in the structured attention and control conditions, it showed no such increase for patients in the hypnosis condition. Hypnosis also significantly reduced procedure time and drug use. Interestingly, hypnosis also significantly reduced the risk of the patient becoming hemodynamically unstable with only 1 hypnosis patient developing instability versus 10 patients in the structured attention and 12 patients in the standard care condition. All three treatments were found to reduce anxiety. These results suggest that hypnosis can produce not only reductions in acute pain during invasive medical procedures, but also reduce drug use and improve hemodynamic stability. More recently, Lang et al44 examined whether a similar selfhypnosis protocol could be effective in reducing pain during large core needle biopsy, a procedure that is painful and anxiety provoking for many women.44 In this study, 236 women scheduled for breast biopsy were randomized to receive structured attention, structured attention plus hypnosis, or standard care. Treatment outcome was assessed by having patients rate their pain and anxiety every 10 minutes during the procedure. Results showed that, although pain increased significantly in all three groups, the slope of the increase was significantly less in the hypnosis and structured attention groups. Anxiety decreased significantly over the course of the procedure in the hypnosis group, whereas it increased significantly in the standard care and showed no change in the structured attention group. These findings suggest that both hypnosis and structured attention may both have benefits for patients undergoing large core breast biopsy. Conscious sedation is becoming widely used in the management of acute pain. Can hypnosis enhance the effects of

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conscious sedation on pain and anxiety? This question was addressed in a controlled study conducted by Faymonville et al.45 In this study, 60 patients scheduled for plastic surgery under local anesthesia and intravenous sedation were randomly assigned to either a hypnosis condition or a stress reduction control condition. Patients in the hypnosis condition were encouraged to focus on a pleasant life experience during the surgery and were given suggestions and relaxation training by an anesthesiologist to facilitate their ability to do so. Those in the stress reduction control condition received instruction from an anesthesiologist in deep breathing, relaxation, and distraction methods. Data analysis revealed that, when compared to the stress reduction intervention, the hypnosis intervention produced significant reductions in self-report and direct observation measures of pain and anxiety. In addition, vital signs during the operation were more stable and postoperative nausea and vomiting were significantly lower for patients in the hypnosis versus stress reduction group. Finally, patients in the hypnosis group reported significantly higher levels of intraoperative control and overall satisfaction with the procedure than patients in the stress reduction group. Overall, this study provides strong support for the efficacy of hypnosis as an adjunct to conscious sedation. Some individuals are more susceptible to hypnosis than others and, therefore, might respond better to hypnotic interventions for acute pain. Harmon et al46 examined the effects of hypnotic susceptibility in a rigorous study testing the effects of a hypnosis protocol for managing pain during childbirth. In this study, 63 nulliparous women (aged 18 to 35 years) completed a measure of hypnotic susceptibility. Based on their scores on this measure they were divided into high and low hypnotic susceptibility groups. All women were then randomly assigned to one of two conditions: childbirth preparation with skill mastery and childbirth preparation with skill mastery plus hypnosis. Patients in the childbirth education and skill mastery condition received six 1-hour sessions that provided information about childbirth, training in coping skills (eg, breathing techniques for different stages of labor, focal point distraction), and practice in applying learned coping skills during an ischemic pain task. Patients in the hypnosis condition received the same training, but also received a hypnotic induction focused on relaxation and analgesia prior to each training session. Data analysis revealed that patients in the hypnosis condition had overall better birth experiences in that they reported significantly less pain and had shorter labors, took less medication, had higher Apgar scores, and had more frequent spontaneous births. Patients in both conditions who were highly hypnotizable reported significantly lower levels of pain than those who were not. Those in the hypnosis group who were highly susceptible to hypnosis also reported significantly lower levels of postpartum depression. These results underscore the utility of hypnosis in managing labor pain and suggest that hypnotic susceptibility may be an important individual difference variable that contributes to heightened responsiveness to hypnotic interventions for acute pain. Taken together the findings of the studies above coupled with those reported in a recent meta-analysis38 and systematic review47 suggest that hypnosis can be beneficial in managing acute pain. What makes hypnosis impressive as a psychosocial intervention is that it appears to produce benefits not only in terms of pain and distress but also in terms of other, important pain-related outcomes (eg, medication intake, surgery time).

There are a number of possible biological mechanisms by which hypnosis can affect pain, including reductions in involuntary sympathetic responses to pain, increases in endogenous opioid release, changes in brain activity (anterior cingulate cortex), and inhibition of pain at the spinal cord level.42 As suggested by the findings of Harmon et al,46 there are likely individual differences in hypnotic susceptibility that influence how much acute pain relief persons might expect with hypnosis. By incorporating assessments of hypnotic susceptibility into clinical practice, one might be able to select those patients who are most likely to benefit from hypnosis.

Virtual Reality Virtual reality is the most recent psychosocial intervention to be used in the management of acute pain. Computer-based virtual reality methods provide persons with exposure to immersive, three-dimensional, interactive environments that can absorb attentional resources and potentially reduce acute pain. Das et al48 conducted the first study to test the effects of playing an interactive virtual reality game on pain experienced by children during burn management procedures. During the virtual reality intervention, children used a computer mouse and wore a head-mount display with a tracking system that enabled them to use head movements to move and interact with the virtual environment. The environment used game software (based on the game Quake by ID Software) and simulated being on a track and shooting monsters. In this pilot study (n = 9 children aged 5 to 16 years), a within-subjects design was used in which pain ratings were collected during burn management procedures under two conditions: (1) when the child was interacting with the virtual reality environment and (2) when the child was not doing so. All children received standard pharmacological management of their pain and the total amount of time taken during the procedure did not differ by treatment condition. Results indicated that pain ratings were significantly lower (P < .01) when virtual reality was provided during burn management procedures (mean = 1.3 on a scale from 0 to 10) than when it was not (mean = 4.1). Comments from nursing staff also revealed that the children were much more cooperative and distracted from the procedures when virtual reality was used. Hoffman and his colleagues49–53 have published a number of studies examining the effects of virtual reality in controlling acute pain in adults. These include case studies demonstrating the benefits of virtual reality in controlling acute pain during transurethral microwave thermotherapy49 and burn wound care during hydrotherapy.50 One of the first controlled studies conducted by this group51 was a small within-subjects study of children (n = 7, aged 9 to 32 years) that compared the effects of virtual reality and a control condition in reducing pain that occurred in burn victims who were doing range-of-motion exercises as part of their physical therapy. In this study, the virtual environments included SpiderWorld, in which the participants could explore a room and pick up and touch virtual objects (eg, spiders, candy) with his/her virtual hand, and SnowWorld, in which the participant could explore a virtual canyon with a river and waterfalls and shoot snowballs at igloos and snowmen. The study was conducted over 3 days of therapy and, on each day, patients rated their pain once after undergoing range-ofmotion exercises while being provided with virtual reality and again after undergoing the exercises when no virtual reality was

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provided. Data analyses revealed that pain ratings were significantly lower when virtual reality was used than when it was not. The virtual reality intervention yielded significant effects on all five pain measures collected (average pain, worst pain, pain unpleasantness, bothersomeness of pain, and time spent thinking of pain). Notably, significant effects were evident even among those patients who reported reporting severe to excruciating pain levels (6 of the 7 patients). In sum, virtual reality is a relatively new intervention for managing acute pain that shows promise in early case reports and small scale, preliminary studies. Larger-scale, randomized clinical trials are needed to more definitively test the efficacy of this psychosocial intervention. Two studies, conducted in pain-free volunteers, suggest some interesting directions for future work in this area. First, because the technology for virtual reality is developing rapidly, there is a need to determine whether older, low-technology virtual reality is just as effective as newer, high-technology virtual reality. Hoffman et al52 conducted a study that systematically compared the effects of high-tech versus low-tech virtual reality on ratings of thermal pain in normal volunteers. The high-tech virtual reality system provided many features: shutting out reality (using helmet and headphones), providing input to multiple senses (both sight and sound), providing a panoramic/surround view rather than a more limited narrow field of view, providing more vivid/high resolution display, using head tracking to enable subjects to view different places in the virtual world by turning their head, and providing participants with the opportunity to interact with the virtual world. The low tech virtual reality environment provided exposure to a virtual environment, but none of these features. All participants were exposed to a baseline thermal pain stimulus and asked to rate its severity. They were then randomly assigned to either the high-tech or low-tech virtual reality environment and during exposure to that environment received a second presentation of the thermal pain stimulus and asked to rate it. Each participant also rated their level of presence in the virtual world (ie, how much they had the illusion of actually being in the virtual world). Data analysis showed that thermal pain ratings were significantly lower (mean = 0.1) for participants receiving the high-tech virtual reality intervention than for those receiving the low-tech virtual reality (mean = 3.1). Furthermore, across both conditions, ratings of presence in the virtual world were strongly correlated with amount of pain relief reported. Based on these findings one might expect improvements in acute clinical pain would be more likely in patients who are exposed to newer and more advanced virtual reality technologies. They also suggest that patients who report a strong sense of presence when initially exposed to virtual reality might show the best outcomes. A second study conducted in pain-free volunteers examined the effects of an intervention that combined virtual reality with post-hypnotic suggestions.53 Participants in this study were tested for hypnotic susceptibility, underwent a baseline thermal pain testing session, and were then randomly assigned to hypnosis or no hypnosis conditions. Half of the participants in each of these conditions was then assigned to either receive a virtual reality distraction or not during delivery of a second thermal pain testing session. Results showed that the virtual reality intervention was effective in reducing pain, regardless of participants’ hypnotic susceptibility. The effects of the hypnosis intervention, however, were evident only in persons who were highly sus-

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ceptible to hypnosis. Although not statistically significant, there was a trend for high hypnotizable participants who received the combination of hypnosis and virtual reality to show larger improvements in worst pain and pain unpleasantness ratings than achieved with virtual reality alone. An interesting direction for future research would be test the efficacy of a combined virtual reality/hypnosis protocol in managing acute clinical pain. FUTURE DIRECTIONS

One of the most important future directions involves translating what is currently known about the psychosocial perspective on acute pain into clinical practice. Although we now know that psychosocial factors, such as anxiety, pain catastrophizing, and pain-related fear, can influence acute pain, these factors are rarely assessed in clinical practice. Brief instruments are available that could enable clinicians to assess such factors in practice settings.54 Information gathered using such measures could be helpful to clinicians in several ways. First, they could increase clinicians awareness of important aspects of each patient’s painrelated psychosocial functioning. Second, they could aid in identifying patients who are likely to have difficulty managing acute pain. Third, they may be useful in selecting patients who are likely to need more intensive psychosocial treatment. Finally, these instruments could be used to monitor psychosocial outcomes among patients whose acute pain is managed with conventional medical and surgical treatments. To date, psychosocial interventions have been tested mainly in efficacy studies. Efficacy studies use carefully screened and selected patients and rely on highly standardized treatment protocols and interventionists who are usually highly trained. An important next step in this area is to conduct effectiveness studies (ie, to determine whether psychosocial interventions can show similar effects in more typical practice settings). In effectiveness studies, patient screening and selection is less rigid, interventions are not as strictly standardized, and the intervention is delivered by staff who typically work in the treatment setting and who usually have not received extensive training and ongoing supervision. If effectiveness studies demonstrate that psychosocial interventions can enhance acute pain management, then these interventions are much more likely to be disseminated into clinical practice. The likelihood that psychosocial interventions for acute pain will be fully disseminated into clinical practice is enhanced by the fact that a number of these interventions (eg, distraction techniques) require relatively little training, are easy to use, and are inexpensive. Another important future direction is to develop and test tailored interventions that are matched to the resources and needs of patients who are experiencing acute pain. Patients who are highly susceptible to hypnosis, for example, might benefit more from a protocol that primarily focuses on teaching them to use suggestion and imagery to manage pain than a multicomponent protocol that teaches unrelated pain coping skills. Patients who are prone to high levels of pain catastrophizing might need a tailored approach that elicits their overly negative thoughts about acute pain and teaches them how to question, challenge, and restructure these thoughts. Patients who have a high level of anxiety and fear about pain may benefit from modelling, graded exposure, and mastery experiences

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designed to enhance their perceived efficacy in pain control and their ability to approach and master rather than avoid pain experiences. A major advantage of treatment tailoring is that it can streamline treatment, making it less costly and more readily available for those patients who need it. One psychosocial factor that potentially can have an important effect on acute pain is the physical environment.55 The environments in which acute pain are treated are typically quite sterile and devoid of distracting features that might divert a person from their pain. There is growing evidence that environmental stimuli, including exposure to light and natural scenes, can affect the acute pain experience.55 Walch et al,56 for example, found that spine surgery patients who recovered from surgery in a room with bright sunlight required significant less opioid analgesics than those who were in a dim room. In a study of myocardial infarction patients, Beauchemin and Hays57 reported that individuals whose hospital rooms were brightly lit had significantly shorter hospital stays and tended to have lower mortality rates than those in darker rooms. Ulrich et al58 examined the effects of randomly assigning heart surgery patients to rooms that provided views of nature as compared to views of abstract art or a control blank panel. Patients whose rooms enabled them to view nature were significantly more likely to switch from strong analgesics to weaker analgesics over the course of their hospital stay. Patients with views of nature also experienced significantly lower levels of anxiety during their hospitalization. Such findings have implications for the design of the treatment facilities in which acute pain is treated. They suggest that incorporating design elements (e.g., more window views of natural scenes and more use of light) into the design of new clinics and hospitals may provide a means of enhancing acute pain control. Much of the research on psychosocial interventions for acute pain has been conducted in children undergoing painful procedures. Clinical observations also suggest that psychosocial interventions are more frequently used in managing acute pain in children than in adults. The underutilization of psychosocial interventions in adults is unfortunate, particularly given the evidence that these interventions can help. In particular, psychosocial interventions could be more widely used in older adults with chronic diseases who often experience episodes of acute pain as a result of their disease or its treatment. There is a clear need for additional research testing the efficacy of psychosocial interventions for acute pain in adults. An interesting direction for future studies of adults is testing the effects of involving a partner or caregiver in psychosocial acute pain management protocols. Partners and caregivers are often interested in helping their loved one manage acute pain but uncertain what role they can play. In the acute care setting, partners and caregivers can benefit from learning how to most appropriately use pain medication and how to assist the patient in their efforts to cope with pain. Partner-assisted pain management interventions have shown promise in the treatment of chronic pain conditions such as arthritis pain, chronic lower back pain, and cancer pain.1 Future studies need to explore the efficacy of partner- and caregiver-assisted approaches to the control of adults experiencing acute pain. C O N C LU S I O N S

Advances in pain theory and research underscore the importance of psychosocial factors in understanding acute pain. Psychosocial

protocols for managing acute pain have been developed and refined and show promise in the management of many acute pain conditions. In the future, psychosocial approaches to assessing and treating pain are likely to become more fully integrated into acute pain practice settings. As psychosocial approaches become more fully disseminated, it is likely that they will be better able to prevent and reduce the pain and suffering accompanying the acute pain experience. Preparation of this chapter was supported by grants from the National Institutes of Health (R01 CA107477-01, R01 CA100743-01, R01 CA91947-01, CA122704, CA014236, AR47218, AR049059, AR050245, and AR05462). We also Dr Verena Knowles, John P. Keefe, and Joni Duke for their assistance with this chapter. REFERENCES 1. Keefe FJ, Rumble ME, Scipio CD, Giardano L, Perri LM. Psychological aspects of persistent pain: current state of the science. J Pain. 2004;5:195–211. 2. Keefe FJ, Abernethy AP, Campbell, LC. Psychological approaches to understanding and treating disease-related pain. Ann Rev Psychol. 2005;56:601–630. 3. Beecher HK. Measurement of Subjective Responses. New York, NY: Oxford University Press; 1959. 4. Melzack R, Wall PD, Ty TC. Acute pain in an emergency clinic: latency of onset and descriptor patterns related to different injuries. Pain. 1982;14:33–43. 5. Melzack R. Pain: past, present and future. Can J Exp Psychol. 1993;47(4):615–629. 6. Melzack R, Wall PD. Pain mechanisms: A new theory. Science. 1965;150(3699):971–979. 7. Melzack R. Pain and the neuromatrix in the brain. J Dent Educ. 2001;65(12):1378–1382. 8. Feeney SL. The relationship between pain and negative affect in older adults: anxiety as a predictor of pain. J Anxiety Disord. 2004;18:733–744. 9. Carr ECJ, Thomas VN, Wilson-Barnet J. Patient experiences of anxiety, depression and acute pain after surgery: a longitudinal perspective. Int J Nurs Stud. 2005;42:521–530. 10. Katz J, Poleshuck EL, Andrus CH, et al. Risk factors for acute pain and its persistence following breast cancer surgery. Pain. 2005;119:16–25. 11. Aaron LA, Patterson DR, Finch CP, Carrougher GJ, Heimbach DM. The utility of a burn specific measure of pain anxiety to prospectively predict pain and function: a comparative analysis. Burns. 2001;27:329–334. 12. McCracken LM, Zayfert C, Gross RT. The pain anxiety symptoms scale: development and validation of a scale to measure fear of pain. Pain. 1992;50:67–73. 13. Ring D, Kadzielski J, Malhotra L, Lee SG, and Jupiter JB. Psychological factors associated with idiopathic arm pain. J. Bone Jt. Surg. (Am.). 2005;87(2):374–380. 14. Thomas JS, France CR. Pain-related fear is associated with avoidance of spinal motion during recovery from low back p-ain. Spine. 2007;32(16):E460–E466. 15. Vlaeyen JWS, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain. 2000;85:317– 332. 16. Swinkels-Meewisse IEJ, Roelofs J, Verbeek ALM, Oostendorp RAB, Vlaeyen JWS. Fear of movement/(re)injury, disability and participation in acute low back pain. Pain. 2003;105:371–379.

Acute Pain: A Psychosocial Perspective 17. Buitenhuis J, Jaspers JPC, Fidler V. Can kinesiophobia predict the duration of neck symptoms in acute whiplash? Clin J Pain. 2006;22(3):272–277. 18. Swinkels-Meewissee IEJ, Roelofs J, Oostendorp RAB, Verbeek ALM, Vlaeyen JWS. Acute low back pain: pain-related fear and pain catastrophizing influence physical performance and perceived disability. Pain. 2006;120:36–43. 19. George SZ, Fritz JM, McNeil DW. Fear-avoidance beliefs as measured by the fear-avoidance beliefs questionnaire: change in fearavoidance beliefs questionnaire is predictive of change in selfreport of disability and pain intensity for patients with acute low back pain. Clin J Pain. 2006;22(2):197. 20. Sullivan MJL, Thorn B, Haythornthwaite J, et al. Theoretical perspectives on the relation between catastrophizing and pain. J Clin Pain. 2001;17:52–64. 21. Pavlin DJ, Sullivan MJL, Freund PR, Roesen K. Catastrophizing: a risk factor for postsurgical pain. Clin J Pain. 2005;21:83–90. 22. Strulov L, Zimmer EZ, Granot M, Tamir A, Jakobi P, Lowenstein L. Pain catastrophizing, response to experimental heat stimuli, and post-cesarean section pain. J Pain. 2007;8(3):273–279. 23. Turner JA, Brister H, Huggins K, Mancl L, Aaron LA, Truelove EL. Catastrophizing is associated with clinical examination findings, activity interference, and health care use among patients with temporomandibular disorders. J Orofac Pain. 2005;19(4):291–300. 24. Gracely RH, Geisser ME, Giesecke T, et al. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain. 2004;127:835–843. 25. Botvinick M, Jha AP, Bylsma LM, Fabian SA, Solomon PE, Prkachin KM. Viewing facial expressions of pain engages cortical areas involved in the direct experience of pain. NeuroImage 2005;25:312–319. 26. Saarela MV, Hlushchuk Y, Williams AC, Schurmann M, Kalso E, Hari R. The compassionate brain: humans detect intensity of pain from another’s face. Cereb Cortex. 2007;17:230–237. 27. Williams AC de C. Facial expressions of pain: an evolutionary account. Behav Brain Sci. 2002;25:439–488. 28. Frank NC, Blount RL, Smith AJ, Manimala MR, Martin JK. Parent and staff behavior, previous child medical experience, and maternal anxiety as they relate to child procedural distress and coping. J Pediatr Psychol. 1995;20:277–289. 29. McMurtry CM, McGrath PJ, Chambers CT. Reassurance can hurt: parental behavior and painful medical procedures. J Pediatr. 2006;148(4):560–561. 30. Blount RL, Corbin SM, Sturges JW, Wolfe VV, Prater JM, James LD. The relationship between adults’ behavior and child coping and distress during BMA/LP procedures: a sequential analysis. Behav Ther. 1989;20:585–601. 31. Lang EV, Hatsiopoulou O, Koch T, et al. Can words hurt? Patientprovider interactions during invasive procedures. [Clinical Trial. Comparative Study. Journal Article. Randomized Controlled Trial. Research Support, U.S. Gov’t, P.H.S.] Pain. 2005;114 (1–2):303–309. 32. McCaul KD, Mallot JM. Distraction and coping with pain. Psychol Bull. 1984;95:516–533. 33. Sparks L. Taking the “ouch” out of injections for children: using distraction to decrease pain. Am J Matern Child Nurs. 2001;26(2):72–78. 34. MacLaren JE, Cohen LL. A comparison of distraction strategies for venipuncture distress in children. J Pediatr Psychol. 2005;30(5):387–396. 35. Manimala MR, Blount RL, Cohen LL. The effects of parental reassurance versus distraction on child distress and coping during immunizations. Child Health Care. 2000;29(3):167– 177.

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36. Cohen LL, Blount RL, Cohen RJ, Schaen ER, Zaff JF Comparative study of distraction versus topical anesthesia for pediatric pain management during immunizations. Health Psychol. 1999;18:591–598. 37. Kleiber C, Harper DC. Effects of distraction on children’s pain and distress during medical procedures: a meta-analysis. Nurs Res. 1999;48(1):44–49. 38. Uman LS, Chambers CT, McGrath PJ, Kisely S. Psychological interventions for needle-related procedural pain and distress in children and adolescents (review). Cochrane Library. 2007;3:1– 77. 39. Manne SL, Redd WH, Jacobsen PB, Gorfinkle K, Schorr O. Behavioral intervention to reduce child and parent distress during venipuncture. J Consult Clin Psychol. 1990;58(5):565–572. 40. Jay S, Elliott CH, Fitzgibbons I, Woody P, Siegel S. A comparative study of cognitive behavior therapy versus general anesthesia for painful medical procedures in children. Pain. 1995;62: 3–9. 41. Liossi C, Hatira P. Clinical hypnosis versus cognitive behavioral training for pain management with pediatric cancer patients undergoing bone marrow aspirations. Int J Clin Exp Hypn. 1999;47(2):104–116. 42. Patterson DR. Jensen MP. Hypnosis and clinical pain. Psychol Bull. 2003;129(4):495–521. 43. Lang EV, Benotsch EG, Fick LJ, et al. Spiegel D. Adjunctive non-pharmacological analgesia for invasive medical procedures: a randomised trial. [Clinical Trial. Journal Article. Randomized Controlled Trial. Research Support, U.S. Gov’t, P.H.S.] Lancet. 2000;355(9214):1486–1490. 44. Lang EV, Berbaum KS, Faintuch S, et al. Adjunctive self-hypnotic relaxation for outpatients medical procedures: a prospective randomized trial with women undergoing large core breast biopsy. Pain. 2006;126:155–164. 45. Faymonville ME, Mambourg PH, Joris J, et al. Psychological approaches during conscious sedation Hypnosis versus stress reducing strategies: a prospective randomized study. Pain. 1997;73:361–367. 46. Harmon TM, Hynan MT, Tyre TE. Improved obstetric outcomes using hypnotic analgesia and skill mastery combined with childbirth education. J Consult Clin Psychol. 1990;58(5):525– 530. 47. Neron S, Stephenson R. Effectiveness of hypnotherapy with cancer patients’ trajectory: emesis, acute pain, and analgesia and anxiolysis in procedures. Int J Clin Exp Hypn. 2007;55(3):336– 354. 48. Das DA, Grimmer KA, Sparnon AL, McRae SE, Thomas BH. The efficacy of playing a virtual reality game in modulating pain for children with acute burn injuries: a randomized controlled trial [ISRCTN87413556]. BMC Pediatrics. 2005;5(1):1–10. 49. Wright JL, Hoffman HG, Sweet RM. Virtual reality as an adjunctive pain control during transurethral microwave thermotherapy. J Urol. 2005;66(6):1320. 50. Hoffman HG, Patterson DR, Magula J, et al. Water-friendly virtual reality pain control during wound care. J Clin Psychol. 2004;60(2):189–195. 51. Hoffman HG, Patterson DR, Carrougher GJ, Sharar SR. Effectiveness of virtual reality-based pain control with multiple treatments. Clin J Pain. 2001;17:229–235. 52. Hoffman HG, Sharar SR, Coda B, et al. Manipulating presence influences the magnitude of virtual reality analgesia. Pain. 2004;111:162–168. 53. Patterson DR, Hoffman HG, Palacios AG, Jensen MJ. Analgesic effects of posthypnotic suggestions and virtual reality distraction on thermal pain. J Abnorm Psychol. 2006;115(4):834– 841.

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54. Jensen MP, Keefe FJ, Lefebvre JC, Romano JM, Turner JA. Oneand two-item measures of pain beliefs and coping strategies. Pain. 2003;104:453–469. 55. Malenbaum S, Keefe FJ, Williams A, Ulrich R, Somers TJ. Pain in its environmental context: implications for designing environments to enhance pain control. Pain. 2008;134(3):241–244. 56. Walch JM, Rabin BS, Day R, Williams JN, Choi K, Kang JD. The effect of sunlight on postoperative analgesic medications use: a

prospective study of patients undergoing spinal surgery. Psychosom Med. 2005;67:156–163. 57. Beauchemin KM, Hays P. Dying in the dark: sunshine, gender, and outcomes in myocardial infarction. J R Soc Med. 1998;91: 352–354. 58. Ulrich RS, Lunden O, Etinge JL. Effects of exposure to nature and abstract pictures on patients recovery from heart surgery. Psychophysiology. 1993;S1–S7.

5 Nonsteroidal Anti-Inflammatory Drugs and Acetaminophen: Pharmacology for the Future Jon McCormack and Ian Power

The nonsteroidal anti-inflammatory drugs (NSAIDs) encompass a heterogeneous group of therapeutic agents used in a wide spectrum of analgesic and anti-inflammatory roles. From aspirin, the first NSAID commercially produced for analgesic prescription over 100 years ago, the conventional NSAIDs were derived, and had been in clinical use for many years before their mechanism of action (ie, inhibiting prostaglandin synthesis) was elucidated. Acetaminophen is an analgesic and antipyretic agent that may be classified as an NSAID by virtue of its mechanism of action on prostaglandin metabolism. The development of the highly selective coxibs has been ongoing since the mid-1990s. This chapter discusses the history, pharmacokinetic properties, perioperative use, and adverse effects of the NSAIDs.

takenly believed would be less irritating to the gastric mucosa as a result of reduced acidity, was produced and launched into clinical practice by Bayer as aspirin, with the a from acetyl, and spirin from Spirsaure, the salicylic acid derivative of the Meadowsweet plant.

Nonsteroidal Anti-Inflammatory Drugs The term nonsteroidal anti-inflammatory drugs, or NSAIDs, is a collective term for a chemically heterogeneous group of drugs synthesized since the early 1900s that have analgesic, anti-inflammatory, and antipyretic properties in common with aspirin. These nonopioid analgesics can be classified by a chemical structure that confers broadly similar characteristics within each group, these being carboxylic acids, pyrazolones, oxicams, napthylalkalones, and p-aminophenol derivatives, as detailed in Table 5.1. All of the NSAIDs have similar effects within a spectrum, but those offering the greatest potential for the relief of acute pain have marked analgesic effect with relatively mild antiinflammatory action. The higher doses of these agents required for anti-inflammatory effects tends to be associated with a higher rate of adverse events.

H I S TO RY

The Salicylates In the 18th century the bark of the willow tree (Salix alba) was noted to have analgesic properties, whereby a letter from Rev. Mr Edward Stone to the Royal Society in 1763 described “a bark of an English tree, which I have found by experience to be a powerful astringent, and very efficacious in curing anguish and intermitting disorders.” These properties were conferred by a glycoside of salicylic acid, named sialicin, first isolated from natural sources as yellow crystals by Buchner in 1828. German chemists also succeeded in isolating salicylic acid from Meadowsweet (Spirea ulmaria) but it was not until the latter part of the century, in 1860, that Kolbe synthesized salicylic acid and its sodium salt from phenol, carbon dioxide, and sodium. Following this, the availability of inexpensive synthetic salicylates encouraged their use for many clinical indications, and their analgesic, antipyretic, and anti-inflammatory effects were used to treat acute rheumatic fever, gout, and arthritis. However, even at this early stage side effects were recognized, prompting a chemist named Hoffman in 1893 to develop a salicylate that was less irritating to the stomach, a side effect displayed by his father following his sodium salicylate treatment for arthritis. Hoffman’s development of acetyl salicylic acid (Figure 5.1), which he mis-

Coxibs Coxib is the term applied to NSAIDs that have a preferential inhibitory action against cyclooxygenase (COX) type 2, an isoform of cyclooxygenase, which is generally undetectable in normal tissues but present in high concentrations in macrophages and is induced at the sites of acute inflammation. Some of the nonselective NSAIDs were discovered to have preferential activity against COX-2 versus COX-1, for example, meloxicam, and it was noted that the rate of gastric irritation in patients on these therapies was comparable to placebo. The quest for COX-2 inhibitors of higher selectivity led to the development of rofecoxib and celecoxib, released to the market in 1999. Sales of these COX-2 inhibitors rapidly expanded into a multibilliondollar industry within 2 years; however, their success was short 53

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Table 5.1: Classification of the NSAIDs Aspirin, and Acetaminophen Chemical Structure

Examples

Carboxylic Acids

Salicylates: acetyl salicylic acid, diflusinal, salsalate Propionic acids: ibuprofen, naproxen, fenbufen, fenoprofen, ketoprofen, flurbiprofen Acetic acids: indomethacin, sulindac, etodolac, ketorolac, tolmetin, diclofenac Anthranilic acids: mefenamic acid Phenylbutazone, azapropazone Piroxicam, tenoxicam, meloxicam Celecoxib, parecoxib, lumiracoxib Nabumetone Acetaminophen

Pyrazolones Oxicams Coxibs Naphthylalkalones Para-aminophenols

H N O HO Figure 5.2: Chemical structure of acetaminophen.

(4-hydroxyphenyl) acetamide (Figure 5.2), or acetaminophen, the production of which popularized its use in clinical practice as an effective analgesic and antipyretic, though not antiinflammatory agent. The launch of solubilized acetaminophen for intravenous (IV) injection to the European market in early 2004 has greatly influenced acetaminophen prescription, particularly in the perioperative period. P RO S TAG L A N D I N P H Y S I O LO G Y

lived, and, by 2004, rofecoxib had been voluntarily withdrawn by the manufacturer, and valdecoxib followed in 2005. When the Food and Drug Administration released more detailed follow-up data from the original studies, it demonstrated that, including gastrointestinal side effects, the overall adverse event rate was higher with rofecoxib than traditional NSAID control, in particular, the rate of adverse ischemic myocardial events was significantly higher. Debate is ongoing as to whether this is a class effect of COX-2 inhibitors,1 and, to date, celecoxib and newer COX-2 agents, such as lumiracoxib, continue to be marketed.

The para-Aminophenols Despite having no effect on prostaglandin metabolism, acetaminophen is frequently classified and described along with NSAIDs as a nonopioid analgesic agent. Acetaminophen is only one of several p-aminophenol compounds synthesized in the 19th century for analgesic and antipyretic purposes. The parent compound, acetanilide, was released in 1886, but was soon found to be excessively toxic by way of methemoglobin production. In 1887, phenacetin was introduced and used for a considerable period of time until a linkage with high dosing for prolonged periods of time and the development of renal papillary necrosis was identified, this being referred to clinically as analgesic nephropathy. In 1949, the active ingredient of both acetanilide and phenacetin was shown to be N-

Prostaglandins, first isolated in 1935 by Van Euler in seminal fluid, were so named after the discovery of their high rate of release from the prostate gland. They were initially described as locally active tissue agents mediating smooth muscle tone, and although various types have been identified, they are all based on prostanoic acid (Figure 5.3). A 20-carbon chain molecule with a 5-carbon ring, with varying degrees of saturation and substitution in this ring between each prostaglandin. The nomenclature of different prostaglandins is derived from their original identification processes, with prostaglandin E first isolated in ether and prostaglandin F in phosphate (Swedish: fosfate). Prostglandins are members of the eicosanoid family, oxygenated metabolites of arachidonic acid, which also includes the leukotrienes.

Prostaglandin Synthesis The basal rate of prostaglandin synthesis is low. An increase in production is triggered by stimuli including trauma, which activates tissue phospholipases to release arachidonic acid from plasma membrane phospholipids. Prostaglandin endoperoxidase synthase (PEH), a membrane bound glycoprotein with cyclooxygenase and hydroperoxidase catalytic activities, then converts arachidonic acid to the various prostaglandins (Figure 5.4). Cyclooxygenase first inserts two oxygen molecules into the 20-carbon arachidonic acid to yield the cyclic endoperoxide PGG2 , which is then converted by hydroperoxidase to PGH2 . From these intermediates, the principal stable prostaglandin products include PGE2 , D2 , F2␣ , I2 (prostacyclin), and thromboxane A2 .

9 10 11

7

8

12

15

3

4

16

14 13

Figure 5.1: Chemical structure of acetyl salicylic acid.

5

6

17

2

1 COOH

20

18

Figure 5.3: Prostanoic acid.

19

NSAIDs and Acetaminophen: Pharmacology for the Future

55

Membrane Phospholipids

Physical, chemical, inflammatory stimuli

Prostaglandin synthetase PGG2 COX-2

COX-1 PGH2

Tissue isomerases

Prostaglandin F 2

Prostacyclin

Thromboxane A2

Prostaglandin D 2

Prostaglandin E 2

Endothelium,

Platelets, Smooth Muscle

Mast cells

Brain, Endothelium,

Uterus, Airways,

Lymphocytes

Kidney, Platelets

Smooth Muscle

Kidneys

Figure 5.4: Schematic representation of prostaglandin biosynthetic pathways.

Prostaglandin Catabolism Prostaglandins are rapidly broken down to inactive metabolites and do not circulate in the bloodstream unchanged. Specific enzymatic catabolic pathways exist, though some prostaglandins are inherently chemically unstable. For example, prostacyclin (PGI2 ) undergoes rapid nonenzymatic PGH2 hydrolysis to 6-keto-PGF1␣ , which is then enzymatically metabolized to 2,3-dinor-6-keto-PGF1␣ . Similarly, the platelet aggregator and vasoconstrictor thromboxane A2 is very unstable and quickly degrades to thromboxane B2 . The rapid spontaneous breakdown of certain prostaglandins implies that measurement of the inactive metabolite may be the best indicator of rate of synthesis of the parent compound.2 Enzymatic and nonenzymatic metabolism limit the action of prostaglandins locally to the site of synthesis, hence they can be thought of as locally acting hormones, allowing tissues to react to their own immediate conditions, without necessarily having systemic effects.

membrane phospholipids. The term COX inhibitors is often used to describe these drugs. Aspirin irreversibly inhibits COX by binding to the protein and acetylating it at Ser350, such that new enzymes must be produced by the cell before prostaglandin synthesis can recommence. In contrast, the other NSAIDs do not acetylate the enzymes, but are reversible inhibitors that prevent cyclooxygenase activity only while there are effective plasma concentrations of the drug present. In general, NSAIDs do not inhibit the alternative lipoxygenase pathway of arachidonic acid metabolism and thus have no effect on the production of inflammatory leukotrienes. Certain NSAIDs are an exception to this, for example, ketoprofen, which may be a dual inhibitor of both cyclooxygenase and lipoxygenase enzymes, thereby interfering with the production of prostaglandins, thromboxane, and leukotrienes. Whether this confers additional clinical advantage to ketoprofen, is unclear.

Inhibition of Neutrophil Aggregation M E C H A N I S M S O F AC T I O N

Many of the effects of these drugs, including analgesia, can be attributed to inhibition of prostaglandin synthesis, though this may not explain all of their actions. There is evidence that these chemical substances interfere with the basic cellular processes involved in neutrophil activation triggered by inflammatory stimuli.

Inhibition of Prostaglandin Synthesis Although salicylates have been used clinically since the 19th century, their mechanism of action was not elucidated until 1971 when Sir John Jane showed that aspirin and indomethacin inhibited prostaglandin synthesis in various tissues.3 It is now clear that aspirin and the NSAIDs work by inhibiting the cyclooxygenase component of PGH synthase, thus locally preventing the production of all prostaglandins and thromboxanes from

Although prostaglandin inhibition seems to explain the analgesic and antipyretic effects of the drugs it may not fully explain their anti-inflammatory actions. Problems have persisted in explaining the anti-inflammatory action solely by an effect on prostaglandin synthesis. For example, sodium salicylate has no effect on prostaglandin synthesis in vitro, but is an effective antiinflammatory agent in vivo. Another problem is that aspirin has anti-inflammatory effects only at doses far higher than those required to inhibit cyclooxygenase. Some of the anti-inflammatory effects of these drugs may result from a completely different mechanism, this being inhibition of neutrophil activation by inflammatory stimuli. When exposed to certain ligands, neutrophils are activated by “twin signals” (intracellular calcium and protein kinase C), inhibition of which by NSAIDs prevents neutrophil aggregation in vivo and in vitro. This may be a chemical effect related to NSAID structure, their planar lipophilic molecules inhibiting many intracellular processes. NSAIDs even inhibit cellular aggregation in primitive

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Table 5.2: Clinical and Pharmacokinetic Data for some NSAIDs Drug Aspirin Propionic acids Ibuprofen Ketoprofen Naproxen Acetic acids Diclofenac Indomethacin Ketorolac Anthranilic acids Mefenamic acid Pyrazolones Phenylbutazone Oxicams Piroxicam Tenoxicam Coxibs Celecoxib Parecoxib (IV) Lumiracoxib Naphthylalkalones Nabumetone p-Aminophenols Acetaminophen

Daily Dose (mg)

Dosing Interval (h)

1800–3600

4

1200–2400 00–200 500–750 150 75–150 40–90 1500 300–400 20 20 200–400 40 200–400 1000 2000–4000

Time to Peak Plasma Concentration (h)

Elimination Half-Life (h)

Plasma Protein Binding (%)

1–2

0.25

80–90

6–8 6–8 10

0.5–1.5 1.5–2 1–2

2–2.5 1.5 12–15

99 94 99

12 6–12 6

1–2 1–2 1

1–2 12–15 4–6

99 92–99 99

8

2–4

3–4

99

6–8

2

50–100

98

24 24

2–4 1–2.6

53 72

99 99

12 24 24

2–3 0.5 5

4–15 8–11 4

97 98 98

24

6

24

99

0.5–1

2

10

6

marine cell cultures that do not synthesize prostaglandin, indicating that this effect is a basic chemical property common to these drugs.

Analgesic Effects Tissue injury leads to nociception, first, by direct damage to nerve endings; second, by inflammation from the release of prostaglandins from damaged tissues; and, third, by hyperalgesia mediated by nerve fiber sprouting and invasion of phagocytes and fibroblasts.4 Prostaglandins are involved in the tissue reaction to injury, and PGE2 and PGI2 produced at the site of damage sensitize pain receptors to histamine and bradykinin, leading to hyperalgesia. It is unclear if prostaglandins produce pain themselves or if they increase the effect of other painful stimuli on nerve endings, but it is recognized that they are involved in nociceptor activation by painful stimuli. For example, PGE2 increases the afferent input from single C fibers in response to heat and bradykinin, an effect prevented by lysine salicylate. Therefore, by preventing prostaglandin synthesis at the site of tissue damage, NSAIDs inhibit nociceptor activation and act as analgesics. As this effect is thought to occur in damaged tissue, NSAIDs have been described as “peripherally acting analgesics.” Although this is the case, there is good evidence that NSAIDs diffuse into the cerebrospinal fluid where they also have an action within the CNS. For example, indomethacin, ibuprofen, and diclofenac depress the evoked response of rat thalamic neurons to peripheral nerve stimulation in a dose-dependent manner, demonstrating a central action contributing to their analgesic effect.5 The analgesic and antipyretic effects of acet-

aminophen are thought to be entirely mediated through central prostaglandin inhibition, as the drug appears devoid of peripheral activity. P H A R M AC O K I N E T I C S O F N S A I D S

General Principles Some details relating to NSAIDs, aspirin, and acetaminophen administration, including dose, frequency, and pharmacokinetic variables, are given in Table 5.2. Absorption following a dose of NSAID is rapid by all routes of administration, whether enteral or by injection, and following an oral dose NSAIDs are generally rapidly absorbed through the upper small intestine, although the rate may be slowed in the presence of food. Sulindac, nabumetone, and parecoxib are prodrugs that are converted to their active forms by hepatic metabolism, and aspirin is activated by rapid hydrolysis in the plasma to salicylate. Notably, diclofenac undergoes significant first-pass hepatic metabolism when administered orally. In general, the NSAIDs are highly protein bound and have relatively low volumes of distribution, on the order of 0.1 L/kg, the unbound fraction being biologically active. As a consequence, NSAIDs can potentiate the effects of other highly protein-bound drugs, including oral anticoagulants, oral hypoglycemics, sulfonamides, and anticonvulsants, by displacing them from plasma protein binding sites. NSAIDs may potentiate the effect of lithium by reducing its clearance and also by interference with the effects of diuretics and antihypertensive drugs, these side effects being more common in elderly patients. The dose of NSAIDs should be reduced if there is any evidence of renal impairment.

NSAIDs and Acetaminophen: Pharmacology for the Future

Hepatic biotransformation followed by renal excretion accounts for the majority of elimination, with only small amounts excreted unchanged. Thirty percent to 40% of the inactive metabolites of the acetic acids and oxicams are excreted in bile.

Aspirin Acetyl salicylate has analgesic, anti-inflammatory, and antipyretic properties and should be considered the forerunner of the NSAIDs. In addition to its widespread use as a minor analgesic, aspirin has a well-established role in the prophylaxis of coronary and cerebral thromboses, and the treatment of myocardial infarction and preeclampsia. An oral dose is rapidly absorbed and hydrolyzed in the plasma, therefore aspirin has a relatively short half-life of 15 minutes, although the resulting salicylic acid has a longer half life of 2–3 hours. Both aspirin and the salicylate contribute to the clinical effects, with the latter perhaps being most important for anti-inflammatory actions. Aspirin also has a uricosuric effect. Common side effects include dyspepsia and peptic ulceration, bleeding problems, tinnitus, and deafness. In low doses of 300–600 mg aspirin is an effective analgesic, which is used for the relief of mild to moderate pain. Higher doses of 3.6– 4.2 g are given for the anti-inflammatory action required to treat rheumatoid arthritis, at which level many patients experience dyspepsia, occult gastrointestinal bleeding, and tinnitus. Severe gastrointestinal bleeding and hepatic and renal problems can rarely occur. Aspirin is contraindicated in children younger than 12 years, because of the potential for precipitating Reye’s syndrome, featuring acute hepatic failure with encephalopathy. Hypersensitivity to aspirin tends to present in two forms. In the first, sensitivity is associated with rhinitis, nasal polyps, and bronchospasm. In the second, aspirin can produce urticaria, wheals, angioneurotic oedema, and severe hypotension. Both forms may be precipitated in aspirin sensitive subjects by other NSAIDs. Various preparations have been introduced to attempt to reduce the gastrointestinal side effects of salicylates. Choline magnesium trisilicate is a long-acting nonacetylated ester, diflusinal is a nonacetylated fluorinated salicylate, and salasalate is an aspirin ester that is hydrolyzed slowly. There is some evidence that patients tolerate these preparations better, especially when high anti-inflammatory doses are required. Mild aspirin intoxication results in the characteristics of “salicylism,” featuring deafness, tinnitus, dizziness, and headache. Severe poisoning can produce a life-threatening metabolic derangement with hyperventilation, tinnitus, deafness, hypotension, metabolic acidosis, and coma. These features develop because of uncoupling of oxidative phosphorylation, increasing metabolic rate and hydrogen ion and carbon dioxide production. Initially a respiratory alkalosis develops, because of direct stimulation of the respiratory center, but later the central nervous system (CNS) becomes depressed and the underlying severe metabolic acidosis is revealed. Treatment includes gastric decontamination, primarily with activated charcoal, but forced gastric emptying with concurrent airway protection may still be considered when presentation to the emergency department is within 1 hour of ingestion. Forced alkaline diuresis with sodium bicarbonate infusion is used if the plasma salicylate level exceeds 500 mg/L (3.6 mmol/L) in adults, as a high urinary pH promotes excretion of this weak acid.

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Propionic Acids Agents of this class are the choice for inflammatory joint disease, because although they have weaker anti-inflammatory actions than aspirin, they are much better tolerated. Of all the NSAIDs, the propionic acids are the group least associated with side effects, though dyspepsia, gastrointestinal hemorrhage, and rashes may occur.

Acetic Acids This group contains the NSAIDs most commonly used for the relief of postoperative pain, including indomethacin, diclofenac, and ketorolac. Indomethacin is the oldest agent and has potent antiinflammatory, analgesic and antipyretic effects. However, it is also the agent within this class associated with a high incidence of gastrointestinal side effects and dose-related CNS problems, including headache, confusion, hallucinations, and vertigo. Rectal administration may reduce gastrointestinal side effects. Diclofenac is also often given rectally, but as a means to avoid the high rate of first-pass metabolism, rather than to avoid upper gastrointestinal side effects, which may still occur with rectal administration. A longer-acting but less potent prodrug, sulindac, is converted to an active metabolite in the liver, the sulfated active product of which is excreted in the bile and then reabsorbed through the small intestine, with this mechanism of absorption reported as having improved gastrointestinal tolerance.

Anthranilic Acids Mefenamic acid is a relatively weak anti-inflammatory agent commonly used for osteoarthritis and rheumatoid arthritis. It is also used extensively for the relief of dysmenorrhea, because of inhibitory actions on uterine prostaglandin metabolism. Side effects include dyspepsia, rashes, gastrointestinal bleeding, and diarrhea, which may lead to dehydration and renal insufficiency in elderly patients. This NSAID has also been associated with interstitial nephritis. Of the newer NSAIDs, mefenamic acid is commonly involved in self-poisoning, which may result in convulsions that are sensitive to benzodiazepine therapy.

Pyrazolones Phenylbutazone is a toxic, extremely potent and very long-acting anti-inflammatory agent. Widespread reactions to phenylbutazone, common and severe, include dyspepsia, peptic ulceration, gastrointestinal bleeding, mouth ulceration, renal and hepatic impairment, and a spectrum of skin rashes ranging from mild erythema to toxic epidermal necrolysis. The drug produces marked salt and water retention that can exacerbate cardiac failure. There is also a reported association with severe bone marrow depression presenting as agranulocytosis or aplastic anemia. Azapropazone is also a pyrazolone that displays less marrow toxicity though a similar gastrointestinal and fluid retention adverse effect profile.

Naphthylalkalones The single member of this group, nabumetone, is a nonacidic, inactive prodrug. After oral administration, it undergoes

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extensive first-pass hepatic metabolism that results in conversion to 6-methoxy-2-naphthylacetic acid, a more potent inhibitor of prostaglandin synthesis than the parent compound. The most common side effects are gastrointestinal, and accumulation can occur with renal impairment or in the elderly.

Oxicams Piroxicam and tenoxicam are very long-acting drugs with elimination half-lives on the order of a couple of days, hence are given as a single daily dose. They are weakly acidic agents that are extensively plasma protein bound with small volumes of distribution. Both are metabolized in the liver, the inactive breakdown products being excreted in the bile and urine, and there is no apparent accumulation in hepatic or renal impairment or in the elderly. Side effects include dyspepsia, gastrointestinal hemorrhage, and rashes. Both drugs may increase serum liver transaminase concentrations and may precipitate cardiac failure.

Coxibs The coxibs comprise a heterogenous group of drugs, all of which have in common a selectivity for COX-2 over COX-1 to variable degrees. Rofecoxib, a coxib recently withdrawn from clinical practice, had up to 300 times greater affinity for COX-2 over COX-1, whereas celecoxib, for example, has greater affinity of approximately 30 times.6 Analgesic efficacy over placebo is well documented, both in acute postoperative pain and in chronic arthritis, although generally coxibs provide analgesia that is as efficacious, but not superior to, conventional NSAIDs.7,8 In similarity to other NSAIDs, the coxibs are well absorbed from the upper small intestine and, with the exception of celecoxib, have a high bioavailability, with a generally slightly longer duration of action allowing once or twice daily dosing. Hepatic metabolism produces inactive metabolites excreted via bile and urine. The coxibs have been demonstrated in extensive trials, notably the VIGOR study, to have a significantly lower upper gastrointestinal side-effect profile compared to traditional NSAIDs; indeed, the rate of these complications approximates that of placebo. However, gastrointestinal side effects aside, the coxibs have a similar adverse event profile to other NSAIDs. Fluid retention may occur within 2 weeks of commencing treatment with rofecoxib, resulting in accumulation of edema and significant elevations in systolic blood pressure. The coxibs also have a reduced antiplatelet activity compared to aspirin and, to a lesser degree, the nonselective NSAIDs, which may predispose to thrombotic events. The controversy surrounding this mechanism and the resultant increase in adverse myocardial events was fundamental to the voluntary worldwide withdrawal of rofecoxib by the manufacturers.

Acetaminophen Acetaminophen is an effective analgesic and antipyretic, but has little, if any, anti-inflammatory action. It has not been shown to be a more efficacious analgesic than traditional nonsteroidal agents; however, fewer adverse events are repeatedly reported, with the incidence of gastrointestinal erosions, nephrotoxicity, and platelet dysfunction being comparable to placebo at therapeutic doses. The mechanism of action of acetaminophen has been debated over many years, and it is now

accepted that acetaminophen has effects at the peripheral, spinal cord, and brain levels. In the periphery, acetaminophen metabolism by peroxidase produces reactive compounds that inhibit bradykinin-generated impulses within nociceptive fibers.9 In animal models, acetaminophen has been demonstrated to weakly inhibit isoform 3 of cyclooxygenase enzyme (COX-3), a splice-variant of COX-1, in the brain,10 although the exact role of COX-3 has not yet been elucidated in humans.11 From this, it has been hypothesized that subsequent reductions in prostaglandin production may result in an increase in the activity of descending serotonergic pathways, so modulating nociceptive inputs.12 At the spinal cord level, acetaminophen has been shown to antagonize neurotransmission via NMDA, substance P, and nitric oxide pathways, all of which are implicated in nociception.13,14 Acetaminophen is rapidly absorbed from the small intestine after oral administration, with the rate of absorption having been used as a marker of gastric emptying, and is now also available as a solubilized preparation for intravenous administration. The preparation of intravenous acetaminophen recently released in the United Kingdom and Europe (Perfalgan, BristolMyers Squibb, New York, USA) is dissolved in mannitol and pH buffered by disodium phosphate, with cysteine added as an antioxidant. A 100-mL solution is presented as 10 mg/mL for administration over a period of 15 minutes. Minor urticaria has been reported, particularly with rapid administration, although systemic hypersensitivity is extremely rare.15 Acetaminophen rapidly crosses the blood-brain barrier,16 where it is preferentially concentrated in the cerebrospinal fluid, and onset of clinical action has been demonstrated within 5–10 minutes with a peak clinical analgesic effect at 1–2 hours.9 In comparison with the other NSAIDs, it is not highly protein bound and has a larger volume of distribution. Unlike nonsteroidal agents, acetaminophen is safe in pregnancy and children, down to neonatal ages. At nontoxic doses, hepatic metabolism by cytochrome p450 2E1 primarily results in inactive glucuronide conjugates, 90% of which are renally excreted. Under normal conditions about 4% of the dose is metabolized by hydroxylation to N-acetyl-p-benzoquinone imine, a hepatotoxic alkylating agent. The healthy liver will rapidly detoxify this reactive intermediate by conjugation with sulfydril groups of glutathione, and subsequent excretion as mercapturic derivatives. With larger doses, the rate of formation of the metabolite exceeds the rate at which it can be conjugated with glutathione, and so it combines with the hepatocyte macromolecules resulting in cellular death. The resultant clinical picture is of acute centrilobular hepatocellular necrosis, occasionally with acute tubular necrosis in the kidneys. Specific treatment for this comprises N-acetylcysteine or methionine, synthetic alternatives to hepatic glutathione, which are conjugated to the reactive metabolite of acetaminophen preventing liver damage. In adults, a relatively small dose of 10–15 g (20– 30 tablets) can produce potentially fatal hepatic, and sometimes renal, damage. Early signs of poisoning are nausea and vomiting, followed by the development of right-sided subcostal pain and tenderness 1 day later. Liver damage is maximal 3 to 4 days later after ingestion and may lead to death. Early signs may therefore be minimal even when toxic doses have been ingested, and, as the specific antidotes effectively protect the liver maximally if given up to 12–15 hours after ingestion, every overdose should be considered serious and managed accordingly. In the hospital, treatment consists of gastric emptying if the acetaminophen was ingested within 4 hours of presentation, and the administration

NSAIDs and Acetaminophen: Pharmacology for the Future

of intravenous N-acetylcysteine according to the measured plasma acetaminophen concentration, which may be a useful predictor of the risk of hepatic failure if taken 4 hours following ingestion. N-acetylcysteine therapy should be administred if the plasma acetaminophen concentration falls above the line joining 200 mg/L (1.32 mmol/L) at 4 hours and 30 mg/L (0.2 mmol/L) at 15 hours following ingestion. N-acetylcysteine may be given even if the patient presents when more than 15 hours have elapsed following the overdose, but its value is then less sure. Patients receiving concomitant drugs inducing hepatic enzymes are more likely to develop hepatotoxicity and should therefore be given acetylcysteine at lower plasma acetaminophen concentrations. Outside the hospital, emesis should be induced and oral methionine given. N S A I D S A N D P E R I O P E R AT I V E A NA LG E S I A

In the perioperative period, parenteral preparations of traditional NSAIDs, coxibs and intravenous acetaminophen are available to allow uninterrupted delivery of analgesics for acute perioperative pain throughout the fasting period. Rectal preparations of acetaminophen, diclofenac, and indomethacin may be used; however, side effects of indomethacin tend to preclude use in the acute perioperative phase.

Acetaminophen The analgesic efficacy of acetaminophen has been widely studied and compared with nonsteroidal anti-inflammatory agents and opioid analgesics. Acetaminophen has been shown to have an efficacy equal to aspirin on a dose-per-dose basis.17 It is important to note that acetaminophen has little or no antiinflammatory properties. Intravenous propacetamol is a prodrug that is rapidly hydrolyzed by plasma esterases to acetaminophen that has been available for over a decade; however, difficulties in solubilizing acetaminophen delayed production of an intravenous preparation of the active agent. The recent European launch of acetaminophen for intravenous injection (Perfalgan) has transformed analgesic prescription, particularly in the perioperative period. It is important to note that all of the pharmacokinetic and pharmacodynamic data presented by the manufacturer of intravenous acetaminophen relates to a different intravenous drug, propacetamol, following reference to a bioequivalence study demonstrating identical pharmacokinetic profiles between propacetamol and acetaminophen.18 The number needed to treat (NNT) is a marker for comparison of clinical efficacy based on pooled results from systematic reviews. The NNT relates to the number of patients needed to receive active treatment versus placebo to achieve a 50% reduction in pain scores. As a single agent for the management of moderate pain, the NNT of acetaminophen is 3.8 (95% CI, 3.4–4.4),19 although for moderate to severe postoperative pain optimal analgesia cannot be achieved using a single agent alone, but a balanced approach in combination with nonsteroidal agents can result in up to a 40%–50% reduction in opioid requirements.15,20–22 Intravenous acetaminophen (1 g) has been demonstrated to be as efficacious as intramuscular morphine (10 mg) following dental extractions,23 and as effective as intramuscular ketorolac (30 mg) following lower limb arthroplasty.24

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Although there is no therapeutic benefit conferred over the same dose of oral or rectal acetaminophen, the advantage in the perioperative period lies with the intravenous dose. With preoperative fasting regulations and impaired oral intake for periods of several hours up to several days depending on the surgical procedure, along with an avoidance of the prescription of regular rectal acetaminophen for prolonged periods, patients may have until recently been denied the analgesic benefit from perioperative acetaminophen administration that has been demonstrated in dental, gynecological, orthopedic, and general surgery.25–29,30–33 The widespread availability of intravenous acetaminophen should now improve analgesic provision in the perioperative period, with the economic caveat that the prescription should be converted to an oral dose as soon as the patient can tolerate enteral intake. In therapeutic doses, acetaminophen is an inherently safe agent, with no statistically different differences between the reported incidence of adverse effects when comparing acetaminophen with placebo.34

Aspirin Aspirin is normally considered to be an oral analgesic for the relief of mild pain, but intravenous salicylates have been compared with opioids in the presence of moderate to severe pain after surgery. In a large systematic review a single dose of aspirin 600 mg was shown to have a NNT of 4.4 (95% CI, 4.0–4.9); however, after a single dose gastric irritation and drowsiness were reported.17 Lysine acetylsalicylate (LAS) (1.8 g IV) is equivalent to 1 g of aspirin, but a single bolus gave poor relief of severe postoperative pain compared with morphine (10 mg). Studies using continuous intravenous infusions of LAS have produced better results. After inguinal herniorraphy infusions of LAS were as effective as morphine and produced less drowsiness, nausea, and vomiting.35 After thoracic surgery, LAS (7.2 g) given intravenously over 24 hours gave analgesia equivalent to morphine (40 mg), although the salicylate was not as effective as the opiate in the immediate postoperative period.36 After major gynaecological surgery, LAS was at least as good an analgesic as morphine, with less nausea, vomiting, and respiratory impairment.37 Although such studies give a favorable view of the use of LAS infusions, the drug is seldom used in clinical practice, perhaps because of injection site problems, including venous thrombosis.

Ibuprofen Ibuprofen has been available in both the UK and the US for over 4 decades and, in that time, has proved itself to be an efficacious and well-tolerated anti-inflammatory and analgesic agent. Oral and topical gel preparations may also be purchased over the counter, and, in addition to medical prescriptions, ibuprofen accounts for almost one-third of all NSAID use. Near complete absorption following oral administration results rapidly in a high bioavailability. The antipyretic and analgesic effects of ibuprofen have been shown to be dependent on plasma concentrations, with ibuprofen being highly protein bound, mainly to albumin. Distribution is widespread, but of note ibuprofen is secreted at significant concentrations in synovial fluid, which is assumed to account for its anti-inflammatory effect.38 Metabolism is primarily accounted for by hepatic biotransformation and

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subsequent renal excretion of glucuronide conjugates. Ibuprofen has been studied extensively in postsurgical, obstetric, and dental pain, where it is consistently found to be more efficacious than placebo, with a combined NNT of 2.7 (95% CI, 2.5–3.0) for the 400-mg oral dose and a dose-dependent improvement in the analgesic effect.39 Ibuprofen (400 mg) has also been shown to be equivalent to diclofenac (50 mg) for postsurgical pain. As would be expected, side effects are in keeping with all other NSAIDs; however, these are uncommon and, where they do present, tend to be mild and transient. Most trials have reported a side-effect rate comparable with that of placebo.

Diclofenac Diclofenac is available in tablet, suppository, and injectable preparations. This was the first parenteral NSAID to be marketed in the UK for the relief of postoperative pain. Additionally, diclofenac has been shown to be effective in relieving pain associated with smooth muscle spasm, including renal and biliary colic, for which it may be the analgesic of choice. Intramuscular diclofenac can be given in a dose of 75 mg up to twice per day as the total daily dose must not exceed 150 mg. Administration by deep intramuscular injection should be for no more than 2 days because of the risk of muscle damage. The advantages associated with diclofenac administration following hip arthroplasty include less cognitive impairment and a reduction in time to mobilization. The benefits of diclofenac in abdominal surgery are less apparent. After major abdominal surgery, diclofenac (75 mg) given every 12 hours reduced morphine consumption, although concern was expressed about the antiplatelet effect and increased postoperative blood loss.40 The results with diclofenac have been more encouraging after minor day case surgery, where it is as effective as fentanyl after arthroscopic surgery and more effective than opioids after surgical removal of impacted wisdom teeth.41 Diclofenac may also be useful in pediatric surgery, for instance, after tonsillectomy rectal diclofenac is as effective as pethidine or papaveretum and after inguinal herniornaphy is comparable in analgesic effect with caudal local anesthetic block.42 A systematic review concluded a combined NNT for diclofenac (50 mg) of 2.3 (95% CI, 2.0–2.7) for postsurgical pain.39

Naproxen Naproxen is a propionic acid derivative like ibuprofen but its higher potency and its side-effect profile limits it to a “prescription only” medicine. It has a similar pharmacokinetic profile to that of ibuprofen, with rapid and complete absorption from the small intestine with a high biovailability, 99% protein binding, and hepatic glucuronidation followed by renal excretion of inactive metabolites. A systematic review of the efficacy of naproxen for postoperative analgesia found an NNT of 2.6 (95% CI, 2.2–3.2), with a side-effect profile similar to that of placebo, though reporting of side effects has been inconsistent.43 Naproxen has recently been brought to public attention in two very different areas. First, naproxen was used as the NSAID comparator in the first major publication comparing the COX-2 inhibitor rofecoxib with older NSAIDs.44 Subsequent detailed analysis of the full data provoked much controversy, with the excess in cardiovascular adverse events in the rofecoxib group being attributed to a

suggested cardioprotective effect of naproxen. Additional exploration implicated other commonly used nonselective NSAIDs, including ibuprofen and diclofenac, in having an excess adverse cardiovascular risks. Further data are awaited to provide a satisfactory conclusion to this debate, though current guidelines from the European Medicines Agency is that nonselective NSAIDs should be prescribed at the lowest dose for the shortest time, and surveillance for adverse effects will continue. The second area in which the profile of naproxen has been raised is a potential role in delaying the progression of Alzheimers disease has been postulated. Epidemiological studies demonstrated a slowing of progression of cognitive impairment in patients treated with long-term NSAIDs, the proposed mechanism of action featuring inhibition of extracellular amyloid-β aggregation. Subsequent randomized controlled trials have as yet failed to demonstrate a conclusive benefit,45 and the definitive ADAPT study, proposed for a 7-year period, was terminated after only 3 years because of concerns about adverse cardiovascular events in the control (naproxen) group.46

Ketorolac Ketorolac was the first injectable NSAID to be marketed in the United States for the relief of acute pain. Chemically, it is a pyrroloacetic acid similar in structure to the earlier compounds tolmetin and zomepirac and is prepared as the trometamol (tromethamine in the United States) salt to increase its water solubility. In animal models, ketorolac has analgesic, antipyretic, and anti-inflammatory actions, which are attributed to prevention of prostaglandin synthesis by inhibition of cyclooxygenase. At the dose used clinically, it has a much greater analgesic than anti-inflammatory action, with the analgesic effect being 800 times greater than that of aspirin. Many studies have assessed the value of ketorolac for postoperative analgesia. The oral form is as effective as acetaminophen and codeine after gynecological surgery.47 After orthopedic surgery oral ketorolac compares well with acetaminophen, diflusinal, and dihydrocodeine.48 Intramuscular ketorolac is effective after minor surgery, although the time to onset of analgesic action is greater than 30–60 minutes. Ketorolac has repeatedly been shown to be superor to placebo and opioid following oral surgery. When given prophylactically before minor operations, ketorolac and morphine reduced postoperative pain to a similar degree, but the opioid produced more sedation. Initial studies suggested that ketorolac was as good an analgesic as opioids after major surgery, but such optimism has not been substantiated. In single-dose intramuscular studies performed on the first or second day following operation in the presence of moderate to severe pain, ketorolac was superior to morphine and had a longer duration of action. However, more recent studies have found that ketorolac alone is unsuitable for the treatment of severe pain immediately after abdominal surgery but is as effective as morphine the day after surgery when pain intensity is less.49 The effect of combining ketorolac with opioids has been examined after upper abdominal surgery. Continual intramuscular infusion of ketorolac at 1.5 and 3 mg/hour significantly reduced patient-controlled morphine consumption by 30% over 24 hours, improved pain scores, and, at the higher dose, reduced postoperative increases in arterial PCO2 . Ketorolac, therefore,

NSAIDs and Acetaminophen: Pharmacology for the Future

appears to have a “morphine sparing” effect that also minimizes the respiratory depressant effects of the opioid. P I ROX I C A M

Piroxicam has a long half-life, allowing once-daily oral administration. It has been repeatedly shown to be an effective postoperative analgesic agent. After hip surgery performed under spinal anesthesia, piroxicam reduced patient requirements for morphine by 50% with no significant side effects.50 Comparing a single dose of piroxicam (20 or 40 mg) against placebo the NNT for 50% pain relief was 2.7 (95% CI, 2.1–3.8) and 1.9 (95% CI, 1.2–4.3), respectively.51 A preemptive analgesic role has also been identified, with a dose given prophylactically before oral surgery substantially reducing the requirements for postoperative analgesia.52

Tenoxicam This preferential COX-2 inhibitor has a longer half-life than piroxicam. Once-daily dosing of 20–40 mg is recommended, with a rapid and complete absorption after oral administration, being unaffected by concomitant food or antacid ingestion and reaching peak plasma concentrations within 2 hours. Despite relatively poor distribution, tenoxicam is preferentially secreted into the synovial fluid, making it an attractive agent for chronic inflammatory joint conditions. Initial studies performed in elderly patients with both rheumatoid disease and osteoarthrititis demonstrated that, despite the long half-life of 49–81 hours, there was no progressive accumulation at steadystate dosing.30 In patients with ankylosing spondylitis both the efficacy and risk of gastrointestinal blood loss is similar to that of piroxicam, seen in around 8% of patients,53 with a susceptibility to toxicity in some individuals thought to relate to mutations in serum albumin, allowing a higher plasma concentration of unbound agent.54 Renal toxicity is rare in patients with normal, age related, or mild to moderate renal impairment, with less than 0.1% patients demonstrating a rise in serum creatinine after 5 years of treatment.32

Valdecoxib Valdecoxib is a second-generation COX-2 inhibitor with a selectivity of around 60:1 for COX-2 over COX-1. It is indicated for relief of symptoms from rheumatoid joint disease, osteoarthritis, and menstrual pain and in these situations it has been shown to be superior to placebo and at least equivalent to conventional NSAIDs. For postsurgical pain, valdecoxib was found to provide comparable analgesia to oxycodone and acetaminophen and was opioid sparing following laparoscopic cholecystecomy and lower-limb arthroplasty.55 It is an orally administered preparation that has a high bioavailability and a half-life of 8–11 hours. Similar to the other COX-2 inhibitors, valdecoxib has a lower rate of endoscopy proven gastrointestinal adverse effects than ibuprofen, naproxen, or diclofenac (5% vs 13%),33 and bleeding complications resulting from platelet inhibition were not reported.56 Valdecoxib was voluntarily withdrawn from the US market after Food and Drug Administration (FDA) recommendations in light of a doubled risk of cardiac and cerebrovascular adverse events compared to placebo (OR 2.3, 95% CI, 1.1–4.7)57

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and case reports of fatal Stevens-Johnson syndrome, these hypersensitivity reactions being triggered by the sulfonamide component of the drug.

Parecoxib The development of an injectable form of the poorly water soluble valdecoxib led to the development of parecoxib, this being a prodrug of valdecoxib, the first COX-2 inhibitor released for parenteral administration. After intravenous or intramuscular injection it is rapidly hydrolyzed, with a half-life of 20 minutes, by hepatic cytochromes to valdecoxib, thereafter displaying the same pharmacokinetic and pharmacodynamic characteristics as valdecoxib described previously. Comparisons between the other injectable NSAIDs, primarily ketorolac, have demonstrated a comparable analgesic efficacy in postsurgical pain, with a reduced incidence of gastric side effects.58 As with valdecoxib, this drug is contraindicated in patients with a history of sensitivity to sulfonamides because of the risk of potentially fatal skin reactions.

Celecoxib Celecoxib was the first COX-2 inhibitor released, in 1998, for symptom control in rheumatoid disease and osteoarthritis. It is relatively highly selective, with a preference of almost 30:1 for COX-2 over COX-1. Oral bioavailability is lower than the other coxibs, at around 40%, but in common with other NSAIDs, widespread distribution and hepatic metabolism confers an attractive pharmacokinetic profile. As with valdecoxib, a sulfonamide moiety may induce serious allergic reactions. Celecoxib was shown to have an efficacy similar to that of active NSAID comparators for symptom control in rheumatoid arthritis, with onset of analgesia within 1 hour of oral administration, no endoscopic evidence of gastric erosions after 7 days of treatment,59 and a 71% (95% CI, 59–79%) reduction in endoscopically proven ulcers at 3 months compared with conventional NSAIDs.60 For acute postoperative pain, celecoxib has been shown to be moderately effective with an NNT of 4.5 (95% CI, 3.3–7.2), comparable to acetaminophen or aspirin alone.34 The largest study comparing the long-term effects of celecoxib administration with conventional NSAIDs was the CLASS study. Over 8000 patients with arthritis were randomized to received celecoxib, ibuprofen, or diclofenac, with 57% receiving treatment for 6 months. The incidences of all upper gastrointestinal complications in the celecoxib and NSAID groups were 1.4% vs 2.9% (P = .02), although any benefit conferred by celecoxib was negated if aspirin was coadministered, and the difference between study groups was not significant at 12 months.61 This study was intentionally designed to be pragmatic with regard to simulation of real-world clinical experience and, unlike patients recruited into the VIGOR study, coadministration of aspirin therapy was permitted; however, only when patients from this group were excluded did the results achieve statistical significance for reduction in gastrointestinal complications. The role of celecoxib in chemoprevention of cancer has been extensively investigated. At present the exact mechanism is unclear, but COX-2 enzyme inhibition by NSAIDs is thought to suppress carcinogenic pathways, possibly by inducing apoptosis in proliferating cancer cells, as the elevated arachidonic acid levels that result from COX-2 inhibition induce the formation

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Table 5.3: Myocardial Infarction Rate, Stroke Rate, and Composite APTC(71) Rate among Naproxen, Conventional NSAIDs, and Placebo Drug/Class Naproxen Non-naproxen NSAIDs Placebo

Myocardial Infarction RR (95% CI)

Stroke RR (95% CI)

APTC Composite End Point RR (95% CI)

1.69 (0.82–3.48) 0.8 (0.28–2.25) 1.27 (0.25–6.56)

1.42 (0.7–2.91) 0.91 (0.35–2.35) 0.59 (0.13–2.74)

1.49 (0.94–2.36) 0.83 (0.46–1.51) 1.08 (0.41–2.86)

of ceramide, a mediator of apoptosis.62 COX-2 expression has been found to be locally elevated in colonic adenocarcinoma in 90% of malignant cases and 40% of premalignant cases, with levels being normally undetectable in healthy mucosa.63 Celecoxib has been demonstrated, mainly experimentally, to suppress the tumor volume and growth advancement of many neoplasms, including colonic, gastric, esophageal, hepatocellular, and breast tumors,64 and, at present, has an FDA licence for inclusion for chemoprophylaxis in patients with familial adenomatous polyposis coli. Further investigation into cancer treatment has led to evidence of adverse cardiovascular effects of celecoxib. The APC trial, over a 33-month period, although demonstrating that celecoxib was an effective carcinoprophylactic agent, also demonstrated an increase in adverse cardiac events compared with placebo, with risk ratios of 2.6 (95% CI, 1.1–6.1) for 400 mg and 3.4 (95% CI, 1.5–7.9) for 800 mg doses.65 On the announcement of these results, the ADAPT study, a proposed 7-year trial assessing the value of celecoxib versus naproxen and placebo in Alzheimer’s disease, was halted after three years of recruitment because of investigator concerns over the cardiovascular safety of naproxen, with a 50% increase in adverse events, though at that stage there was no significant increase in risk with celecoxib.46 At present, the precise answer on the cardiovascular risk profile of celecoxib is awaited. Adverse events have been documented as secondary outcomes from meta-analyses or trials with effects on cancer or Alzheimer’s disease as primary aims. A recent systematic review of the cardiovascular risk of celecoxib and conventional NSAIDs, demonstrating an odds ratio of myocardial infarction of 2.3 (95% CI, 1.0–5.1) compared to placebo and 1.9 (95% CI, 1.1–3.1) compared to other NSAIDs, although for composite cardiovascular end points there were no differences between agents.66 Recruitment has recently commenced in the PRESCISION trial, a large (manufacturer sponsored) multicenter randomized study to evaluate exclusively the cardiovascular risk of celecoxib and traditional NSAIDs in 20,000 patients with arthritis (and, as such, placebo comparison would be unethical), the results of which are due to be available in 2010.

Lumiracoxib Lumiracoxib is the most selective COX-2 inhibitor with a COX2:COX-1 selectivity of 400:1.6 It has a carboxylic acid group, resembling that of diclofenac, and in binding to a unique site on the enzyme is suggested it may have an improved biochemical selectivity over the other coxibs. It is also the only acidic coxib, and it has been hypothesised that this property results in accumulation in sites of inflammation, hence prolonging clinical effect. It has rapid absorption following oral administration, with a high bioavailability reaching peak plasma concentrations within 2 hours and a short half-life of 3–6 hours, although despite

this rapid action once daily dosing has been shown to provide effective analgesia in osteoarthritis and rheumatoid arthritis and following orthopedic surgery that is superior to placebo and as efficacious as diclofenac and celecoxib. As with tenoxicam, drug concentrations peak within synovial fluid from 5 hours following administration up to 24 hours postdose.67 Endoscopic identification of gastroduodenal ulceration confirms a comparable rate to celecoxib and 3 times less than ibuprofen (0.32 versus 0.92%); however, abnormalities in liver function tests were over 4 times more common (2.57% vs 0.63%), though an increased risk of hepatitis in the clinical setting has not yet been documented.68 Despite the high COX-2 selectivity, myocardial and cerebrovascular adverse events have been demonstrated to be equivalent to traditional NSAIDs, coxibs, and placebo (Table 5.3)69 ; however, lumiracoxib has not yet received FDA approval for launch in the United States while further data are awaited.

Other NSAIDs Indomethacin has marked anti-inflammatory actions and is normally used in the management of chronic inflammatory diseases, including ankylosing spondylitis and gout. Early studies confirmed its efficacy as a postoperative analgesic, with evidence of impressive reductions in both pain intensity and morphine requirements; however, the lack of a parenteral preparation, and a frequently demonstrated association with bleeding complications, including wound hematoma, hematemesis, and increased surgical blood loss, has limited its use in clinical practice. Parenteral ketoprofen use following surgery has also been studied, where intravenous administration following nasal surgery significantly reduced pain scores and requirements for further analgesia compared with patients given opioids. SIDE EFFECTS

Unfortunately, the NSAIDs possess undesirable effects as a consequence of their mechanism of action, and they are a major cause of serious adverse reactions reported to the regulatory authorities. Prostaglandins acts as paracrine hormones and interference with them can cause disturbances in local tissue metabolism. These effects are well recognized in association with long-term aspirin or NSAID therapy. In the postoperative period, the main concerns are the possibility of peptic ulceration, interference with platelet function, and renal impairment. Previously, the lack of investigation into the effects of NSAIDs in the postoperative period led to the following comment: “NSAID therapy should also be withheld from patients who are about to undergo surgery because of the risk of acute renal failure, as well as impaired hemostasis resulting from the effects of these agents on platelet function.”71 Increasing

NSAIDs and Acetaminophen: Pharmacology for the Future

evidence is now available demonstrating both the benefits and risks of these valuable analgesic agents when given perioperatively, with regard to cardiovascular, gastrointestinal, platelet, and renal function. NSAID adverse events are consistently shown to be dose dependent, for all agents, and appropriate selection of dose and patient groups should minimize the risk of these events occurring.

Cardiovascular Effects Since the late 1990s, the introduction of COX-2-specific NSAIDs and subsequent head-to-head comparisons with conventional agents, primarily for examination of analgesic or antiinflammatory benefits, has unmasked the differing cardiovascular risk profiles between agents, leading to unanswered questions regarding cardiovascular safety stimulating reevaluation of risk not only of the coxibs, but also of the conventional NSAIDs. The mechanism of these adverse events can be explained by the effect of all NSAIDs on platelet prostaglandin metabolism. Reversible inhibition of the vasodilator prostacyclin (PGI2 ) from endothelial cells, without a balanced reduction of platelet thromboxane A2 (TXA2 ), as seen with aspirin, leads to unopposed vasoconstriction and enhanced platelet aggregation, predisposing the patient to hypertension and thrombosis resulting in myocardial infarction, stroke, or cardiovascular mortality. In vitro evidence for this effect of COX-2 inhibitors had been previously documented, and confirmation of the importance of unopposed TXA2 action in the face of PGI2 inhibition in humans was subsequently published.72 Placebo-based comparisons of several coxibs have suggested this is a class-mediated effect, and all agents of this class have the same attributable risks to varying degrees. This was highlighted by the VIGOR study, post hoc analysis of which preempted the global withdrawal of rofecoxib from the market. In achieving the primary aim of demonstrating a significantly reduced rate of serious gastrointestinal adverse events compared to naproxen, a 5-fold increase in myocardial infarction was reported.44 There may be two explanations for this not being replicated in the celecoxib CLASS trial.61 First, participants suffered predominantly from osteoarthritis, as opposed to predominance of rheumatoid disease in the VIGOR study, with the latter being associated with a 50% higher myocardial infarction rate, and, second, 21% of patients in CLASS were on concomitant aspirin therapy and hence were exposed to conventional antiplatelet therapy. Valdecoxib was approved by the FDA on the basis of trials demonstrating gastrointestinal side effects; however, an application for licensing of its injectable prodrug parecoxib was rejected on the basis of an increase in cardiovascular events, this trial having been conducted in patients undergoing coronary artery bypass grafting. Confirmation of an adverse cardiovascular profile came with the results of the APPROVe trial, where rofecoxib was compared with placebo for chemoprophylaxis of colorectal adenocarcinomas, demonstrating a 2-fold increase in cardiovascular and cerebrovascular events.73 To date, controversy persists as to whether this is a classor agent-specific effect. Rofecoxib, parecoxib/valdecoxib, and etoricoxib have all been implicated in raising cardiovascular risk but celecoxib and lumaricoxib have not, as yet, shown these adverse events with statistical significance. Following the release of details regarding termination of the ADAPT trial, an explanation for the increase risk of adverse events with naproxen was required. Suggestions of differing behavior between naproxen

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Table 5.4: Relative Risk of Cardiovascular Adverse Events in Coxibs and Conventional NSAIDs Relative Risk of Serious CVS Events

95% Confidence Interval

Rofecoxib

2.19

1.64–2.91

Celecoxib

1.06

0.91–1.23

Diclofenac

1.41

.16–1.7

Naproxen

0.97

0.87–1.07

Drug

Ibuprofen

1.07

0.97–1.18

Piroxicam

1.06

0.70–1.59

and “non-naproxen NSAIDs” cannot be explained pharmacologically, with diclofenac being the conventional NSAID that structurally most resembles a coxib (celecoxib). A retrospective population analysis of over 16,000 patients prescribed 1 of 4 conventional NSAIDs or celecoxib demonstrated no difference in cardiovascular adverse events between the five agents studied.74 Similarly, a recent systematic review supported the results of randomized trials (Table 5.4), although diclofenac appeared to have a significantly increased risk, further suggesting an emphasis on its relative COX-2 affinity.75 This has been reaffirmed with results from the MEDAL trial assessing long-term therapy in arthritis, suggesting that dicofenac has a similar cardiovascular risk profile as etoricoxib.76 The most up-to-date evidence, a European systematic review, concluded that, excluding naproxen, nonselective NSAIDs may be associated with a small increase in adverse cardiac and cerebrovascular events comparable to that of the coxibs,77 this relating to a population incidence of 3 additional adverse events per 1000 patients compared with placebo. As yet, ibuprofen at up to 1200 mg/d has not been shown to increase cardiovascular risk, which is compatible with its pharmacological profile of relatively equal potency and duration of COX-1 and COX-2 inhibition.78

Gastrointestinal Effects The association of NSAID ingestion with gastric and duodenal ulcers is well recognized, with up to 20% of patients on NSAID therapy having endoscopically proven ulceration at any one time79 and 1% to 4% developing symptomatic ulcers annually. NSAIDs have also been demonstrated to produce enteropathy.

Peptic Ulcers Aspirin has been known to damage the human gastric mucosa for some time and many investigations have suggested that NSAIDs have similar effects. The gastric and duodenal epithelia have various protective mechanisms against acid and enzymatic attack: mucous, bicarbonate secretion, hydrophobic properties of the mucosa, rapid cellular regeneration, and an abundant blood supply. Prostaglandins are involved with many of these protective factors, the mechanisms of which can be disrupted by aspirin and NSAIDs, although the exact relationship between ulceration and these drugs has been questioned. Prostaglandins work at various sites to maintain mucosal integrity. This knowledge led to the development of a synthetic prostaglandin analog, misoprostil, to prevent NSAID induced ulcers. NSAIDs inhibit regenerative cellular proliferation at ulcer margins, a critical mechanism for mucosal repair, and

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Table 5.5: Relative Risk of Gastrointestinal Side Effects of Conventional NSAIDs Agent

RR of GI Side Effects

95% CI

Indomethacin

2.25

1.01–5.08

Naproxen

1.83

1.25–2.68

Diclofenac

1.73

1.21–2.46

Piroxicam

1.66

1.14–2.44

Tenoxicam

1.43

0.4–5.14

Meloxicam

1.24

0.98–1.56

Ibuprofen

1.19

0.53–1.54

misoprostil has been shown to reduce this harmful effect. The gastric microvascular endothelium is known to be a major target for aspirin-mediated injury, and, in combination with the antiplatelet effect, this significantly increases the risk of upper gastrointestinal hemorrhage. The clinical implications of this are unclear as it is not known if such effects are produced by administering NSAIDs at relatively high doses in the acute postoperative period. It could be that prolonged fasting, the stress of surgery, manipulation of the tissues at operation, and administration of other drugs may render surgical patients at greater risk of mucosal damage from NSAIDs. Even NSAID therapy of relatively short duration can produce severe peptic ulceration and bleeding. Without doubt, NSAIDs should be avoided if the patient has a history of gastric ulceration as this predisposes to further problems developing. A comprehensive meta-analysis of randomized controlled trials assessing the risk of gastrointestinal side effects compared with NSAID nonusers demonstrated that indomethacin has the highest risk of adverse events compared to other NSAIDs (Table 5.5), with a maximal risk of events at 14 days, and ibuprofen has the lowest risk. The peak time of adverse events for other NSAIDs was 50 days, although this varied depending on increasing age, increasing dose, and underlying pathology.80 With regard to the coxibs, rofecoxib was shown to have a 50% relative risk reduction in adverse gastrointestinal events compared with diclofenac44 ; however, celecoxib could not be demonstrated to have a beneficial effect over ibuprofen or diclofenac for symptomatic peptic ulcer incidence.61 A significant reduction in adverse events was demonstrated only following subgroup analysis (excluding participants on concomitant aspirin therapy) for the development of complicated and symptomatic ulcers. Evidence regarding parenteral administration of NSAIDs is less conclusive. Early animal experimentation suggested that ketorolac had a favorable therapeutic ratio for gastrointestinal erosions but human studies have been less reassuring, with dose-dependent invasive gastric ulceration present in volunteers following intramuscular administration.

Enteropathy NSAIDs also have effects on the lower gut, producing enteropathy. This may be a common problem, and it is estimated that 10% of cases of newly diagnosed colitis may be related to ingestion of NSAIDs. Animal studies have shown that NSAIDinduced enteropathy is similar to inflammatory bowel disease

with an increase in bowel wall permeability, and indomethacin can produce intestinal lesions temporally related to inhibition of prostacyclin synthesis. The production of protective intestinal mucin is increased by prostaglandins and reduced by aspirin. Patients receiving long-term NSAID therapy for arthritis have an abnormal increase in bowel permeability affecting the small and large intestine. This enteropathy may be similar to Crohn’s disease and has been shown to persist for up to 16 months following ingestion. It is thought that NSAIDs impair bowel wall integrity and allow damage from bacterial translocation by decreasing mucosal prostaglandin synthesis.

Platelet Clotting Function Platelet cyclooxygenase is essential for the production of cyclic endoperoxidases and thromboxane A2 , important mediators of aggregation and vasoconstriction, which constitute the primary hemostatic response to vessel injury. Although it is clear that aspirin and the NSAIDs inhibit aggregation and prolong skin bleeding time in volunteers by around 30% on average, information suggests that significant perioperative bleeding results in 1% of patients treated with NSAIDs, although in the perioperative situation the hemostatic response may be altered by the physiological stress response to surgery. Aspirin is well recognized as a factor increasing blood loss after surgery, a problem also encountered with NSAIDs. Any aspirin ingestion in the 7 days before cardiac surgery significantly increases the risk of repeat surgery for rebleeding and the requirement for platelets and other blood products and prolongs the stay of the patient in the intensive care unit and in the hospital.81 The hemostatic effects of aspirin may last up to 14 days as it irreversibly inhibits platelet cyclooxygenase by acetylation of this enzyme. After aspirin therapy, hemostasis returns to normal only when new platelets have been made, as after being formed they cannot produce new enzymes. In comparison, other NSAIDs are reversible inhibitors of cyclooxygenase and affect platelets only while there are effective circulating concentrations of the drug present. It is therefore likely that the duration of the antiplatelet effect of NSAIDs will be shorter than that of aspirin, although the magnitude of the effect may be the same. Ketorolac is known to inhibit platelet function in volunteers, as does diclofenac, which can also produce severe spontaneous bruising. In patients having surgery, both ketorolac and diclofenac prolong skin bleeding time and inhibit platelet function in vitro within 1 hour of intramuscular administration, although a significant increase in operative blood loss is not apparent.82 Unfortunately, surgical patients are often given other agents that could potentially interact with the antiplatelet effect of NSAIDs. Warfarin, unfractionated heparin, and, more commonly, low-molecular-weight heparins are given prophylactically against deep venous thrombosis and pulmonary embolism, with interaction between these agents and NSAIDs potentially leading to increased bleeding at operation. The combination of heparin and ketorolac has been studied in volunteers with the conclusion that the interaction is probably clinically insignificant. Examination of the effect of concurrent administration of ketorolac and warfarin demonstrated that there is no interaction, although close monitoring of patients on this combination was recommended.

NSAIDs and Acetaminophen: Pharmacology for the Future

In certain pain states the antiplatelet effect of NSAIDs may paradoxically be beneficial. For example, ketorolac has been shown to be very useful for the relief of pain in sickle cell disease, vaso-occlusive crises, and complex regional pain syndrome.

Renal Function The adverse renal effects are a serious and significant problem. Most studies have examined the effects of long-term oral NSAID intake for medical conditions and have found the regular consumption of nonopioid analgesics should be routinely considered as a risk factor for any noncongenital cause of chronic renal failure. However, NSAIDs are valuable adjuncts to postoperative analgesic regimes and should not be withheld as there is an absence of evidence to suggest that short-term therapy in appropriately selected patients predisposes to any chronic renal impairment.

Renal Prostaglandin Physiology The kidney has enzymes for the synthesis of most prostaglandins, where they have various physiological roles, including the maintenance of renal blood flow and glomerular filtration rate in the presence of circulating vasoconstrictor hormones, regulation of tubular handling of electrolytes, and modulation of the actions of other renal hormones. PGI2 and PGE2 are the prostaglandins produced in the kidney in greatest abundance. There is a degree of specialization of function and PGI2 and PGE2 are produced at different sites with distinct actions. PGI2 is synthesized in the collecting tubules where it enhances sodium, chloride, and water excretion, and PGE2 is synthesized in the medullary interstitial cells, producing vasodilation and natriuresis and in the glomeruli to maintain glomerular filtration rate. Prostaglandins and Renal Blood Flow Normally renal prostaglandins have little effect on the control of blood flow to the kidneys, but in certain circumstances their effect is greatly enhanced. Vasoconstrictor hormones, including renin, angiotensin, norepinephrine, and vasopressin, produce a compensatory increase in renal vasodilator prostaglandins by inducing the enzyme phospholipase. In clinical conditions where there are high concentrations of circulating vasoconstrictors renal blood flow may become prostaglandin dependent. In such circumstances, NSAIDs may impair renal function by abolishing the protective vasodilator action of prostaglandins, thus allowing the unopposed action of vasoconstrictors. During and after anaesthesia and surgery, there is an increase in circulating hormones with vasoconstrictor properties, often described as a component of the metabolic response to surgical stress. It has been postulated that the anesthetized patient is particularly susceptible to the adverse renal effects of NSAIDs, as the compensatory increase in vasodilator prostaglandins is prevented. Animal work has supported this view, where the anesthetized dog having a laparotomy is much more sensitive to the adverse affects of NSAIDs than the awake animal. The risk of unexpected blood loss and acute hypotension during surgery may further increase the risks associated with NSAID administration. During experimental hemorrhage and hypotension, renal prostaglandins oppose the actions of angiotensin II to

65

activate the specific chemoreceptors contributing to autoregulation of renal blood flow.

Prostaglandins and Renal Tubular Function Prostaglandins are also important in regulating the handling of electrolytes by renal tubules. They inhibit reuptake of chloride ions from the ascending limb of the loop of Henle, resulting in increased excretion of salt and water. Animal experiments show that normal tubular excretion of sodium and water is dependent on prostaglandins that suppress renal medullary sodiumpotassium ATP-ase, and PGE1 stimulates chloride ion secretion in the renal epithelial cells. Fluid retention based on these mechanisms is implicated in the development of congestive cardiac failure in patients with established cardiac disease, with an odds ratio of 2.1 (95% CI, 1.2–3.3) compared to controls not taking NSAIDs prior to hospital admission. The coxibs have also been implicated in causing fluid retention resulting in hypertension. A meta-analysis of coxibs vs placebo and coxibs vs conventional NSAIDs demonstrated a mean rise of systolic blood pressure of 3.8 mmHg and 2.8 mmHg, respectively.83 COX-2 is widely implicated in renal prostaglandin synthesis, and at present it is not possible to attribute the proportion of adverse cardiovascular events from salt and water retention with resulting vascular congestion and hypertension from the adverse events suspected to result from unopposed TXA2 action in platelets.84 Additional fluid retention may be caused by rofecoxib, as this is metabolized by the same enzyme as aldostereone, cytosol reductase. An argument has been proposed that there may be direct competition for the enzyme binding site between rofecoxib and aldosterone, resulting in an increase in plasma concentrations of the latter and hence further sodium retention,85 although this has not been proved in a randomized controlled trial. Interestingly, blood pressure does not seem to be elevated with celecoxib treatment, as celecoxib has been reported to have inhibitory properties on certain isoforms of carbonic anhydrase, possibly offsetting some of the effects of sodium and fluid retention and hence preventing the expected rise in blood pressure. Interaction with Renin and Vasopressin Renal prostaglandins also increase the release of renin and inhibit the effect of vasopressin on the collecting ducts. Intravenous infusions of prostacyclin increase renin release in humans and consequently affect aldosterone production and potassium excretion. Indeed, excessive renal prostaglandin production has been implicated in the hypokalemic alkalosis associated with high renin, aldosterone, and angiotensin II concentrations of Barrter’s syndrome, in which platelet defects are also found. NSAIDs also potentiate vasopressin. Renal prostaglandins and vasopressin interact and modulate each other. Vasopressin enhances renal tubular production of cyclic adenosine monophosphate, thus increasing permeability and water resorption, this being prevented by prostaglandins therefore increasing water excretion. Inhibition of prostaglandin production by certain NSAIDs may increase renal water retention, such that indomethacin has been used as a treatment for nephrogenic diabetes insipidus. NSAIDs and Renal Function Renal prostaglandins are important in regulating renal blood flow, tubular function, renin and aldosterone release, and the

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Jon McCormack and Ian Power

action of vasopressin. Therefore, NSAIDs may reduce renal blood flow and impair excretion of water and electrolytes. The clinical significance of this depends on the age and general medical condition of the patient. Studies examining the effect of short-term NSAID administration of renal function have shown that adverse effects can occur after only a few doses in susceptible individuals. A systematic review demonstrated that as a group, NSAIDs cause a statistically significant, but clinically unimportant, transient mean fall in creatinine clearance of 18 mL/min in healthy adults in the acute postoperative period, and there were no reported cases of postoperative renal failure requiring dialysis attributable to NSAID administration.86 Risk factors for NSAID nephrotoxicity include age (over 60 years), atherosclerosis, diuretic therapy, existing renal impairment, and states of renal hypoperfusion, including cardiac failure, hepatic cirrhosis, and hypovolemia. Many of these factors are present in patients having general surgery, and general anesthesia and surgery may produce an additional tendency toward NSAID-induced adverse effects.

Other Renal Effects “Analgesic nephropathy” comprising papillary necrosis or interstitial fibrosis is a recognized cause of drug-induced renal failure that has been reported with most NSAIDs. The “renal flank pain” syndrome, a sudden onset renal failure with hematuria and discomfort, has been produced by various NSAIDs, including ketorolac, even after only a few doses. Other Side Effects of Nonsteroidal Anti-Inflammatory Drugs Aspirin-sensitive asthma is the precipitation of bronchospasm by aspirin and is commonly seen in patients who have asthma with chronic rhinitis or allergic polyps. The effect becomes obvious soon after the ingestion of aspirin, and individuals may be sensitive to other NSAIDs. This affects about 10% of asthmatics, usually in middle age. The importance of this syndrome has been emphasized by reports of fatal bronchospasm precipitated in asthmatic patients by ingestion of proprietary preparations containing NSAIDs. The mechanism of this is unclear but the potency of the drug as a cyclooxygenase inhibitor is important. By inhibiting cyclooxygenase, more arachidonic acid precursor may be available to lipoxygenase pathways, producing substances known to cause bronchospasm, including leukotrienes. There may be an interaction with peptide endothelin-1, which may be involved in exaggerating bronchial muscle tone in asthmatics and which increases lipoxygenase products of arachidonic acid metabolism. Other factors are certainly involved as individuals with this disorder have an abnormal platelet response to aspirin in vitro, with the release of cytotoxic mediators, a prostaglandin-dependent mechanism. The ability of an NSAID to produce this syndrome is directly related to its potency as an inhibitor of prostaglandin synthesis. It may be prudent to avoid parenteral NSAIDs, including diclofenac and ketorolac, in all asthmatic patients because of their very powerful cyclooxygenase inhibition. Hepatotoxicity Aspirin and the NSAIDs can have adverse effects on the liver, normally after prolonged and excessive exposure. Diclofenac may produce fatal hepatitis, which can develop within a few weeks of commencing oral therapy. The risk of precipitating liver effects as a consequence of a short course of NSAIDs is

unclear, although borderline increases in serum aminotransferase concentrations may occur in almost 15% of patients.

Injection Site Damage Intramuscular diclofenac may produce appreciable pain on injections and is associated with muscle damage and increases in serum creatinine phosphokinase. Studies have shown that intramuscular ketorolac does not produce pain or changes in serum creatinine phosphokinase. The irritant nature of parenteral diclofenac was empahsized by the observation that afterintramuscular injection diclofenac produces venous thrombosis, although this can be minimized by dilution in dextrose solution. Injection site pain is a significant problem with diclofenac and has led to the widespread use of rectal preparations. Other Side Effects Mild CNS effects have been reported after ketorolac, including somnolence, headache, and dizziness. Blood dyscrasias, erythema multiforme, anaphylaxis, urticaria, pancreatitis, and aseptic meningitis have been reported, although all are uncommon. In preterm infants, indomethacin reduces cerebral blood flow and oxygen delivery, potentially increasing the risk of hypoxic brain injury, although it is not known if NSAIDs do this in older children or adults. Some myocardial protection against coronary vessel occlusion can be conferred in animals by preconditioning episodes of ischemia, an effect blocked by cyclooxygenase inhbitors, suggesting a possible protective role for prostaglandins, probably prostacyclin. It is unclear if this implies that NSAIDs have any effect on the consequences of acute myocardial ischemia in humans. All NSAIDs should be used with caution during pregnancy as they may increase the length of gestation by delaying spontaneous labor and affect closure of the ductus arteriosus in the newborn. C O N C LU S I O N

Aspirin and the NSAIDs have been used therapeutically for analgesic and anti-inflammatory purposes for over 100 years. They have a well-established role in both acute pain management and chronic pain conditions, though the limitations of adverse events must be recognized with long-term use. Increasing the selectivity of the enzyme targets of NSAIDs has resulted in the development of the coxibs, these agents having an analgesic efficacy comparable to conventional NSAIDs, with an improved gastrointestinal side-effect profile. Debate regarding the risk from the antiplatelet effect of both coxibs and conventional NSAIDs is ongoing; however, it is paramount that patients should not be denied effective analgesic provision from NSAID therapy. Considering the presented data, and the continued emergence of evidence of increased thrombotic risk with coxib use, optimal outcome should be achieved by careful prescribing in an appropriate group of patients with therapy tailored to the minimum effective dose and minimum duration of therapy possible for NSAIDs of any class. The requirement for long-term therapy, particularly if at high doses, should be reviewed regularly. The reformulation and European launch of solubilized acetaminophen in solution has greatly improved the delivery of this efficacious analgesic. Previously, where fasting regulations and postoperative ileus may have prevented oral administration, and with variable bioavailability from rectal absorption, one now has the facility

NSAIDs and Acetaminophen: Pharmacology for the Future

to administer regular acetaminophen throughout the perioperative period, hence improving analgesia and reducing the potential for adverse effects as a result of its opioid-sparing effect. A switch to the less expensive oral route is recommended as soon as possible.

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40. Hodsman NB, Burns J, Blyth A, Kenny GN, McArdle CS, Rotman H. The morphine sparing effects of diclofenac sodium following abdominal surgery. Anaesthesia. 1987;42(9):1005–1008. 41. Campbell WI, Kendrick R, Patterson C. Intravenous diclofenac sodium. Does its administration before operation suppress postoperative pain? Anaesthesia. 1990;45(9):763–766. 42. Moores MA, Wandless JG, Fell D. Paediatric postoperative analgesia. A comparison of rectal diclofenac with caudal bupivacaine after inguinal herniotomy. Anaesthesia. 1990;45(2):156–158. 43. Mason L, Edwards JE, MRMH. Single dose oral naproxen and naproxen sodium for acute postoperative pain. Cochrane Database Syst Rev. 2004; 4. 44. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343(21):1520–8, 2. 45. Gasparini L, Ongini E, Wenk G. Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease: old and new mechanisms of action. [Review] [141 refs] Journal of Neurochemistry. 91(3):521–36, 2004 Nov. 46. ADAPT Research Group. Cardiovascular and Cerebrovascular Events in the Randomized, Controlled Alzheimer’s Disease AntiInflammatory Prevention Trial (ADAPT). PLoS Clini Trials. 2006;1(7):e33. 47. Vangen O, Doessland S, Lindbaek E. Comparative study of ketorolac and paracetamol/codeine in alleviating pain following gynaecological surgery. J Int Med Res. 1988;16(6):443–451. 48. McQuay HJ, Poppleton P, Carroll D, Summerfield RJ, Bullingham RE, Moore RA. Ketorolac and acetaminophen for orthopedic postoperative pain. Clin Pharmacol Ther. 1986;39(1):89– 93. 49. Power I, Noble DW, Douglas E, Spence AA. Comparison of i.m. ketorolac trometamol and morphine sulphate for pain relief after cholecystectomy. Br J Anaesth. 1990;65(4):448–455. 50. Serpell MG, Thomson MF. Comparison of piroxicam with placebo in the management of pain after total hip replacement. Br J Anaesth. 1989;63(3):354–356. 51. Edwards JE, Loke YK, Moore RA, McQuay HJ. Single dose piroxicam for acute postoperative pain. Cochrane Database Syst Rev. 2000;4:CD002762. 52. Hutchison GL, Crofts SL, Gray IG. Preoperative piroxicam for postoperative analgesia in dental surgery. Br J Anaesth. 1990;65(4): 500–503. 53. Gonzalez JP, Todd PA. Tenoxicam. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. [erratum appears in Drugs 1988 Jan;35(1): preceding 1]. 54. Albengres E, Urien S, Barre J, Nguyen P, Bree F, Jolliet P et al. Clinical pharmacology of oxicams: new insights into the mechanisms of their dose-dependent toxicity. 55. Fenton C, Keating GM, Wagstaff AJ. Valdecoxib: a review of its use in the management of osteoarthritis, rheumatoid arthritis, dysmenorrhoea and acute pain. Drugs. 2004;64(11):1231–1261. 56. Chavez ML, DeKorte CJ. Valdecoxib: a review. Clin Ther. 2003;25(3):817–851. 57. Aldington S, Shirtcliffe P, Weatherall M, Beasley R. Increased risk of cardiovascular events with parecoxib/valdecoxib: a systematic review and meta-analysis. N Z Med J. 2005;118(1226): U1755. 58. Jain KK. Evaluation of intravenous parecoxib for the relief of acute post-surgical pain. Expert Opin Investig Drugs. 2000;9(11):2717– 2723. 59. Simon LS, Lanza FL, Lipsky PE, et al. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2

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inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum. 1998;41(9):1591– 1602. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000;284(10):1247–1255. Hilmi I, Goh KL. Chemoprevention of colorectal cancer with nonsteroidal anti-inflammatory drugs. Williams CS, Luongo C, Radhika A, et al. Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology. 1996;111(4):1134–1140. Kismet K, Akay MT, Abbasoglu O, Ercan A. Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention. [Review] [168 refs] Cancer Detection & Prevention. 28(2):127–42, 2004. Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355(9):873–884. Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. [See comment]. [Review] [36 refs] Journal of the Royal Society of Medicine. 99(3):132–40, 2006 Mar. Rordorf CM, Choi L, Marshall P, Mangold JB. Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor. Clin Pharmacokinet. 2005;44(12):1247–1266. Bannwarth B, Berenbaum F. Clinical pharmacology of lumiracoxib, a second-generation cyclooxygenase 2 selective inhibitor. Expert Opin Investig Drugs. 2005;14(4):521–533. Matchaba P, Gitton X, Krammer G, et al. Cardiovascular safety of lumiracoxib: a meta-analysis of all randomized controlled trials > or =1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis. Clin Ther. 2005;27(8):1196–1214. Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ. 1994;308(6921):81– 106. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med. 1984;310(9):563–572. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science. 2002;296(5567):539–541. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352(11):1092–1102. Huang WF, Hsiao FY, Wen YW, Tsai YW. Cardiovascular events associated with the use of four nonselective NSAIDs (etodolac, nabumetone, ibuprofen, or naproxen) versus a cyclooxygenase-2 inhibitor (celecoxib): a population-based analysis in Taiwanese adults. Clin Ther. 2006;28(11):1827–1836. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. Merck provides preliminary analyses of the completed MEDAL program for ARCOXIA (etoricoxib). www.merck.com. 2006. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk

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of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006;332(7553):1302–1308. Wang D, Wang M, Cheng Y, Fitzgerald GA. Cardiovascular hazard and non-steroidal anti-inflammatory drugs. [erratum appears in Curr Opin Pharmacol. 2005 Oct;5(5):556 Note: Wong, Dairong [corrected to Wang, Dairong]]. Hawkey CJ, Skelly MM. Gastrointestinal safety of selective COX-2 inhibitors. Richy F, Bruyere O, Ethgen O, et al. Time dependent risk of gastrointestinal complications induced by non-steroidal antiinflammatory drug use: a consensus statement using a metaanalytic approach. Bashein G, Nessly ML, Rice AL, Counts RB, Misbach GA. Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery. Arch Intern Med. 1991;151(1):89– 93.

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82. Power I, Chambers WA, Greer IA, Ramage D, Simon E. Platelet function after intramuscular diclofenac. Anaesthesia. 1990;45(11): 916–919. 83. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005;165(5):490–496. 84. Krum H, Aw TJ, Liew D, Haas S. Blood pressure effects of COX-2 inhibitors. 85. Aw TJ, Liew D, Tofler GH, Schneider HG, Morel-Kopp MC, Billah B et al. Can the blood pressure effects of COX-2 selective inhibitors be explained by changes in plasma aldosterone levels? J Hypertens. 2006;24(10):1979–1984. 86. Lee A, Cooper MC, Craig JC, Knight JF, Keneally JP. Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function. Cochrane Database Syst Rev. 2004;(2):CD002765.

6 Local Anesthetics in Regional Anesthesia and Acute Pain Management John Butterworth, MD

present, subunits regulate expression, insertion into plasma membranes, voltage dependence, and kinetics of ␣ subunits.8,9 Humans have 10 Na channel genes, only 9 of these genes are “functional,” distributed over 4 chromosomes.7,8 Na channel forms for unmyelinated axons, nodes of Ranvier, small dorsal root ganglion nociceptors, skeletal muscle, and cardiac muscle each derive from specific genes.8 Specific channel isoforms have differing affinities for tetrodotoxin and responses to local anesthetics.10

G E N E R A L C O N S I D E R AT I O N S

Although the multiple medicinal properties of cocaine (including its ability to produce numbness) were appreciated by indigenous South Americans long before European explorers arrived, the birth of local and regional anesthesia is usually designated as 1884, the year when K¨oller and Gartner published their findings after producing topical cocaine anesthesia of frogs, rabbits, dogs, and each other’s corneas.1–5 Unhindered by drug registration agencies, regulations regarding human experimentation, or standards for safety, purity, or efficacy, physicians quickly adopted the “new” agent and used it for an expanding array of procedures. Within the same calendar year (1884) but on a distant continent the American surgeon Halsted performed mandibular nerve and brachial plexus blocks.1 By the end of the first quarter of the 20th century, cocaine and other local anesthetics (LA) had been used for spinal, caudal, epidural, paravertebral, celiac, and intravenous regional blocks, and physicians had begun compounding local anesthetics with additives to enhance their duration and safety. Building on this rapid early progress, the field continues to advance on multiple fronts. This chapter will focus on mechanisms of local anesthetic action, pharmacodynamics, additives, and toxicity, and, in particular, on how local anesthetics can be most effectively used in regional anesthesia (RA) and pain medicine. We will also consider how potential new formulations and new compounds might lead to improved options for the clinician.

E L E C T RO P H Y S I O LO G Y O F Na + C H A N N E L S

Na channels exist in at least 3 native, functional conformations: “resting,” “open,” and “inactivated.6,11 These three conformations were first identified in the early 1950s in experiments conducted by Professor Sir Alan Hodgkin and Professor Sir Andrew Huxley, and, in some cases, with Professor Sir Bernard Katz (all three were recipients of a Nobel Prize). During action potentials Na channels “open” briefly, allowing extracellular Na ions to flow into the cell, depolarizing the plasma membrane. After a few milliseconds, Na channels “inactivate” (whereupon the Na current ceases). In lower animals (eg, squid), repolarization of nerve membranes is facilitated by a contribution from K channels with K ion flow from inside to outside the cell; this contribution is much emphasized in physiology and anesthesiology textbooks. Nevertheless, most readers of this chapter will have greater interest in human than squid neurophysiology. Mammalian myelinated fibers require no contribution from K currents for membrane repolarization; they only require that the Na channels quickly cease to conduct Na ions.6,11 The total number of Na ions that enters the cell during a typical nerve action potential is vanishingly small relative to prevailing transmembrane gradients such that each action potential has essentially no lasting effect on the membrane potential. Ion-selective permeability and voltage gating are both remarkable evolutionary accomplishments on the part of ion channel molecules. Of the two ion channel features, the mechanism underlying ion-selective permeability is more easily understood and multiple forms of selectively permeable glasses are

S T RU C T U R E A N D F U N C T I O N S O F Na C H A N N E L S

Local anesthetics produce peripheral nerve blocks by binding and inhibiting voltage-gated Na channels in nerve membranes. Na channels are large, integral membrane proteins that contain a larger ␣-subunit and 1 or 2 smaller ␤-subunits. Ion conduction and local anesthetic binding both take place within the subunit, which contains 4 homologous domains each with 6 helical, membrane-spanning segments (Figure 6.1).6,7 When 70

Local Anesthetics in Regional Anesthesia

71

TTX binding PKA PKC IFM Inactivation OUT

II

I

III

IV

IN

COO NH3+ Subtype

Rat Orthologs

Nav1.1

Brain I

Nav1.2

TTX Activation Inactivation Sensitivity Threshold Rate (nM)

Tissue Localization CNS, also in DRG and motor neurons CNS

-

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Brain IIA

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Brain III

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Embryonic nervous system; adult CNS;

Nav1.4

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H1

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PN5, NaN

39,000

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Heart; embryonic DRG DRG; motor neurons, also in CNS Mostly DRG, also in CNS DRG (80% small diameter; 20% large DRG (small diameter); also in CNS

Figure 6.1: Mammalian voltage-gated Na channel subtypes. TTX = tetrodotoxin, PKA = protein kinase A, PKC = protein kinase C, IFM = intracellular loop responsible for first inactivation. III S6 and IV S1 responsible for inactivation. Reprinted from: Lai J, Porreca F, Hunter J, Gold M. Voltage-gated sodium channels and hyperalgesia. Annu Rev Pharmacol Toxicol. 2004;44:372.7

produced for use as ion-selective electrodes. Recent x-ray crystallographic studies have provided us with a better appreciation for voltage-gating phenomena. Channels are likely “gated” by paddle-shaped voltage sensors (containing a dipole) that move within and out of the plasma membrane, contorting the ion conducting “pore” of voltage-gated ion channels.12,13 E L E C T RO P H A R M AC O LO G Y O F LO C A L ANESTHESIA

Local anesthesia results when local anesthetics bind Na channels in peripheral neurons, inhibiting the increased Na permeability that underlies action potentials.6,11 Molecular biologic techniques have permitted investigators to isolate regions of the Na channel molecule that are relevant to the production of local anesthesia. In particular, local anesthetic binding has been localized to S6 regions of ␣ subunits.6,7,14 Local anesthetic inhibition of Na currents increases with repetitive depolarizations, a phenomenon often called “use dependent,” “frequency dependent,” or “phasic” block.6,11 But, why does the extent of local anesthetic inhibition increase with repetitive depolarizations? Each succeeding depolarization presents a new opportunity for local anesthetics to encounter a Na channel that, not yet having bound a local anesthetic,

is “open” or “inactivated,” both of which forms have greater local anesthetic affinity than “resting” channels.6,11,15 Thus, the fraction of channels that are bound by local anesthetic progressively increases with repetitive depolarizations, resulting in a progressive decline in the magnitude of the Na current and action potential. Many compounds other than local anesthetics will inhibit Na channels: general anesthetics, ␣2 agonists, tricyclic antidepressants, and nerve toxins.11,16–19 Perhaps one of these “nontraditional” Na channel antagonists will prove safer or more effective than traditional local anesthetics. LO C A L A N E S T H E T I C AC T I O N S AT S I T E S U N R E L AT E D TO Na + C H A N N E L S O R N E RV E B LO C K

Local anesthetics have many actions other than those related to Na channels and nerve block, and these local anesthetic actions have been the subject of recent review articles.20–22 Circulating local anesthetics have profound effects on coagulation, inflammation, microcirculation, immune responses to infection and malignancy, postoperative gastrointestinal function, and analgesia.20,21 Infused local anesthetics may relieve neuropathic pain.22

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LO C A L A N E S T H E T I C S T RU C T U R E S

All local anesthetics used in clinical medicine share certain structural features that render them all amphiphilic.2,5,19,23,24 One end of the molecule is more hydrophobic as a consequence of its containing a benzene ring, often with alkyl substituents. The other end of the molecule is more hydrophilic as a consequence of its containing a tertiary amine. The pKa of this amine is generally >7.4; therefore, the preponderance of local anesthetic molecules found in vivo will be protonated (positively charged). These two structural elements are separated by a hydrocarbon chain or ring and by an amide or ester bond.3,5,11,25 Two of the currently available local anesthetics, ropivacaine and levobupivacaine, are prepared for clinical use as single S(−) enantiomers.26 Mepivacaine, bupivacaine, etidocaine, prilocaine, and cocaine are prepared as racemic mixtures; the remaining local anesthetics have no asymmetric carbon atoms. The various local anesthetics available commercially differ markedly in their potential clinical applications and toxicity. In clinical practice, not every local anesthetic is suitable for every regional block procedure. Thus, an astute clinician will select among a restricted set of compounds for the one with the onset and duration of action most consistent with surgical needs. A variety of other compounds other than “conventional” local anesthetics have been used in animal and human experiments to produce regional anesthesia (as well as to block the Na channels, as was previously discussed).10,11,19,27,28 Some amphiphilic compounds share multiple structural features with local anesthetics (eg, calcium channel blockers and tricyclic antidepressants). Others (eg, the nerve toxins tetrodotoxin and saxitoxin) bear no structural similarities to conventional local anesthetics, clearly bind to a different active site, and resemble “classical” local anesthetics only by being organic compounds that inhibit Na currents.6 Still other agents that inhibit nerve conduction, for example, the general anesthetic halothane, bind at Na channel sites yet to be specifically identified. P H Y S I C O C H E M I C A L P RO P E RT I E S O F LO C A L A N E S T H E T I C S

Local anesthetics may be characterized by their potency, delay of onset, and duration of action, and there are associations between the physicochemical properties of local and these properties. On the basis of their anesthetic profile in humans, the local anesthetics may be classified as follows: 1. Agents with relatively short durations of action and low potency, including procaine and chloroprocaine 2. Agents with intermediate durations of action and moderate potency, including lidocaine and mepivacaine, and prilocaine 3. Agents with prolonged duration of action and high potency including tetracaine, bupivacaine, levobupivacaine, ropivacaine, and etidocaine. Chloroprocaine, lidocaine, mepivacaine, prilocaine, and etidocaine possess a relatively rapid onset of action. Tetracaine, bupivacaine, and ropivacaine have prolonged latencies of onset. In general, increasing potency associates with increasing lipid solubility, protein binding, delay of onset, and duration of action.

Physicochemical properties that have been linked to clinical local anesthetic actions include lipid solubility, plasma protein binding, and pKa . Lipid solubility has a strong association with the potency of local anesthetic compounds, particularly among chemically similar compounds in experiments on isolated nerves in vitro. However, the correlation is less robust in human anesthesia. Chloroprocaine has a relatively low lipid solubility, with an octanol:buffer partition coefficient for the free-base, neutral form of 810 at body temperature. Chloroprocaine is administered at concentrations of 2% to 3% for epidural anesthesia. However, bupivacaine has much greater lipid solubility, with an octanol:water partition coefficient for the free-base hentral form of 3420 at body temperature.29 Bupivacaine produces effective epidural anesthesia at concentrations between 0.50% to 0.75%, indicating that it may be (roughly) 4 times more potent than chloroprocaine. Increasing lipid solubility also associates with increasing duration of action. Among the following pairs of related anesthetics, lidocaine and etidocaine, mepivacaine and bupivacaine, and procaine and tetracaine, the second agent in the pair has greater lipid solubility and the longer duration of action. Increased lipid solubility also associates with increased delay of onset for every drug pair just cited, save that of lidocaine vs etidocaine, where etidocaine has an onset as fast as lidocaine’s. Etidocaine’s anomalously rapid onset remains poorly understood. All clinically useful compounds must have at least some minimal lipid solubility. The protonated (charged) forms of local anesthetics have much lower octanol:buffer partition coefficients than the neutral (uncharged) forms.29 At body temperature, the charged form of bupivacaine has an octanol-water partition coefficient of 2, whereas the neutral base local anesthetic has a coefficient of 3420. Compounds that do not readily permeate membranes (eg, QX314, an obligatorily charged quaternary analog of lidocaine) will not produce conduction block if applied on the extracellular side of a nerve (as would take place during clinical regional anesthesia). Obligatorily charged local anesthetics will potently block Na currents when applied within cytoplasm, a finding that promotes many useful insights about the local anesthetic binding site.6,11,19 The pKa of a compound identifies the pH at which the neutral and charged forms are present in equal concentrations. pKa has a much-discussed but, in truth, nonexistant association with the speed of onset of local anesthesia.30 Local anesthetics must diffuse across tissue and/or membrane to inhibit Na channels in all circumstances save when a drug is introduced directly into the cytoplasm. Therefore, in nearly all clinical circumstances, rapid onset is favored by increasing the amount of drug in the base (uncharged or neutral) form. The percentage of a specific local anesthetic that is present in the base form when injected into tissue is inversely related to the pKa of that agent. Using these facts, many authors make a leap of faith and assert that one can predict the relative speed of onset among differing local anesthetics by comparing their pKa s.30 Unfortunately, faith in this rule is not supported by the available data, despite the many examination questions that have been written on this topic. Mepivacaine, lidocaine, and etidocaine, for example, possess pKa s of 7.7, 7.8, and 7.9, respectively, at body temperature.29 Yet, despite a greater pKa , the onset of block with etidocaine is at least as fast as with the other two agents. Tetracaine possesses a pKa of 8.4 at 36◦ C. At the same temperature, chloroprocaine has a pKa of 9.1. Nevertheless, the onset of block with chloroprocaine for all forms of regional anesthesia is considerably faster than with tetracaine

Local Anesthetics in Regional Anesthesia

(and this holds true even when adjustments are made for their relative potencies). Die-hard, zealous devotees of the pKa “rule” have argued that chloroprocaine is used at greater concentrations than other local anesthetics, and attribute chloroprocaine’s more rapid onset of action to the larger number of molecules of this agent that are administered compared to other agents. This explanation finally collapsed when exactly the same doses of 1% chloroprocaine and 1% lidocaine were compared for spinal anesthesia,31 and chloroprocaine had a shorter onset time than lidocaine. Thus, pKa does not predict rate of onset. It has long been part of the “canon” that the extent of protein binding of local anesthetics determines their duration of action.30 There is no question that one can demonstrate a correlation among lipid solubility, protein binding, potency, and duration of action. Nevertheless, despite the correlation, there is no direct relationship between local anesthetic protein binding and local anesthetic binding to Na channels. For any drug, the less water soluble the compound the greater fraction of the drug will be protein bound in blood.32 The only conceivable connection between protein binding and duration of local anesthetic action lies in the fact that local anesthetics of increased lipid solubility (by definition) are protein bound to greater extent when they reach the blood stream. For thermodynamic reasons, more lipid soluble agents will have a greater tendency than less lipid soluble agents to remain in a lipid-rich environment (eg, the plasma membrane) than to diffuse into the blood. The greater the propensity that the local anesthetic molecule has for remaining within the membrane (rather than diffusing away from the nerve towards the blood stream), the longer that the molecule has the potential to bind the Na channels contained within the membrane and produce nerve block. Once the local anesthetic molecule enters the blood stream, it is highly unlikely to reenter the nerve membrane and contribute to conduction block. Bupivacaine is about 95% protein bound. It has an octanol: buffer partition coefficient for the free base form of 3420, great potency, and a long duration of action.29 However, procaine is only 6% protein bound and much less potent. It has an octanol:buffer partition coefficient for the free base form of 100 and a relatively short duration of action. Mepivacaine and lidocaine are both intermediate in terms of protein binding (55% to 75%) and in terms of lipid solubility (partition coefficients for the free base forms of 130 and 366, respectively), potency, and anesthetic duration. As should be obvious, it is silly to consider the nonspecific binding of a drug to ␣1 -acid glycoprotein and albumin (the two serum proteins to which local anesthetics bind) as having any direct relationship to the duration of binding of that drug to its specific binding site in the Na channel, other than as an index of lipid solubility, which defines the propensity of a molecule to remain within a lipid-rich environment (eg, membrane).33 LO C A L A N E S T H E T I C P H A R M AC O DY NA M I C S

Local Anesthetic Volumes and Concentrations during Nerve Block When 40–35 mL of 0.5% ropivacaine is injected to produce a brachial plexus block, only a very small fraction of the local anesthetic molecules will actually be bound by Na channels in the brachial plexus.34 As is generally true during regional anesthesia, most of the injected local anesthetic will be “nonspecifically” bound by other nearby membranes and tissues and/or removed

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by the blood stream. As a consequence, the extent and the duration of local anesthetic effects can be only loosely correlated with local anesthetic content of nerves in animal experiments.35–38 To block conduction, the anesthesia must cover a sufficient length of nerve. This “critical length” exceeds 2 cm (far more than the 3 Ranvier nodes specified in textbooks) except at very increased local anesthetic concentrations.39 In all circumstances, the mass of drug (the total number of local anesthetic molecules) administered will influence the onset, quality, and duration of anesthesia.30 For any agent, as the mass of drug increases, the likelihood of satisfactory anesthesia and the duration of anesthesia will increase and the latency of onset of anesthesia will decrease. In general, the dosage of local anesthetic administered can be increased by administering a larger volume of a less concentrated solution or a smaller volume of a more concentrated solution. Clinicians and basic scientists continue to debate whether volume, concentration, or total mass (the product of volume and concentration) of drug is paramount in determining the success of blocks. For example, in laboring women, increasing the bupivacaine concentration from 0.125% to 0.5% while maintaining the same injectate volume (10 mL) decreased latency, improved the incidence of satisfactory epidural analgesia, and increased the duration of action.40 In surgical anesthesia increasing the bupivacaine concentration from 0.5% to 0.75% (at constant volume) produced a faster onset and longer duration of sensory anesthesia and increased the likelihood of satisfactory sensory anesthesia and the degree of motor block.41 When prilocaine was administered in the epidural space either as 30 mL of a 2% solution or 20 mL of 3% solution, there was no difference in onset, depth, or duration of anesthesia or of motor block.41 In epidural analgesia the volume of anesthetic solution administered may influence the “spread” of anesthesia; for example, 30 mL of 1% lidocaine administered in the epidural space anesthetized 4 more dermatomes than 10 mL of 3% lidocaine.42 However, in rat sciatic nerve blocks a smaller volume of a more concentrated local anesthetic solution produce a denser, more persistant block than a larger volume of a less concentrated solution.36 Nevertheless, multiple clinical studies suggest that except for a consistent positive correlation between injectate volume and the dermatomal spread of epidural anesthesia, the primary qualities of regional anesthesia, namely onset, depth, and duration of blockade, are related to the mass of drug injected (ie, the product of volume times concentration) and the proximity of the local anesthetic molecules to the intended target.43,44 MAXIMUM DOSES

Most review articles and book chapters present a table of “maximal safe doses” of local anesthetics, despite there being no way to specify one, universal, practical, maximal “safe” dose of a local anesthetic.45 The maximal tolerable dose depends on many factors, including the intended (and actual) site of injection, the duration of time over which the local anesthetic was injected, additives, and patient-related factors such as size and body habitus and the presence of pregnancy or disease. The same drug dose given for intercostal blocks produces greater peak local anesthetic concentrations than when given for plexus or epidural blocks.1,30 A dose given over 24 hours may be well tolerated, but not when given over 24 seconds. Forty milliliters of local anesthetic is well tolerated when administered for

John Butterworth

Figure 6.2: Earlier inhibition of sensory nerve action potentials improved to compound motor action potentials in volunteers receiving median nerve blocks with bupivacaine. Volunteers receiving mepivacaine showed no difference in latency of inhibition of sensory versus motor nerves. Reprinted from: Butterworth J. Clinical pharmacology of local anesthetics. Adapted from Hadzic A ed. Textbook of Regional Anesthesia and Acute Pain Management. New York, NY: McGraw Hill; 2007.1

interscalene block; 0.4 mL is poorly tolerated if injected into the nearby vertebral artery. D I F F E R E N T I A L S E N S O RY N E RV E B LO C K

In addition to the properties already described, one other important clinical consideration is the ability of local anesthetic agents to differentially inhibit sensory versus motor fibers. Physicians have long known that nerve fibers of differing sizes have differing susceptibility to local anesthetics (directly applied pressure, lack of oxygen, and lack of glucose). In general, among fibers of similar types, larger fibers are more resistant to local anesthetic block.37 Smaller myelinated fibers (eg, A␦ fibers) are more susceptible to local anesthetics than larger myelinated fibers (eg, A␣ or A␤ fibers). Larger unmyelinated fibers are less susceptible to block than smaller unmyelinated fibers.46 The “size principle” fails when unmyelinated fibers are compared with myelinated fibers, because the (smaller) unmyelinated fibers (eg, C fibers) as a group are less susceptible to local anesthetics than the (generally larger) myelinated fibers.35 As a consequence, conventional local anesthetic techniques cannot completely block all pain-transmitting A␦ and C fibers without also inhibitioning some motor fibers. In other words, local anesthetics will not produce analgesia sufficient for surgical incision without motor block.1,3,11 Some agents (eg, bupivacaine and ropivacaine) are relatively selective for sensory fibers.47 These agents are often used in epidural solutions for surgical anesthesia, obstetric analgesia, and postoperative relief of pain owing to their ability to provide adequate sensory analgesia while preserving motor function, particularly at concentrations ≤0.25%. Thus, laboring parturients can be pain free yet still able to walk. Etidocaine and lidocaine, however, show little separation between sensory and motor blockade.30 At concentrations required to achieve adequate epidural sensory anesthesia required, etidocaine and lidocaine have a rapid onset of action and, in the case of etidocaine, a prolonged duration of anesthesia; however, with both

sensory anesthesia is associated with a profound degree of motor blockade, and the motor block can sometimes outlast the sensory block during offset of anesthesia. Differences among local anesthetics are sometimes most apparent during the onset or offset of peripheral nerve block.47 For example, during onset of median nerve block with mepivacaine there is almost no difference in the relative inhibition of sensory nerves as assessed by the amplitude of sensory nerve action potentials (SNAPS) vs motor nerves as assessed by compound motor action potential (CMAP) amplitudes. Onset of bupivacaine was slower than with mepivacaine, but inhibition of SNAP amplitude occurred earlier than CMAP. At steady state, both agents inhibited SNAPs and CMAPs comparably and profoundly after 20 minutes of injection (Figure 6.2).47 As previously noted, the fact that specific genes produce the Na channels found in unmyelinated nerves, motor nerves, and dorsal root ganglia offers the tantalizing possibility that structural differences in these various channel forms might be sufficient to permit design and development of selective inhibitors.10,48 OT H E R FAC TO R S I N F LU E N C I N G AC T I V I T Y

Many factors influence the adequacy of regional anesthesia, including the local anesthetic dose, temperature, site of administration, pregnancy, and drug additives. In general, the fastest onset and shortest duration of anesthesia occur with spinal and subcutaneous injections. Plexus blocks have a slower onset and longer duration.1,30 For a given dose of local anesthetic, spread of neuraxial anesthesia increases during pregnancy because of decreases in thoracolumbar cerebrospinal fluid (CSF) volume and an increased neural susceptibility to local anesthetics (Figure 6.3).49–51 U S E O F A D D I T I V E S W I T H LO C A L A N E S T H E T I C S O LU T I O N S

With most agents and most block procedures, onset, duration, and adequacy of anesthesia may be altered by addition of

120 Sensory Nerve Action Potential (Percent of Baseline Values)

74

Not Pregnant

100

Pregnant

80 60 40 20 0 0

5 10 15 Minutes Following Local Anesthetic Injection

20

Figure 6.3: Inhibition of sensory nerve action potentials in pregnant women contrasted with women who were not pregnant. All subjects received median nerve blocks with 5 mL of 1% lidocaine. All data expressed as means ± SEM. Reprinted from: Butterworth J, Walker F, Lysak S. Pregnancy increases median nerve susceptibility to lidocaine. Anesthesiology. 1990;72:963.49

Local Anesthetics in Regional Anesthesia 1

100 Percent inhibition of Action Potential Amplitude

vasoconstrictors. Attempts have been made to alter the onset and duration of anesthesia by using mixtures of local anesthetics, carbonation (adding carbon dioxide), or addition of bicarbonate or any of a long list of other additives to local anesthetic solutions. Vasoconstrictors, typically epinephrine, are frequently added to local anesthetic solutions to decrease the rate of vascular absorption and allow a greater fraction of injected anesthetic molecules to reach the nerve membrane. In the end, the goal is to increase the time over which local anesthetic mollecules persist near nerves, potentially increasing the depth and duration of anesthesia. In clinical anesthesia, local anesthetic solutions often contain a 1:200,000 (5 ␮g/mL) concentration of epinephrine.25,30 Limited information is available regarding the optimum concentration of epinephrine with local anesthetic agents other than lidocaine or block procedures other than local infiltration.52 Epinephrine has differing effects on differing local anesthetics. Procaine, lidocaine, and mepivacaine are significantly prolonged by epinephrine during infiltration anesthesia, peripheral nerve blocks, or epidural anesthesia.3,2,30,53 The effect of epinephrine on bupivacaine depend on the setting, block technique, and concentration of drug used. Bupivacaine local infiltration blocks are prolonged by epinephrine.54 Epinephrine does not produce clinically useful prolongation of bupivacaine epidural blocks. The frequency and duration of adequate labor analgesia were improved when epinephrine 1:200,000 was added to 0.125% or 0.25% bupivacaine40 ; however, addition of epinephrine to 0.5% or 0.75% bupivacaine did not significantly improve epidural blocks for either obstetric or surgical patients.40,55 Motor block is increased following the epidural administration of epinephrine-containing solutions of bupivacaine and etidocaine.55 Epinephrine improves the quality of analgesia provided by dilute intrathecal solutions of bupivacaine + opioid.56 The differing effects of epinephrine in prolonging the duration of differing local anesthetics is most apparent during spinal anesthesia. Epinephrine greatly increases the duration of tetracaine spinal anesthesia but prolongs lidocaine and bupivacaine spinal anesthesia to a lesser extent.57–61 Other ␣ agonists such as clonidine and phenylephrine also have been used as additives to solutions of local anesthetics. ␣2 agonists have local anesthetic properties in vitro. Clonidine and quanfacine will block both A␣ and C fibers (Figure 6.4).16 Prolongation of regional anesthesia by clonidine could be the result of pharmacodynamic prolongation of local anesthetic effects, a direct action of clonidine on nerves, a central action of clonidine, or some combination of these effects.62 Clonidine markedly prolongs the duration of mepivcaine and lidocaine plexus blocks.63 Either oral or intrathecal clonidine prolongs the duration tetracaine spinal anesthesia.64,65 Intrathecal clonidine prolongs the duration of lidocaine, mepivacaine, and bupivacaine spinal anesthesia.66,67 Clonidine, like epinephrine, has less effect on the duration of plexus blocks produced by bupivacaine or ropivacaine than on those produced by mepivacaine or lidocaine.68 Carbonation (addition of carbon dioxide) of local anesthetic solutions was once thought to speed the onset of action of various local anesthetics.1,69 Carbon dioxide enhances diffusion of local anesthetics through nerve sheaths of isolated nerves and hastens inhibition of action potentials.70,71 A double-blinded study, however, failed to demonstrate a significantly more rapid onset of action when lidocaine carbonate was compared with lidocaine hydrochloride for epidural blockade.72 In fact, addition

75 3 3

80

60

5 2

4

A α fiber C fiber

40

9

20 5 8

0

4

23

10-5 10-4 10-3 10-2 10-1 Figure 6.4: Concentration-dependent inhibition by clonidine of A␣ and C fibers in rat sciatic nerves. The total number of nerves studied at each concentration is given on the figure. All data provided as means and standard derivatives. Reprinted from: Butterworth J, Strichartz G. The ␣2 adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg. 1993;76:297.16

of NaHCO3 to lidocaine (which would be expected to reduce the fraction of the protonated local anesthetic form) reduced the onset delay relative to the carbonated preparation.72 Other double-blind studies failed to show benefit from carbonation of bupivacaine.73,74 Thus, the available date show no consistent benefit to carbonation of local anesthetic solutions under clinical conditions. Adding sodium bicarbonate to local anesthetic solutions immediately before injection inconsistently speeds the onset of conduction blockade.72,75–77 Bicarbonate will increase the pH of the local anesthetic solution and increase the fraction of local anesthetic molecules in the uncharged base form. In theory, more local anesthetic molecules could diffuse across the nerve sheath and nerve membrane, speeding the onset of anesthesia. In vitro studies of pH adjustment suggest that the apparent potency of local anesthetics increases at more basic pH.78 Addition of bicarbonate to lidocaine prior to median nerve block increased rate of onset of motor block without altering sensory nerve block.77 Numerous clinical studies have been performed in which the addition of sodium bicarbonate to local anesthetic solutions has either improved or had no effect on the latency, duration, or effectiveness of local anesthesia.79 Bicarbonate likely has its greatest benefit when added to local anesthetic solutions compounded with epinephrine by the manufacturer. Epinephrinecontaining solutions have a reduced pH relative to “plain” solutions to increase the shelf life. Finally, addition of bicarbonate reduces the pain from subcutaneous injection of local anethetics.80 Other additive effects are specific to a particular regional block (Table 6.1).

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John Butterworth

Table 6.1: Additives in Local Anesthetic Solutions Used for Specific Regional Anesthetic Procedures Opthalmic Blocks Hyaluronidase, epinephrine, bicarbonate, and clonidine improve reliability of anesthesia.85,113 ; multiple local anesthetics and multiple additives are often employed.

Intravenous Regional Anesthesia

Minor Peripheral Blocks

Brachial Blocks Plexus

Clonidine and dexmedetomidine reduce discomfort during and after IVRA; ketorolac improves intraoperative and postoperative analgesia.28,91

Solutions containing epinephrine have been used for digital nerve blocks without ischemic sequelae.73,129

Epinephrine is often used to reduce blood LA concentrations and serves as a marker for accidental iv injection.99 Clonidine improves anesthesia with lidocaine and mepivacaine, with less effect on bupivacaine or ropivacaine.99 Bicarbonate reduces the onset time for anesthesia and may reduce duration.

VA S O D I L ATO R P R O P E RT I E S

The clinical activity of local anesthetics is modified by their vasodilator properties. Faster vascular absorption reduces the number of local anesthetic molecules available for binding to Na channels. Faster absorption into the blood stream reduces the apparent local anesthetic in vivo potency and duration of action. All local anesthetics except cocaine both constrict and dilate vascular smooth muscle, depending on the concentration.81–83 At reduced concentrations local anesthetics inhibit nitric oxide release and cause vasoconstriction. At the much greater concentrations used for regional anesthesia these agents cause vasodilations.83

Local Anesthetic Blood Concentrations, Protein Binding, Metabolism, and Pharmacokinetics As previously mentioned, in blood, all local anesthetics are partially protein bound, primarily to ␣1 -acid glycoprotein (AGP) and secondarily to albumin.30,32 Affinity for AGP increases with LA hydrophobicity and decreases with protonation and acidosis.84 Extent of protein binding is influenced by the concentration of AGP. Both protein binding and protein concentration

Intercostal Blocks Epinephrine is nearly always included to decrease local anesthetic concentrations in blood.11,32,127

Epidural Anesthesia and Analgesia Epinephrine reduces local anesthetic concentrations in blood and increases cardiac output.9 Clonidine produces analgesia, sedation, and increases local anesthetic blood concentrations.92 Epidural combinations of local anesthetics and opioids provide better analgesia to than from the agents given separately.33 Clonidine is popular for postoperative caudal analgesia in children.83

Spinal Anesthesia and Analgesia Addition of dextrose or water will influence baricity, distribution of local anesthetics within the CSF, and permit patient positioning to influence dermatomal spread of spinal anesthesia.48 Vasoconstrictors greatly prolong tetracaine spinal anesthesia.30,68 Clonidine (intrathecal or oral) may be used to prolong spinal anesthesia.37,102 Adding fentanyl to LA solutions improves the quality of intraoperative and postoperative analgesia without prolonging motor block, time to voiding, or recovery time.5,74

decline during pregnancy, but these changes have limited clinical importance.85 During longer-term infusion of LA and LAopioid combinations concentrations of serum binding proteins progressively increase.84 There is considerable first-pass uptake of local anesthetics by lung.86 Esters undergo rapid hydrolysis in blood, catalyzed by pseudocholinesterase.30,87 Procaine and benzocaine are metabolized to p-aminobenzoic acid (PABA). The amides undergo oxidative N-dealkylation in the liver (by cytochrome P450).1,30 Amide LA clearance depends on hepatic blood flow, hepatic extraction, and enzyme function and is reduced by drugs that decrease hepatic blood flow such as ␤-adrenergic or H2 -receptor blockers and by heart or liver failure.30,87 TOX I C S I D E E F F E C T S O F LO C A L ANESTHETICS

It is often assumed that all toxic side effects of local anesthetics are caused by unwanted binding of local anesthetic to Na channels in the central nervous and cardiovascular systems.88 However, local anesthetics will inhibit many other targets aside from the Na channels, including multiple forms of voltage-gated

Local Anesthetics in Regional Anesthesia

77

Table 6.2: Concentrations of Local Anesthetics that Inhibit Cardiac Function dP/dt max (65%) (μg/mL)

EF (65%) (μg/mL)

FS (65%) (μg/mL)

CO (75%) (μg/mL)

BUP

2.3 (1.7–3.0)

3.2 (2.2–4.7)

2.1 (1.5–3.1)

3.6 (2.1–6.0)

LBUP

2.4 (1.9–3.1)

3.1 (1.4–2.9)

1.3 (0.9–1.8)

3.3 (2.0–5.5)

ROP

4.0 (3.1–5.2)a

4.2 (3.0–6.0)

3.0 (2.1–4.2)b

LA

LID

8.0 (5.7–11.0)

c

6.3 (4.0–9.9)

d

5.5 (3.5–8.7)

c

5.0 (3.1–8.3) 15.8 (8.3–30.2)c

Note: Data represented are concentration estimates and 95% confidence intervals. Abbreviations: dP/dtmax (65%) = local anesthetic concentration that reduced maximal change in left-ventricular pressure over time to 65% of baseline value. EF (65%) = local anesthetic concentration that reduced left-ventricular ejection fraction to 65% of baseline value. FS (65%) = local anesthetic concentration that reduced fractional shortening to 65% of baseline value. CO (75%) = local anesthetic concentration that reduced cardiac output to 75% of baseline value. BUP = bupivacaine; LBUP = levobupivacaine; ROP = ropivacaine; LID = lidocaine. a

ROP > BUP, LBUP; P < .05.

b

ROP > LBUP; P < .05.

c

LID > BUP, LBUP, ROP; P < .01

d

LID > BUP, LBUP; P < .01.

Reprinted from: Groban L, Deal D, Vernon, Jason, James R, Butterworth J. Does local anesthetic stereoselectivity or structure predict myocardial depression in anesthetized canines? Reg Anesth Pain Med. 2002;27:460–468.102

ion channels, enzymes, receptors, and G-protein-mediated signaling.11,19,23,89–94 Local anesthetic binding to any or all of these sites could contribute to toxicity, spinal or epidural analgesia, or analgesia during local anesthetic infusions.99 C E N T R A L N E RVO U S S Y S T E M S I D E E F F E C T S

Local anesthetic central nervous system toxicity most likely results from disinhibition of inhibiting pathways, with the ultimate potential result of convulsion. Increasing LA doses produce a stereotypical sequence of signs and symptoms culminating in seizures.1,3,5,25,30,86 Further LA dosing may lead to central nervous system (CNS) depression, possibly including respiratory arrest. More potent local anesthetics, such as bupivacaine, produce seizures at lower blood concentrations and lower doses than less potent local anesthetics, such as lidocaine. Both metabolic and respiratory acidoses decrease the convulsive dose of lidocaine in experimental amounts, and the result can likely be extrapolated to other anesthetics and to humans.96 CNS toxicity can promote cardiac toxicity.87 Cardiovascular signs of CNS excitation (eg, increased arterial blood pressure) appear at lower local anesthetic concentrations than those associated with cardiac depression.97 C A R D I OVA S C U L A R TOX I C I T Y

Bupivacaine binds more avidly to cardiac Na channels and, once bound, remains bound for a longer time than lidocaine.6,11,98 Bupivacaine R(+) isomers bind cardiac Na channels more avidly than S(−) isomers (levobupivacaine and ropivacaine).26 Local anesthetics inhibit conduction within the heart with the same

rank order of potency as they demonstrate inhibition of impulses in peripheral nerve.98 Local anesthetics produce concentrationdependent myocardial depression. Local anesthetics bind and inhibit Ca and K channels in the heart, but only at concentrations much greater than those required for maximal binding to Na channels.11,90 Local anesthetics bind ␤-adrenergic receptors and inhibit epinephrine-stimulated cyclic adenosine monophosphate (AMP) formation.23,88 Most local anesthetics will not produce cardiovascular toxicity in animals until blood concentration exceed 3 times those that produce seizures. Nevertheless, there are reports of simultaneous seizures and cardiac toxicity with bupivacaine in patients.1,5,25 Supraconvulsant doses of bupivacaine more commonly produce arrhythmias in dogs than supraconvulsant doses of ropivacaine or lidocaine.24 In most species and in most animal models of cardiac toxicity, the rank order of local anesthetic potency appears to be bupivacaine > levobupivacaine > ropivacaine (Table 6.2).97,99 Furthermore, arrhythmias were more common in dogs receiving toxic doses of bupivacaine or levobupivacaine than those receiving lidocaine or ropivacaine.100–102 There were notable differences among local anesthetics in the responses to attempted resuscitation. Dogs given lidocaine could be resuscitated, but required continuing infusion of epinephrine to maintain an adequate blood pressure. Conversely, many dogs receiving bupivacaine or levobupivacaine could not be resuscitated using standard drugs and techniques. Those dogs receiving bupivacaine, levobupivacaine, or ropivacaine that could be defibrillated often required no other therapy.100–102 Similar differences were observed in pigs: Bupivacaine had a greater propensity for arrhythmias than lidocaine. Bupivacaine was 4 times more potent than lidocaine at producing myocardial depression but 16 times more potent at producing arrhythmias in pigs.105 As

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noted earlier, it is often assumed that all LA cardiovascular toxicity arises from one, common fundamental mechanism. Given that bupivacaine seems much more prone to arrhythmias than lidocaine, and that the response to resuscitation drugs and techniques differ among these drugs, it seems likely that the mechanism of cardiovascular toxicity may also differ between these two agents. M E T H E M O G LO B I N E M I A

Generations of anesthesia textbooks have focused on the unique metabolism of prilocaine to o-toluidine, and the resulting (and allegedly predictable) production of methemogloblinemia in adults with prilocaine doses >600 mg.30 A recent study demonstrates the unpredictability of the prilocaine dose that will result in clinically important methemoglobinemia in adults.104 More importantly, perioperative methemogloblinemia more commonly arises in North America from use of the topical local anesthetic benzocaine, dehydration, or treatment of infections with dapsone than from use of prilocaine in any form.105 A L L E RG Y

Textbooks state that there is an increased incidence of allergy to ester local anesthetics metabolized to p-aminobenzoic acid (procaine and benzocaine) and a greater incidence of allergy to ester than amide local anesthetics.30 If there are convincing data confirming these assertions I cannot find them. Evidence for allergic cross reactions between methylparaben and p-aminobenzoic acid is also sparse, despite this being a frequent topic of questions on certification examinations. The most important fact about local anesthetic allergy is that it is rare. Multiple studies show that when patients with apparent “allergic” or even anaphylactoid reactions to local anesthetics are subjected to standard testing, almost none will have immune responses to preservative-free local anesthetics.106,107 T R E AT M E N T O F LO C A L A N E S T H E T I C TOX I C I T Y

Treatment of adverse local anesthetic reactions should be guided by their severity. Serious degrees of methemoglobinemia are treated with intravenous (IV) oxygen and methylene blue (1 mg/kg). Anaphylactoid reactions may require epinephrine, corticosteroids, and fluid resuscitation. Minor degrees of central nervous system excitation can be allowed to terminate spontaneously. Even when local anesthetics produce seizures, the only requirement is that one maintain the airway and provide oxygen. Seizures may be terminated with intravenous thiopental (1–2 mg/kg), midazolam (0.05–0.10 mg/kg), or propofol (0.5– 1 mg/kg). In the event of local anesthetic-induced cardiovascular depression, milder degrees of hypotension may be treated by infusion of intravenous fluids and vasopressors (phenylephrine, 0.5–5 mcg/kg/min, norepinephrine, 0.02–0.2 mcg/kg/min, or vasopressin, 2–20 units IV). If contractile failure is evident, epinephrine (1–15 mcg/kg IV bolus) may be required. Unfortunately, a recent survey of academic anesthesia departments confirmed a lack of consensus regarding resuscitation drugs for local anesthetic cardiovascular toxicity.108,109 I suggest that the

Guidelines for Advanced Cardiac Life Support be followed with a few substitutions.109 I suggest that amiodarone and vasopressin be substituted for lidocaine and epinephrine, respectively.110–112 Once advanced cardiac life support begins, intravenous lipid should be considered. Animal experiments demonstrate the remarkable ability of lipid infusion to resuscitate animals from bupivacaine overdosage, even after unsuccessful attempts of “conventional” resuscitative techniques and drugs.113,114 The mechanism remains controversial, but may involve the lipid serving as a “sponge” for the local anesthetic, facilitating its removal from heart and brain.115,116 A growing number of case reports (see http://www.lipidrescue.org/) provide evidence that lipid infusion may also be effective in humans.117,118 In the case of a continuing lack of response to resuscitation efforts, consideration should be given to placing the patient on cardiopulmonary bypass with the hope of supporting the circulation long enough to permit the liver to clear the local anesthetic.119

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Local Anesthetics. Vol. 81. New York, NY: Springer-Verlag; 1987. Sinnott CJ, Cogswell III LP, Johnson A, et al. On the mechanism by which epinephrine potentiates lidocaine’s peripheral nerve block. Anesthesiology. 2003;98:181–188. Raymond SA, Steffensen SC, Gugino LD, et al. The role of length of nerve exposed to local anesthetics in impulse blocking action. Anesth Analg. 1989;68:563–570. Littlewood DG, Buckley P, Covino BG, et al. Comparative study of various local anesthetic solutions in extradural block in labour. Br J Anaesth. 1979;51:47. Scott DB, McClure JH, Giasi RM, et al. Effects of concentration of local anaesthetic drugs in extradural block. Br J Anaesth. 1980;52:1033. Erdimir HA, Soper LE, Sweet RB. Studies of factors affecting peridural anesthesia. Anesth Analg. 1965;44:400. Krenn H, Deusch E, Balogh B, et al. Increasing the injection volume by dilution improves the onset of motor blockade, but not sensory blockade of ropivacaine for brachial plexus block. Eur J Anaesthesiol. 2003;20:21–25. Liu SS, Ware PD, Rajendran S. Effects of concentration and volume of 2-chloroprocaine on epidural anesthesia in volunteers. Anesthesiology. 1997;86:1288–1293. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med. 2004;29:564–575. Gissen AJ, Covino BG, Gregus J. Differential sensitivities of mammalian nerve fibers to local anesthetic agents. Anesthesiology. 1980;53:467–474. Butterworth J, Ririe DG, Thompson RB, et al. Differential onset of median nerve block: randomized, double-blind comparison of mepivacaine and bupivacaine in healthy volunteers. Br J Anaesth. 1998;81:515–521. Amir R, Argoff CE, Bennett GJ, et al. The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain. 2006;7:S1– S29. Butterworth JF, Walker FO, Lysak SZ. Pregnancy increases median nerve susceptibility to lidocaine. Anesthesiology. 1990;72: 962–965. Fagraeus L, Urban BJ, Bromage PR. Spread of epidural analgesia in early pregnancy. Anesthesiology. 1983;58:184–187. Popitz-Bergez FA, Leeson S, Thalhammer JG, et al. Intraneural lidocaine uptake compared with analgesic differences between pregnant and nonpregnant rats. Reg Anesth. 1997;22:363–371. Harwood TN, Butterworth JF, Colonna DM, et al. Plasma bupivacaine concentrations and effects of epinephrine after superficial cervical plexus blockade in patients undergoing carotid endarterectomy. J Cardiothorac Vasc Anesth. 1999;13:703–706. Liu S, Carpenter RL, Chiu AA, et al. Epinephrine prolongs duration of subcutaneous infiltration of local anesthesia in a doserelated manner: correlation with magnitude of vasoconstriction. Reg Anesth. 1995;20:378–384. Swerdlow M, Jones R. The duration of action of bupivacaine, prilocaine, and lignocaine. Br J Anaesth. 1970;42:335. Sinclair CJ, Scott DB. Comparison of bupivacaine and etidocaine in extradural blockade. Br J Anaesth. 1984;56:147. Soetens FM. Levobupivacaine-sufentanil with or without epinephrine during epidural labor analgesia. Anesth Analg. 2006;103:182–186. Armstrong IR, Littlewood DG, Chambers WA. Spinal anesthesia with tetracaine – effect of added vasoconstrictor. Anesth Analg. 1983;62:793. Chambers WA, Littlewood DG, Logan MR, et al. Effect of added epinephrine on spinal anesthesia with lidocaine. Anesth Analg. 1981;60:417.

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59. Chambers WA, Littlewood DG, Scott DB. Spinal anesthesia with hyperbaric bupivacaine: effect of added vasoconstrictors. Anesth Analg. 1982;61:49. 60. Concepcion M, Maddi R, Francis D, et al. Vasoconstrictors in spinal anesthesia with tetracaine: a comparison of epinephrine and phenylephrine. Anesth Analg. 1984;63:134. 61. Moore J M, Liu SS, Pollock JE, et al. The effect of epinephrine on small-dose hyperbaric bupivacaine spinal anesthesia: clinical implications for ambulatory surgery. Anesth Analg. 1998;86:973– 977. 62. Gaumann DM, Brunet PC, Jirounek P. Clonidine enhances the effects of lidocaine on C-fiber action potential. Anesth Analg. 1992;74:719–725. 63. Ohom G, Machmachi A, Diarra DP, et al. The effects of clonidine added to mepivacaine for paronychia surgery under axillary brachial plexus block. Anesth Analg. 2005;100:1179–1183. 64. Larsen B, Dorscheid E, Macher-Hanselmann F, et al. Does intrathecal clonidine prolong the effect of spinal anesthesia with hyperbaric mepivacaine? A randomized double-blind study. Anaesthesist. 1998;47:741–746. 65. Ota K, Namiki A, Iwasaki H, et al. Dose-related prolongation of tetracaine spinal anesthesia by oral clonidine in humans. Anesth Analg. 1994;79:1121–1125. 66. Dobrydnjov I, Samarutel J. Enhancement of intrathecal lidocaine by addition of local and systemic clonidine. Acta Anaesthesiol Scand. 1999;43:556–562. 67. Racle JP, Benkhadra A, Poy JY, et al. Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesth Analg. 1987;66:442–446. 68. Ilfeld BM, Morey TE, Thannikary LJ, et al. Clonidine added to a continuous interscalene ropivacaine perineural infusion to improve postoperative analgesia: a randomized, double-blind, controlled study. Anesth Analg. 2005;100:1172–1178. 69. Morrison DH. A double-blind comparison of carbonated lidocaine and lidocaine hydrochloride in epidural anaesthesia. Can Anaesth Soc J. 1981;28:387. 70. Catchlove RF. The influence of CO2 and pH on local anesthetic action. J Pharmacol Exp Ther. 1972;181:298–309. 71. Gissen AJ, Covino BG, Gregus J. Differential sensitivity of fast and slow fibers in mammalian nerve. IV. Effect of carbonation of local anesthetics. Reg Anaesth. 1985;10:68. 72. Curatolo M, Petersen-Felix S, Arendt-Nielse L, et al. Adding sodium bicarbonate to lidocaine enhances the depth of epidural blockade. Anesth Analg. 1998;86:341–347. 73. Brown DT, Morrison DH, Covino BG, et al. Comparison of carbonated bupivacaine and bupivacaine hydrochloride for extradural anaesthesia. Br J Anaesth. 1980;52:419. 74. McClure JH, Scott DB. Comparison of bupivicaine hydrochloride and carbonated bupivacaine in brachial plexus block by the interscalene technique. Br J Anaesth. 1981;53:523. 75. Arakawa M, Aoyama Y, Ohe Y. Block of the sacral segments in lumbar epidural anaesthesia. Br J Anaesth. 2003;90:173–178. 76. Candido KD, Winnie AP, Covino BG, et al. Addition of bicarbonate to plain bupivacaine does not significantly alter the onset or duration of plexus anesthesia. Reg Anesth. 1995;20:133–138. 77. Ririe DG, Walker FO, James RL, et al. Effect of alkalinization of lidocaine on median nerve block. Br J Anaesth. 2000;84:163–168. 78. Butterworth JF, Lief PA, Strichartz GR. The pH-dependent local anesthetic activity of diethylaminoethanol, a procaine metabolite. Anesthesiology. 1988;68:501–506. 79. Hilgier M. Alkalinization of bupivacaine for brachial plexus block. Reg Anaesth. 1985;10:59. 80. Davies RJ. Buffering the pain of local anaesthetics: a systematic review. Emerg Med. 2003;15:81–88.

81. Benzaquen BS, Cohen V, Eisenberg MJ. Effects of cocaine on the coronary arteries. Am Heart J. 2001;142:402–410. 82. Blair MR. Cardiovascular pharmacology of local anaesthetics. Br J Anaesth. 1975;47:247. 83. Johns RA, DiFazio CA, Longnecker DE. Lidocaine constricts or dilates rat arterioles in a dose dependent manner. Anesthesiology. 1985;62:141–144. 84. Thomas JM, Schug SA. Recent advances in the pharmacokinetics of local anaesthetics. Long-acting amide enantiomers and continuous infusions. Clin Pharmacokinet. 1999;36:67–83. 85. Fragneto RY, Bader AM, Rosinia F, et al. Measurements of protein binding of lidocaine throughout pregnancy. Anesth Analg. 1994;79:295–297. 86. Rothstein P, Arthur GR, Feldman HS, et al. Bupivacaine for intercostal nerve blocks in children: blood concentrations and pharmacokinetics. Anesth Analg. 1986;65:625–632. 87. Mather LE, Copeland SE, Ladd LA. Acute toxicity of local anesthetics: underlying pharmacokinetic and pharmacodynamic concepts. Reg Anesth Pain Med. 2005;30:553–566. 88. Butterworth J, Cole L, Marlow G. Inhibition of brain cell excitability by lidocaine, QX314, and tetrodotoxin: a mechanism for analgesia from infused local anesthetics? Acta Anaesthesiol Scand. 1993;37:516–523. 89. Butterworth JF, Brownlow RC, Leith JP, et al. Bupivacaine inhibits cyclic-3’,5’-adenosine monophosphate production: a possible contributing factor to cardiovascular toxicity. Anesthesiology. 1993;79:88–95. 90. Hirota K, Browne T, Appadu BL, et al. Do local anaesthetics interact with dihydropyridine binding sites on neuronal L-type Ca2+ channels? Br J Anaesth. 1997;78:185–188. 91. McCaslin PP, Butterworth J. Bupivacaine suppresses [Ca(2+)](i) oscillations in neonatal rat cardiomyocytes with increased extracellular K+ and is reversed with increased extracellular Mg(2+). Anesth Analg. 2000;91:82–88. 92. Olschewski A, Olschewski H, Br¨au ME, et al. Effect of bupivacaine on ATP-dependent potassium channels in rat cardiomyocytes. Br J Anaesth. 1999;82:435–438. 93. Siebrands CC, Friederich P. Structural requirements of human ether-a-go-go related gene channels for block by bupivacaine. Anesthesiology. 2007;106:523–531. 94. Ueta K, Sugimoto M, Suzuki T, et al. In vitro antagonism of recombinant ligand-gated ion-channel receptors by stereospecific enantiomers of bupivacaine. Reg Anesth Pain Med. 2006;31:19–25. 95. McClean G. Intravenous lidocaine: an outdated or underutilized treatment for pain? J Palliat Med. 2007;10:798–805. 96. Englesson S, Grevsten S. The influence of acid-base changes on central nervous system toxicity of local anaesthetic agents. II. Acta Anaesthesiol Scand. 1974;18:88–103. 97. Ohmura S, Kawada M, Ohta T, et al. Systemic toxicity and resuscitation in bupivacaine-, levobupivacaine-, or ropivacaine-infused rats. Anesth Analg. 2001;93:743–748. 98. Heavner JE. Cardiac toxicity of local anesthetics in the intact isolated heart model: a review. Reg Anesth Pain Med. 2002;27:545– 555. 99. Chang DH, Ladd LA, Copeland S, et al. Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep. Br J Pharmacol. 2001;132:649–658. 100. Groban L, Deal DD, Vernon JC, et al. Ventricular arrhythmias with or without programmed electrical stimulation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine. Anesth Analg. 2000;91:1103–1111. 101. Groban L, Deal DD, Vernon JC, et al. Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine,

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102.

103.

104.

105.

106.

107. 108.

109. 110.

levobupivacaine, and ropivacaine in anesthetized dogs. Anesth Analg. 2001;92:37–43. Groban L, Deal DD, Vernon JC, et al. Does local anesthetic stereoselectivity or structure predict myocardial depression in anesthetized canines? Reg Anesth Pain Med. 2002;27:460– 468. Nath S, H¨aggmark S, Johansson G, Reiz S. Differential depressant and electrophysiologic cardiotoxicity of local anesthetics: an experimental study with special reference to lidocaine and bupivacaine. Anesth Analg. 1986;65:1263– 1270. Vasters FG, Eberhart LH, Koch T, et al. Risk factors for prilocaineinduced methaemoglobinaemia following peripheral regional anaesthesia. Eur J Anaesthesiol. 2006;23:760–765. Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine. 2004;83:265–273. Berkun Y, Ben-Zvi A, Levy Y, et al. Evaluation of adverse reactions to local anesthetics: experience with 236 patients. Ann Allergy Asthma Immunol. 2003;91:342–345. Jacobsen RB, Borch JE, Bindslev-Jensen C. Hypersensitivity to local anaesthetics. Allergy. 2005;60:262–264. Corcoran W, Butterworth J, Weller RC, et al. Local anestheticinduced cardiac toxicity: a survey of contemporary practice strategies among academic anesthesiology departments. Anesth Analg. 2006;103:1322–1326. Guidelines 2000 for cardiopulmonary resuscitation. Circulation. 2000;102(Suppl 1):I-1-I-384. Krismer AC, Hogan QH, Wenzel V, et al. The efficacy of epinephrine or vasopressin for resuscitation during epidural anesthesia. Anesth Analg. 2001;93:734–742.

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111. Mayr VD, Raedler C, Wenzel V, et al. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid intravenous injection of bupivacaine. Anesth Analg. 2004;98:1426–1431. 112. Simon L, Kariya N, Pelle-Lancien E, et al. Bupivacaine-induced QRS prolongation is enhanced by lidocaine and by phenytoin in rabbit hearts. Anesth Analg. 2002;94:203–207. 113. Weinberg GL, Ripper R, Feinstein D, et al. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 2003;28:198–202. 114. Weinberg GL, VadeBoncouer T, Ramaraju, GA, et al. Pretreatment or resuscitation with a lipid infusion shifts the doseresponse to bupivacaine-induced asystole in rats. Anesthesiology. 1998;88:1071–1075. 115. Stehr SN, Ziegeler JC, Pexa A, et al. The effects of lipid infusion on myocardial function and bioenergetics in I-bupivacaine toxicity in the isolated rat heart. Anesth Analg. 2007;104:186–192. 116. Weinberg GL, Ripper R, Murphy P, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med. 2006;31:296– 303. 117. Litz RJ, Popp M, Stehr SN, et al. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia. 2006;61:800–801. 118. Rosenblatt MA, Abel M, Fischer GW, et al. Successful use of a 20%lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. 2006;105:217– 218. 119. Soltesz EG, van Pelt F, Byrne JG. Emergent cardiopulmonary bypass for bupivacaine cardiotoxicity. J Cardiothorac Vasc Anesth. 2003;17:357–358.

7 Pharmacology of Novel Non-NSAID Analgesics P. M. Lavand’homme and M. F. De Kock

Although many patients undergo surgery on a daily basis, perioperative and more specifically postoperative pain still remain underevaluated and poorly treated.1 There is now growing recognition that poorly relieved acute pain increases the occurrence of cognitive dysfunction, immune suppression, and chronic postsurgical pain. Consequently, perioperative treatments may have long-term implications on patient outcome and quality of life.2 Unfortunately, commonly used analgesics such as opioids and nonsteroideal anti-inflammatory drugs (NSAIDs) are not devoid of side effects that interfere with early rehabilitation and may impair patient outcome.3 A recent consensus on acute postsurgical pain management supports the use of multimodal analgesia (a combination of two or more analgesic agents or analgesic modalities with different mechanisms of action) to improve perioperative pain control and to reduce analgesia-related adverse effects.4 Adjuvant drugs such as ␣2 -adrenoceptor agonists, N-methyl-Daspartate (NMDA) receptor antagonists, and gabapentin present with interesting properties to improve perioperative pain control. Specifically, these classes of compounds are more effective to relieve pain in states where the central nervous system is sensitized, as it is the case after tissue incision and display interesting antihyperalgesic properties. In combination with opioids, use of these adjuvant drugs result in relevant opioid sparing effect. Thus, reducing opioid-related adverse effects such as nausea and vomiting, sedation, and opioid-induced hyperalgesia that contributes to further sensitization of the central nervous system (CNS). When studying the mechanism of action of drugs that modulate pain sensation, it is important to consider not exclusively their interactions with the nervous system, but also their effects on components of the immune reaction. This is readily apparent for drugs directly related with the course of the inflammatory process (ie, NSAIDs). An immune mechanism may also account for the pain modulation obtained with drugs such as clonidine, ketamine, gabapentin and pregabalin. Reasons underlying this assertion are found in the close interrelation between the nervous and immune systems. Drugs acting on the nervous system interfere directly or indirectly with the immune function and results in the therapeutic effect. An ideal drug in

the perioperative setting would be the one that does not negatively affect, but rather helps to maintain immune homeostasis by preventing any excessive systemic pro- or anti-inflammatory reaction. This chapter reviews the basic knowledge concerning the use of ␣2 -adrenoceptor agonists (clonidine), NMDA receptor antagonists (ketamine), and gabapentin as analgesic adjuvants. For each class of drug, our approach considers the following: ■ ■ ■ ■ ■

Receptors involved and underlying mechanisms Pharmacology of analgesia under different pain conditions Pharmacology of the drug and related side effects Interaction with other analgesics, specifically, opioids Immune modulatory effects

C LO N I D I N E A N D ␣2 - A D R E N O C E P TO R AG O N I S T S

␣2 -Adrenergic Receptors and Pain Modulation Adrenergic receptors, ␣ and ␤ receptors, form the interface between the endogenous catecholaminergic system and the target cells that mediate the biological effects of the sympathetic nervous system in the body. Among the adrenergic receptors, ␣2 -adrenergic receptors (␣2 -AR) mediate several physiological functions and have a great therapeutic potential in the field of pain control.5 Although three major subtypes of ␣2 -AR have been defined (␣2A , ␣2B , ␣2C ), no significant subtype-selective ligands are clinically available to date.6 The descending noradrenergic system has an inhibitory effect on nociceptive processing at both supraspinal and spinal levels. Furthermore, a peripheral expression of ␣2 -AR also seems to participate in the control of pain processing. Noradrenergic innervation of the spinal cord arises from the locus coeruleus (A5 and A6) and subcoeruleus (A7) nuclei located in the brainstem. Like electrical stimulation of these noradrenergic nuclei, local injection of ␣2 -agonist 82

Pharmacology of Novel Non-NSAID Analgesics

will activate the descending noradrenergic system and release norepinephrine (NE), which in turn activates adrenoceptors in the spinal cord and produces analgesia.7 NE-containing terminals are distributed in the laminae of the dorsal horn. This includes superficial laminae, substantial gelatinosa, where primary nociceptive afferents terminate, and the intermediolateral column, which comprises sympathetic preganglionic neurons. In contrast to opioids, the major site of ␣2 -agonists analgesic effect is the spinal cord, where these drugs have shown an efficacy and potency similar to that of opioids in both animal models and humans. The ␣2 -adrenoceptors belong to Gprotein-coupled receptor family (Gi/o), which inhibitory effects rely on the increase of potassium channels conductance and the depression of calcium conductance, resulting in either membrane hyperpolarization or decrease in transmitter release.7 Mimicking the action of endogenous NE, antinociceptive effects of ␣2 -AR agonists are mediated by spinal modulation of pain transmission at both pre- and postsynaptic sites on small afferent fibers. The postsynaptic inhibition of dorsal horn neurons results from the ability of ␣2 agonists to hyperpolarize dorsal horn neurons and to decrease neuronal excitation mostly by activation of postsynaptic G-protein-coupled inwardly rectifying potassium channels (GIRKs).8 Presynaptic binding to ␣2 adrenoceptors in the spinal cord leads to the reduction of excitatory neurotransmitters release. Both A␦ and C primary afferent transmission are depressed, yielding a reduction of the release of excitatory transmitters like substance P, calcitonin gene-related peptide (CGRP), and glutamate.9,10 This modulatory effect of ␣2 -AR agonists on excitatory neurotransmitter release is due to activation of the ␣2 A-receptor subtype because glutamate release is inhibited by adrenergic agonists with a relative potency of clonidine = dexmedetomidine > norepinephrine > ST91  phenylephrine = 0. In addition to the aforementioned mechanisms, the antinociceptive effect of spinal norepinephrine and therefore ␣2 -AR agonists is also mediated through a local release of inhibitory neurotransmitters like acetylcholine (ACh) and subsequent nitric oxide (NO) release, ␥ -aminobutyric acid (GABA), and perhaps NE and endogenous opioid peptide. Several experimental studies suggest a cholinergic interaction in ␣2 -AR-mediated antinociception at the level of the spinal cord. In the rat, spinal injection of muscarinic antagonist attenuates the analgesic effect of intrathecal clonidine, whereas intrathecal administration of cholinesterase inhibitor is potentiated. In a larger animal model, with a spinal cord size closer to that of humans, the antinociceptive effect of spinal clonidine is enhanced by cholinesterase inhibitor neostigmine and associated to ACh release in cerebrospinal fluid (CSF).11 These observations are consistent with the fact that ACh release plays an important role in the antinociceptive effect of spinally administered ␣2 -AR agonists. The mechanism of ␣2 -AR-mediated release of ACh is not fully understood but might rely on a postsynaptic activation of ␣2 -AR on intrinsic spinal inhibitory interneurons that in turn release ACh (for schematic representation of possible neuronal circuits in the dorsal horn, see Detweiler et al).11 In human volunteers, epidural administration of clonidine increases CSF concentrations of ACh inhibitory neurotransmitter12 and under intraoperative conditions, analgesic doses of intrathecal but not intravenous clonidine increase ACh in CSF of patients.13 These observations indicate that the analgesic effects observed after intravenous

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clonidine administration are not mediated by a cholinergic mechanism at the spinal level and support the combination of ␣2 -AR agonists with a cholinesterase inhibitor to enhance neuraxial analgesia. Finally, it is worth noting that, according to different binding to spinal ␣2 -AR, specifically dexmedetomidine being more ␣2 selective than clonidine, dexmedetomidine induces a greater ACh release than clonidine after intrathecal administration. Adrenergic receptors located on either supraspinal or peripheral noradrenergic terminals act in an autoinhibitory manner to diminish further NE release. At the spinal cord level, similar autoinhibitory ␣2 -adrenoceptors exist, probably of the ␣2A subtype. However, the regulation of NE release in the spinal cord is complex because experimental studies have implicated a local release of NE in the antinociceptive effect of spinal ␣2 -AR agonists. This local NE release must occur from indirect actions because of activation of a spinal circuit, perhaps following ACh and subsequent NO release.14 Finally, an important contribution to the spinal mechanisms that underlie norepinephrine antinociceptive action is mediated through GABA and glycine inhibitory neurotransmitter release following presynaptic activation of ␣1 -adrenoceptors.15 This effect certainly contributes to analgesic and antihyperalgesic effects of clonidine because the drug is a mixed ␣2 -/␣1 -AR agonist. Progress in molecular biology and immunochemistry has facilitated the mapping of ␣2 -adrenergic receptors in normal and pathophysiologic conditions in animal species and in humans. Effectively, ␣2 -AR subtype expression and function seems to be species specific. In rodents, there is a strong expression of ␣2A AR in brain and supraspinal adrenergic nuclei. At the spinal level, ␣2A -AR are predominant and found in the terminals of peptide-containing primary afferents, which supports their role in the presynaptic inhibition of substance P and CGRP release. Whereas, the ␣2C -AR subtype appears to be expressed on local spinal neurons where they mediate adrenergic agonists-induced hyperpolarization.16 In human spinal cord, ␣2 -AR are present in the gray matter only, in dorsal horn laminae with expression sacral > cervical > thoracic = lumbar. In addition, adrenoceptors are found in thoracic and the lumbar intermediolateral cell column and also in the ventral horn lamina IX.17 These findings support the mediated effects of ␣2 -agonists on nociception, autonomic function, and motor tone. The ␣2A and ␣2B subtypes are predominant, whereas the ␣2C -AR is virtually absent, restricted to the lumbar area. The ␣2 -adrenoceptors expressed in human dorsal root ganglia represent another possible site of action for adrenergic agonists (for example, after epidural administration) and contribute to 20% of the ␣2 -AR found in the dorsal horn after being trafficked centrally. In human dorsal root ganglia, ␣2B and ␣2C subtypes are found at all spinal levels.17 To date, clinically available drugs are not selective for a particular ␣2 subtype. However, whether ␣2 -AR agonists may be an attractive analgesic alternative because they are devoid of respiratory depressant effect and addictive liability. Some of their related side effects, namely sedation and hypotension, are currently hindering the clinical use of nonselective ␣2 -agonists for pain management.6 Experimental studies have shown that ␣2A AR activation accounts for analgesic, hemodynamic and sedative effects of ␣2 -adrenoceptor agonists. Whereas, activation of ␣2C AR, a subtype predominant in humans, also produces analgesia without major side effects.18 All these findings might support

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P. M. Lavand’homme and M. F. De Kock

Supraspinal effects (brainstem level) activation of descending inhibitory systems (↑ spinal release of NE)

Sympathetic system preganglionic block (↓ circulatory catecholamines)

Peripheral nerve conduction block unrelated to α 2AR binding (i.e. Ih channels block ) modulation of local cytokines expression when nerve injury

Spinal cord = major site of analgesic effect presynaptic α 2-AR (↓ release of excitatory mediators) postsynaptic α2-AR (hyperpolarization by activation GIRKs) local release of inhibitory neurotransmitters ACh, NO, NE and GABA*

Topical effect Mechanism unknown under normal conditions ? Local reduction of NE under neuropathic conditions (CRPS)

Figure 7.1: Analgesic mechanisms of clonidine, an ␣2 -adrenoceptor agonist.

the future development of subtype selective drugs to improve clinical practice (Figure 7.1).

Pharmacology of Analgesia under Different Pain Conditions Both clinical and experimental observations have clearly highlighted the fact that ␣2 -AR agonists are more effective to relieve pain in pathological states where central sensitization is present.19 In addition, ␣2 -AR agonists, and specifically clonidine, which is commonly used in clinical practice, demonstrate greater analgesic effects after spinal than systemic administration, favoring the neuraxial route of injection.20 Early observations have revealed the considerable potential of spinal ␣2 AR agonists to alleviate neuropathic pain poorly responsive to opioids both in animal models and in humans.21,22 In animals following nerve injury, spinal adrenoceptor agonists relieve mechanical allodynia and thermal hyperalgesia. These are features of neuropathic pain, an effect mediated locally in the vicinity of the spinal cord and the intermediolateral cell column. In patients suffering intractable cancer pain, epidural clonidine reduces pain scores in those with a neuropathic pain component (56% success vs 16% success when pain is from somatic or

visceral origin).21 Among the possible explanations, the fact that ␣2 -AR agonists inhibit sympathetic outflow in the intermediolateral cell column of the dorsal horn might contribute to their efficacy in neuropathic pain states involving a sympathetic component. Moreover, and perhaps more importantly, animal studies have pointed out the fact that nerve injury strongly modifies CNS mechanisms underlying the ␣2 -AR antinociceptive effect. In normal animals, clonidine effect mostly relies on binding to ␣2A - and ␣2 -nonA-adrenoceptors. Under neuropathic pain conditions, the antiallodynic effect of clonidine depends primarily on its interaction with ␣2 -nonA-adrenoceptors, probably ␣2C AR.23 The plasticity of spinal ␣2 -AR subtypes after nerve injury has been demonstrated in animal models. Not only an ipsilateral decrease of immunoreactivity for the ␣2A subtype located on C fiber terminals occurs, but also a significant increase for the ␣2C subtype immunoreactivity ipsilateral to the injury is present.24 The fact that ␣2C -AR are located in the deep dorsal horn close to the normal terminations of large-diameter fibers involved in the processing of mechanical inputs may support the efficacy of spinal clonidine against mechanical allodynia and hyperalgesia. Finally, the spinal ␣2 -adrenergic-cholinergic interaction for analgesia is also modified following nerve injury whereby clonidine antiallodynic effects are mediated by

Pharmacology of Novel Non-NSAID Analgesics

activation of spinal inhibitory cholinergic interneurons.25 A subsequent local release of NO seems also to play an important role in the antihyperalgesic effect of spinal clonidine under neuropathic conditions.

Postoperative Pain Condition Postoperative pain also represents a state of central hypersensitivity but presents with specific features and underlying mechanisms clearly distinct from those that result from inflammatory or neuropathic pain.1 The extent of postoperative mechanical hyperalgesia surrounding the wound seems to correlate to the degree of CNS sensitization and can be modulated by intrathecal administration of clonidine in both an animal model of paw incision26 and postoperative patients.27 Experimental observations have shown that descending noradrenergic inhibitory systems are activated in the postoperative period. The potency of intrathecal clonidine against mechanical hypersensitivity in a postincisional pain model is similar to that observed in animals subjected to acute noxious stimuli, mostly limited by side effects such as sedation and diuresis.26 In contrast, ST-91 (the diethyl derivative of clonidine, a hydrophilic and mostly ␣2 nonA-adrenergic agonist) shows a greater efficacy than clonidine in the incisional pain model. By consequence, postoperative hypersensitivity most resembles nerve injury-induced hypersensitivity and clonidine antihyperalgesic effect is mediated through both ␣2A - and ␣2 -nonA-adrenoceptors activation. Further, subsequent spinal cholinergic activation underlies the effect of clonidine but not that of ST-91 (and spinal muscarinic as well as nicotinic receptors are involved in the antihyperalgesic action of clonidine after incision.26 ) These experimental findings have allowed a better understanding of clinical observations related to the potency and the efficacy of ␣2 -AR agonists under different conditions. In summary, neuraxial but not systemic administration of clonidine reduces experimental pain and hyperalgesia.20 Clinical trials have shown that the doses of neuraxial clonidine, either spinal or epidural, needed to relieve neuropathic pain are less than 25% of those needed to treat postoperative pain. In acute pain conditions, the potency ratio of intrathecal:epidural clonidine is >6:1; whereas in neuropathic conditions or experimental conditions involving a state of mechanical hypersensitivity such as peri-incisional mechanical hyperalgesia, the ratio is P (both in the preoperative period and 24 hours after completion of surgery)

31

550 mg PO N (21)

P (23)

Outpatient laparoscopic tubal ligation

Preoperatively: less than 1 h before procedure

1. Visual analog scale pain score 2. Analgesic requirement 3. Adverse effects 4. Length of day surgery stay

Analgesic efficacy of the preemptive use of N > P (no increase in analgesic adverse effect)

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2 h preoperatively: 20 mg PO PIRO (20) Immediately before induction: 20 mg PO PIRO (20)

1 h postoperatively: 20 mg PO PIRO (20)

Gynecological laparoscopic surgery

Preoperatively: 2 h before procedure Preoperatively: immediately before induction Postoperatively: 1 h after procedure

1. Visual analog scale pain score 2. Analgesia requirement

PIRO given 2 hours preoperatively > PIRO given immediately before induction or 1 hour postoperatively

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Preoperatively: 40 mg SL PIRO (25)

Postoperatively: 40 mg SL PIRO (27)

Laparoscopic bilateral inguinal hernia repair

Preoperatively: 2 h before procedure Postoperatively: 10 min after procedure

1. Visual analog scale pain score 6 h after surgery 2. Consumption of Tr

PIRO given 2 hours preoperatively > PIRO given 10 min postoperatively

Ref

Type of Surgery

Analgesic Efficacy Resultsb

(continued )

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Table 21.3 (continued) Dose and Route of NSAID (n)

Dose and Route of Comparators

Type of Surgery

69

40 mg PO PIRO (25)

P (24)

Oral surgery

Preoperatively: 2.5 h before procedure

1. Time at which analgesia was first received 2. Total amount of analgesics consumed in 24 h

PIRO > P

1

20 mg IV T (40)

P (40)

Laparoscopic cholecystectomy or groin hernia repair

Preoperatively: immediately before induction

1. Postoperative analgesic requirement 2. Perioperative adverse effects 3. Visual analog scale pain score 4. Hospitalization time

T>P

146

Group T: 40 mg IV T + 20 mg IM CPM (20) Group DM + T: 40 mg IV T + 40 mg IM DM (20)

Laparoscopic cholecystectomy

Preoperatively: 30 min before skin incision

1. Visual analog scale pain score 2. Time to first request of Mep for pain relief 3. Total Mep consumption

DM + T > DM > T > Control

116

1600 mg PO IBU SR, then 1600 mg PO IBU, 24 h after the initial dose

Group DM: (40 mg DM + 20 mg of CPM) IM + 4 ml NS IV (20) Control: 20 mg IM CPM + 4 ml IV NS (20) P

Lower abdominal gynecological surgery

Preoperatively: 2–4 hours before procedure, then 24 h after the first dose

1. Pain scores 2. Occurrence of adverse events 3. Morphine consumption

IBU > P (no increase in adverse effects)

101

800 mg PO IBU

60 mg IV K

Elective laparoscopic hernia repair

Preoperatively: IBU given 1 h before procedure Preoperatively: K given at time of trocar insertion

1. Postoperative pain in 18 and 24 h

IBU = K

16

Preoperatively: 100 mg IV Ket Postoperatively: 100 mg IV Ket

Preoperatively: 2 gm IV Prop Postoperatively: 2 gm IV Prop

Laparoscopic cholecystectomy

Preoperatively: before induction Postoperatively: immediately after surgery

1. Visual analog scale pain score 2. Nalbuphine consumption

Preoperative Ket > Postoperative Ket Preoperative Ket > Preoperative Prop and postoperative Prop

Ref

Duration/Timing of Dose

Outcome Measuresa

Analgesic Efficacy Resultsb

Abbreviations: Ref = reference; n = number of patients in group; mg = milligrams; g = grams; IV = intravenous route; IM = intramuscular; PR = per rectum; PO = by mouth; SL = sublingual; K = ketorolac; PCA = patient-controlled analgesia; P = placebo; Tr = tramadol; DM = detromethorphan; CPM = chlorpheniramine; Mep = meperidine; D = diclofenac; Dia = diazepam; N = naproxen sodium; Ket = ketoprofen; PIRO = piroxicam; T = tenoxicam; NS = normal saline; IBU = ibuprofen; Prop = propacetamol. a

Outcome measures/endpoints presented in summary table might not be all the end points that were presented in the study.

b

Analgesic efficacy results presented in table are a general summary of author(s)’ conclusions.

Preincisional Use of NSAIDs for Surgical Pain Given the mechanism of action and pharmacodynamic and pharmacokinetic properties of the NSAIDs, nociceptor modulation necessitates their administration in advance of the anticipated time for the patient to achieve the desired analgesic effect.150 However, the use of the NSAIDs in preemptive analgesic therapy in surgical procedures has been debated extensively and is still controversial.78,79,81,102,112 Because of the effects

of the nonselective NSAIDs on platelet aggregation, some studies recommend that NSAIDs should not be used in the immediate pre- or perioperative period, because they may increase the risk of bleeding.132,144 However, Slappendel et al,146 studying patients undergoing total hip surgery and the use of the NSAID nabumetone, showed that the preoperative pain intensity that occurred after stopping NSAIDs is directly related to, and determines, the postoperative morphine dose that would

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Table 21.4: Postoperative Use of NSAIDs: Summary of Clinical Trials Dose and Route of NSAID (n)

Dose and Route of Comparator(s)

Outcome Measuresa

Analgesic Efficacy Resultsb

35

20 mg PO K followed by 10 mg PO K 4–6 hours after the first dose (66)

10 mg/1000 mg PO H/A followed by 10 mg/1000 mg PO H/A 4–6 hours later (59)

Anterior cruciate ligament reconstruction

Postoperatively: 1st dose: at least 48 hours after surgery 2nd dose: 4–6 hours after 1st dose

1. Pain intensity 2. Pain score 3. Adverse events

K > H/A (no bleeding problems observed in either group)

36

10 mg PO K every 6 hours for up to 3 days (83)

7.5 mg/750 mg PO H/A every 6 hours for up to 3 days (82) P(87)

Ambulatory arthroscopic or laparoscopic tubal ligation

Postoperatively: after awakening with moderate to severe pain

1. Pain intensity 2. Pain score 3. Adverse effects

K = H/A > P (overall tolerability favored the K group)

37

120 mg IV K over 24 hours

P

Lower abdominal surgery

Postoperatively: Immediately after surgery

1. Cumulative morphine consumption 2. Pain score at rest 3. Occurrence of adverse events

K > P (there was no difference between treatments in the incidence of adverse respiratory effects, nausea, or vomiting)

38

30 mg IV K 30 mg IV K + 0.1 mg/kg morphine (503)

Morphine (500)

Different types of surgeries: Abdominal surgery, orthopedic surgery, craniofacial surgery, thoracic surgery, spinal surgery

Postoperatively: K or morphine started after surgery. If pain intensity is 5 or more (on a scale of 1–10) 30 minutes after analgesic administration, patients were given 2.5 mg of morphine every 10 minutes until pain intensity was 4 or less

1. Proportion of patients who reported a decrease in pain intensity 30 minutes after the initiation of analgesics 2. Opioid-related adverse effects

Morphine > K (adding K to morphine reduced opioid consumption and morphine related adverse effects)

39

30 mg IV K (loading dose) followed by 15 mg IV K every 6 hours (20) or 60 mg IV K (loading dose) followed by 30 mg IV K every 6 hours (21) 1.5 mg/mL IV K + 5 mg/ml Tr (30)

P (21)

Intraabdominal gynecologic surgery

Postoperatively: immediately at the end of surgery

1. Visual analog pain and satisfaction scores 2. Opioid consumption 3. Frequency and severity of adverse effects

K>P

10 mg/mL Tr (30)

Major abdominal surgery

Postoperatively: at the beginning of wound closure

1. Total analgesic consumption 2. Sedation score

K + Tr = Tr (sedation score was significantly lower in the K + Tr)

44

40 mg IV Teno (256)

P (258)

Abdominal or orthopedic surgery

Postoperatively: at the end of surgery and then 24 hours later

1. Analgesic efficacy 2. Incidence of adverse effects

Teno > P (Teno was associated with minimal adverse effects and high tolerability)

45

20 mg IV Teno (45)

P (48)

Cesarean section

Postoperatively: at the end of surgery

1. Wound pain 2. Uterine cramping pain 3. Opioid consumption

Teno > P (no additional effect on wound pain)

Ref

40

Type of Surgery

Duration/Timing of Dose

(continued )

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Table 21.4 (continued) Dose and Route of NSAID (n)

Dose and Route of Comparator(s)

Type of Surgery

46

500 mg PO NAP + morphine (40)

P + morphine (40)

Cesarean section

Postoperatively: every 12 hours after surgery

1. Visual analog scale pain score (incision pain, uterine cramping, gas pain) 2. Analgesic use 3. Adverse effects

NAP > P (does not reduce the incidence of inadequate analgesia)

47

100 mg IV Ket (25) (all patients received morphine and propacetamol)

P (25)

Spinal fusion surgery

Postoperatively: every 8 hours after surgery

1. Visual analog scale pain score 2. Morphine consumption

Ket > P

48

100 mg IV Ket + 2 g IV Prop (32) 100 mg IV Ket (33)

2 g IV Prop (33)

Thyroidectomy

Postoperatively: 30 minutes before the end of surgery, then every 6 hours

1. Visual analog scale pain score 2. Tramadol consumption

Ket = Ket + Prop > Prop

49

100 mg PR D (40)

P (42)

Cesarean section

Postoperatively: every 12 hours after surgery

1. Visual analog scale pain score 2. Need for rescue analgesics 3. Adverse effects

D > P (the average level of postoperative pain was lower in the diclofenac group, but was not significant. No difference in adverse effects)

50

100 mg PR D + 1 g PR Acet (17) 100 mg PR D (17)

1 g PR Acet (20)

Cardiac surgery

Postoperatively, 2 hours after surgery: D – every 18 hours after surgery for 24 hours Acet- every 6 hours after surgery for 24 hours

1. Visual analog scale pain score 2. Morphine consumption 3. Sedation

D + Acet = D > Acet

51

100 mg PR Ind + morphine (44)

P + morphine (46)

Major abdominal surgery

Postoperatively: every 8 hours for 3 days

1. Postoperative subjective pain assessment 2. Analgesic requirement 3. Respiratory function

Ind + morphine > P + morphine

52

100 mg PR Ind + morphine (25)

P + morphine (25)

Total hip arthroplasty

Postoperatively: every 8 hours for 5 doses

1. Visual analog scale pain score 2. Morphine consumption

Ind + morphine > P + morphine

Ref

Duration/Timing of Dose

Outcome Measuresa

Analgesic Efficacy Resultsb

Abbreviations: Ref = reference; n = number of patients in group; mg = milligrams; g = grams; IV = intravenous route; IM = intramuscular; PR = per rectum; PO = by mouth; SL = sublingual; K = ketorolac; Ket = ketoprofen; PCA = patient-controlled analgesia; P = placebo; Tr = tramadol; Teno = tenoxicam; D = diclofenac; H/A = hydrocodone/acetaminophen; NAP = naproxen sodium; NS = normal saline; Ind = indomethacin; Acet = acetaminophen; Prop = propacetamol. a

Outcome measures/end points presented in summary table might not be all the end points that were presented in the study.

b

Analgesic efficacy results presented are a general summary of author(s)’ conclusions.

be needed for surgical pain (see Figure 21.4), which therefore means that a patient who does not have any contraindication to the use of NSAIDs would benefit by requiring less opiate postsurgically (and hence less prone to the opiate adverse effects) if NSAIDs are used preemptively during surgical procedures. The efficacy of some of the nonselective NSAIDs

(eg, ketorolac, diclofenac, naproxen, piroxicam, tenoxicam, flurbiprofen, indomethacin, ketoprofen, fenbufen, and several others) in preemptive analgesic therapy have been evaluated in clinical trials and this section of the chapter evaluates these studies to provide information about the role of the NSAIDs in preemptive analgesic therapy.

NSAIDs, COX-2 Inhibitors, and Acetaminophen in Acute Perioperative Pain

*

Postoperative PCA Morphine (mg)

30

20

10

0

Mild

Moderate

Severe

Preoperative Pain Intensity

Figure 21.4. Pain intensity after stopping NSAIDs determines the postoperative morphine dose required for analgesia. Slappendel et al (1999).146

The preemptive use of ketorolac (alone and in combination with other analgesics) has been evaluated in orthopedic surgery, oral surgery, abdominal surgery, and vaginal hysterectomy. In a study that evaluated patients who were undergoing ankle fracture repair surgery, a 30-mg intravenous dose of ketorolac given once preemptively was shown to prevent an increase in pain from baseline rather than when given after the surgery. There was no difference in opiate consumption between the two groups, but the preemptive group had a lower nausea score.108 In a study that evaluated the preemptive versus the postoperative effectiveness of a multimodal analgesic regimen that included a 30-mg intravenous (IV) dose of ketorolac, an intraarticular injection of 20 mL of ropivacaine (0.25%) with 2 mg of morphine and epinephrine, and a femoral nerve block of 20 mL ropivacaine (0.25%) in patients undergoing arthroscopic knee repair surgery, the preemptive use of the multimodal analgesic regimen resulted in lower pain scores and a lower opiate consumption in the initial stay in the postanesthesia care unit (PACU). There was, however, no measurable long-term advantage associated with preemptive multimodal drug administration, when compared to its postoperative use.134 In another study that evaluated the preemptive use of a 60-mg IV dose of ketorolac, when compared to its postoperative use and placebo in patients undergoing total hip replacement surgery, the preemptive use of ketorolac had a greater analgesic effect in the immediate postoperative period than when it was administered after the surgical procedure. There was no statistical difference in the number of blood transfusions that occurred in the study groups.52 In studies that evaluated patients undergoing oral surgery, the preemptive use of a 30-mg IV dose of ketorolac was shown to be more efficacious than when it is used postoperatively. It was also found to be more effective than the preemptive use of tramadol.113,114 The preoperative cotreatment of ketorolac with dextromethorphan (an NMDA receptor antagonist) in patients undergoing laparoscopic-assisted vaginal hysterectomy was shown to be more efficacious than either dextromethorphan or ketorolac alone.88 In patients undergoing ambulatory laparoscopic cholecystectomy, the preoperative cotreatment of ketorolac with meperidine was also shown to be more effective than placebo.100 The preemptive use of diclofenac has also been assessed in several types of surgical procedures. In one study that evaluated the morphine-sparing effects of diclofenac sodium compared to ketorolac in patients undergoing

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major orthopedic surgeries, the preoperative administration of a 75-mg IV dose of diclofenac or 60-mg IV dose of ketorolac significantly reduced morphine requirements and associated adverse effects after major orthopedic surgeries.3 In patients undergoing gynecological laparoscopy, a 50-mg dose of diclofenac given rectally before induction of anesthesia was shown to result in better pain relief and less postoperative analgesic consumption, when compared to placebo.56 In patients undergoing day case knee arthroscopy and varicose vein repair, a 50-mg oral dose of diclofenac given preemptively was shown to be very effective in reducing analgesic requirements postoperatively in these procedures.119,120 The use of naproxen sodium as a preemptive analgesic has been studied in arthroscopic knee surgery and patients undergoing outpatient laparoscopic tubal ligations. In both procedures, a single preoperative oral dose of 550 mg naproxen sodium was effective in reducing postoperative pain, postoperative analgesic requirement, without any increase in morbidity.30,31 Use of a 20-mg oral dose of piroxicam given 2 hours preoperatively in patients undergoing gynecological laparoscopic surgery reduced pain scores, time to first analgesia, and postoperative analgesic requirements compared to its administration prior to induction or 1 hour postoperatively.111 In another study that evaluated patients undergoing laparoscopic bilateral inguinal hernia repair, a 40-mg sublingual dose of piroxicam given 2 hours before the procedure was shown to be more effective than when it was administered postoperatively.62 In dental surgery, the use of a 40-mg oral dose of piroxicam, given 2.5 hours before surgery, was shown to be opioid sparing with a reduction in postoperative analgesic requirement when compared to placebo.69 In a study that proposed to investigate the postoperative pain relief effect of preoperative tenoxicam usage in patients undergoing laparoscopic cholecystectomy or inguinal hernia repair, a 20-mg intravenous dose of tenoxicam given immediately before induction was shown to be safe and effective for postoperative pain relief after surgery when compared to that of placebo.1 However, another study evaluated the preemptive use of tenoxicam and dextromethorphan in patients undergoing laparoscopic cholecystectomy, and the results suggested that the pretreatment of tenoxicam alone did not provide significant preemptive analgesia in patients after the surgery. In that study, the use of tenoxicam in combination with dextromethorphan, and dextromethorphan alone, provided significant pain relief (see Figure 21.4).146 The preemptive use of sustained release ibuprofen as an adjunct to morphine PCA was evaluated in a study that involved patients scheduled for lower abdominal gynecological surgery. In this study, 1600 mg of ibuprofen was given preoperatively and then 24 hours after the first dose, and its postoperative analgesic effect monitored after the surgery. Patients who received ibuprofen reported significantly less pain when compared to placebo.116 A study that compared the preemptive use of an oral dose of 800 mg ibuprofen with that of a 60-mg IV dose of ketorolac in patients scheduled for elective laparoscopic inguinal hernia repair showed that pain relief from ibuprofen given preemptively is not statistically different from that obtained with the preemptive use of ketorolac.101 In a study that evaluated the preemptive use of a 100-mg IV dose of ketoprofen in laparoscopic cholecystectomy as compared to its postoperative use, and the use of a 2-g dose of propacetamol (preemptively and postoperatively), the preemptive use of

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ketoprofen was shown to be opioid sparing and more effective in improving postoperative analgesia than all the other comparators.16 There are many other studies that have evaluated the preemptive use of the NSAIDs in various types of surgical procedures and different routes of administration and, in most of these, NSAIDs have proved to be efficacious and opioid sparing with little to no adverse effects when compared to placebo or their active comparators. There are other studies on the preemptive use of the NSAIDs that have not demonstrated a clear benefit to the adjunctive use of the NSAIDs.19,38,151 It is also known that NSAIDs are capable of increasing bleeding time because of the effect they have on platelet aggregation, but in most of the studies that were evaluated, the risk of bleeding was not significantly different from placebos or their active comparators. However, the opioid-sparing effect of the NSAIDs and the analgesic effect of the NSAIDs were significant in most of these studies.16,31,56,88,101,114,116 The current recommendation for the preemptive use of the NSAIDs is controversial and it is still not a universally accepted method of managing postoperative pain.

Postoperative Use of the NSAIDs The post- and perioperative use of NSAIDs like ketorolac, diclofenac, indomethacin, piroxicam, tenoxicam, naproxen, and several others have been evaluated in several types of surgical procedures and in several dosage forms either as a single therapy compared with other analgesics or placebo or in a multimodal approach in combination with different kinds of analgesics to determine their efficacy, opiate-sparing effects, and safety. In abdominal surgery, the postoperative use of a 120-mg dose of ketorolac, given as an IV infusion over 24 hours, as an adjunct to opiates, significantly reduced morphine requirements.15 In patients who have undergone anterior cruciate ligament reconstruction, the use of oral ketorolac, given after a loading dose of parenteral ketorolac, was shown to have a better pain reduction with similar safety profile when compared to hydrocodone/acetaminophen.10 In yet another study that evaluated the efficacy of oral ketorolac to that of hydrocodone/acetaminophen in patients who have undergone ambulatory arthroscopic or laparoscopic tubal ligation procedures, the investigators found no difference in the analgesic efficacy between ketorolac or hydrocodone/acetaminophen, but overall tolerability to the medications favored the ketorolac group.159 A large trial, involving 1003 adult patients undergoing a diverse number of surgical procedures (eg, abdominal surgery, orthopedic surgery, craniofacial surgery, thoracic surgery, spinal surgery), showed that a combination of a 30-mg dose of intravenous ketorolac and 0.1 mg/kg morphine, when compared to either ketorolac or morphine alone, significantly reduced morphine requirements and opioid-related adverse effects in the immediate postoperative period.21 In patients recovering from intraabdominal gynecologic surgery, the use of a 30-mg IV loading dose of ketorolac followed by a 60-mg dose every 6 hours or a 60-mg loading dose followed by a 30-mg dose every 6 hours were shown to be significantly effective, opioid-sparing, and safer than placebo.141 The postoperative use of ketorolac in combination with tramadol in patients who underwent abdominal surgery was found to be as safe and effective with similar pain relief when compared to a higher dose of tramadol when used as a monotherapy in these patient population.85

The postoperative use of a 40-mg IV dose of tenoxicam in patients who have undergone abdominal or orthopedic surgery was shown to provide reliable analgesia, reduction in opioid consumption, and minimal adverse effects when compared to placebo.155 In patients who have undergone cesarean section, the use of a 20-mg IV dose of tenoxicam was shown to be opioid sparing and able to potentiate opioid analgesic effects.67 The postoperative use of a 500-mg oral dose of naproxen given every 12 hours was also shown to lead to improved analgesia in patients who have undergone cesarean delivery.4 In patients who underwent spinal fusion surgery and were already receiving morphine and propacetamol, the addition of a 100-mg IV dose of ketoprofen every 8 hours reduced morphine requirements and improved postoperative analgesic requirements.7 Another study that was performed in patients who underwent thyroidectomy showed no improvement in analgesia in the concomitant use of ketoprofen with propacetamol compared to when propacetamol was administered alone.53 In patients undergoing cesarean section, the use of a rectal dose of 100 mg diclofenac given every 12 hours after surgery was shown to be opioid sparing with no significant adverse effects.37 In cardiac surgery, the use of diclofenac alone or its combined use with rectal acetaminophen was shown to have significant opioid-sparing effects and improvement in pain relief.49 In studies that evaluated patients who underwent either major abdominal surgery or total hip arthroplasty, the postoperative use of a 100-mg rectal dose of indomethacin given every 8 hours as an adjunct to morphine was shown to provide superior analgesia than in situations when morphine was used alone.95,122 Even though the preemptive use of the NSAIDs remains controversial,19,38,151 the studies that have been presented and several others (not discussed in this chapter) have demonstrated that multimodal regimens that include the NSAIDs are more likely to be effective when used preemptively and continued during the postoperative period.19,38,51,140,151

COX-2 Inhibitors in Perioperative Pain The identification of the DNA sequence in human tissues for COX-1 in 1991 and COX-2 in 199298 led to the belief that drugs that were designed to specifically block COX-2, but not COX1, would have anti-inflammatory properties that would be as effective and potent as the nonselective NSAIDs, but would have none of their gastrotoxic or bleeding risks.50 It was believed that the sole inhibition of the COX-2 isoenzyme (by blocking arachidonic acid binding and prostaglandin synthesis [see Figure 21.5]) would avoid inhibition of the synthesis of gastrointestinal PG (thereby avoiding ulcers) and platelet thromboxane (thereby avoiding bleeding).50 These discoveries led to the development and the subsequent approval of celecoxib, rofecoxib, and valdecoxib by the US FDA in 1998, 1999, and 2001, respectively. Rofecoxib and valdecoxib have since been voluntarily withdrawn from the market due to safety concerns of an increase risk of cardiovascular events, including heart attack and stroke.99 Currently, celecoxib is the only COX-2 inhibitor available for use in the U.S. market, but there are other COX-2 inhibitors (eg, etoricoxib, parecoxib, lumiracoxib) that are either undergoing clinical trials or in use in some parts of Europe. Following the evolution and the general acceptance of the concept of multimodal analgesic therapy, the effort to minimize

NSAIDs, COX-2 Inhibitors, and Acetaminophen in Acute Perioperative Pain

347

Figure 21.5. COX-2 inhibitors block aracadonic acid (AA) binding and hence PG synthesis. Figure courtesy of Drs Ian Rodger and Raymond S. Sinatra.

the risk of bleeding and bleeding complications, and the risk of gastrointestinal complications that have traditionally been associated with the use of the nonselective NSAIDs, the use of the COX-2 inhibitors became increasingly popular for use as nonopioid adjuvants for minimizing pain during the perioperative period.55,157 There were many studies that were initiated to evaluate the efficacy of the COX-2 inhibitors, as monotherapy and in combination with other analgesics, for use in surgical pain as a preemptive, postoperative, and/or perioperative analgesic in different types of surgical procedures.98,157,158 This section of the chapter reviews the efficacy and opiate-sparing effects of the COX-2 inhibitors (including those that are no longer on the market) based on some of the available clinical trials that compare the uses of the COX-2 inhibitors with the other nonselective NSAIDs and other analgesics. A summary of all the clinical trials that were evaluated can be seen in Tables 21.5 to 21.9.

Use of Celecoxib in Surgical Pain Celecoxib was the first COX-2 inhibitor to be approved for use in the US market and it is currently the only COX-2 inhibitor currently available for use in the United States. This COX-2 inhibitor was approved by the US FDA for the management of the discomfort caused by ankylosing spondylitis, familial multiple polyposis syndrome, juvenile rheumatoid arthritis, osteoarthritis, acute pain, primary dysmenorrhea, and rheumatoid arthritis.99 In this section, evidence supporting its use and tolerability in acute perioperative pain is discussed (see Table 21.6). The role and efficacy of the preemptive use of celecoxib in surgical pain has been assessed in clinical trials that involved patients undergoing surgical procedures such as spinal fusion surgery and minor otolaryngologic (ENT) procedures.71,123,125 In one study that evaluated the use of celecoxib in patients undergoing otolaryngologic surgery, a 200-mg oral dose of celecoxib was found to be comparable to that of a 2-g oral dose of acetaminophen; this dose was not significantly more effective than that of patients who were on placebo in that particular study.71 However, when the 200-mg dose of celecoxib was added onto a 2-g dose of acetaminophen, it was found to work synergistically with acetaminophen in significantly reducing

pain in patients undergoing ENT procedures.71 The preemptive use of the same dose of celecoxib was also found to be less effective than an oral dose of 50 mg rofecoxib in patients undergoing spine stabilization surgery.125 However, in a dose-ranging study that involved ambulatory patients undergoing ENT procedures, the analgesic efficacy of celecoxib has been shown to be dose related and a 400-mg oral dose of this COX-2 inhibitor has been shown to be significantly more effective in relieving severe postoperative pain.123 The current recommendation for the use of celecoxib as a preemptive analgesic in acute postoperative pain is 400 mg.123 The postsurgical utilization of celecoxib has also been assessed in dental pain models and patients undergoing ambulatory orthopedic surgery.46,58,91 In dental pain, the postsurgical use of 200- and 400-mg oral doses of celecoxib was found to be less effective than a 50-mg dose of rofecoxib and a 400-mg oral dose of ibuprofen; celecoxib proved to be more effective than placebo in all cases.46,91 The postoperative use of a 200-mg oral dose of celecoxib in orthopedic patients experiencing moderate to severe pain proved to have comparable analgesic efficacy with a single dose of hydrocodone/acetaminophen (10 mg/1000 mg). In that same study, a 200-mg oral dose of celecoxib taken up to 3 times a day (majority of the subjects only required twice daily doses) over a 5-day period demonstrated superior analgesia and tolerability compared with hydrocodone/acetaminophen (10 mg/1000 mg).58 Celecoxib has also been assessed perioperatively in patients undergoing spinal fusion surgery. In these studies, a 400-mg oral dose of celecoxib given preoperatively, followed by a postoperative dose of 200 mg every 12 hours for the next 5 days after surgery, showed improved analgesia, a reduction in chronic donor site pain 1 year after surgery, and a significant reduction in opioid use when compared to placebo.12

Use of Rofecoxib in Surgical Pain The FDA initially approved rofecoxib, in 1999, for the relief of osteoarthritis, management of acute pain in adults, treatment of primary dysmenorrhea, and the relief of the signs and symptoms of rheumatoid arthritis. As discussed previously, rofecoxib was

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Table 21.5: COX-2 Inhibitorsa Generic Name

Brand Name

COX-2/ COX-1 Activity

Onset (minutes)

Duration (hours)

Celecoxib

Celebrex

8

30–50

4–8

Oral capsule: 100 mg, 200 mg, 400 mg

200–400 mg PO three times a day

Hypertension, peripheral edema, abdominal pain, diarrhea, flatulence, indigestion, nausea, back pain, dizziness, headache, insomnia, pharyngitis, rhinitis, sinusitis, upper respiratory infection, sulfonamide allergy

Rofecoxib

Vioxx

35

30–50

12–24

Oral suspension: 12.5 mg/5 mL, 25 mg/5 mL Oral tablet: 12.5 mg, 25 mg, 50 mg

25–50 mg PO daily

Hypertension, peripheral edema, abdominal pain, diarrhea, epigastric pain, heartburn, indigestion, nausea, back pain, dizziness, headache, bronchitis, nasopharyngitis, rhinitis, sinusitis, upper respiratory infection, fatigue Note: Rofecoxib was voluntarily withdrawn from the market because of increased risk for cardiovascular events, including heart attack and stroke

Valdecoxib

Bextra

30

30–40

6–12

Oral tablet: 10 mg, 20 mg

20–40 mg PO daily

Hypertension, peripheral edema, abdominal pain, diarrhea, flatulence, indigestion, nausea, back pain, myalgia, dizziness, headache, sinusitis, upper respiratory infection Note: Valdecoxib was voluntarily withdrawn from the market because of safety concerns of an increased risk for cardiovascular events, including heart attack and stroke

Parecoxib

Rayzon

Prodrug of valdecoxib

10–15

6–12

Injection powder: 40 mg

Initial dose: 40 mg IV/IM, followed by 20–40 mg every 6–12 hours IV/IM; MAX = 80 mg/day

Peripheral edema, tachycardia, pruritus, ecchymosis, nausea, vomiting, abdominal pain, headache, dizziness, somnolence, rises in serum creatinine and blood urea nitrogen, pharyngitis, higher incidence of sternal wound infection, cardiovascular and cerebrovascular events

Etoricoxib

Arcoxia

106

20–30

≥24

Oral tablet: 60 mg, 90 mg, 120 mg

120 mg PO daily

Nausea, vomiting, diarrhea, heartburn, taste disturbances, decreased appetite, flatulence, headache, dizziness, fatigue, insomnia, myocardial infarction, unstable angina, ischemic stroke, and transient ischemic attacks

–

∼38

≥12

Oral tablet: 200 mg, 400 mg

400 mg PO daily

Abdominal pain, myocardial infarction, stroke, cerebrovascular death, severe edema, GI perforation, gastroduodenal ulceration

Lumiracoxiba Prexige

Dosage Forms

Suggested Doses for Acute Postoperative Painb

Common Adverse Effectsc

Abbreviations: PO = by mouth; IV = intravenous; IM = intramuscular. a

The table was created based on references from micromedex, lexicomp drugs.

b

The suggested doses were doses that have been used in clinical trials; they do not necessarily apply to all patients.

c

Adverse effects reported are a list of only some of the most common adverse effects that have been associated with the drug in question; the table lists neither frequency of occurrence nor all the adverse effects.

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349

Table 21.6: Analgesic Efficacy of Celecoxib Reference

Dose and Route of Celecoxib (n)

Dose and Route of Comparators (n)

Type of Surgery

Duration/Timing of Dose

Outcome Measuresa

Analgesic Efficacy Results

71

200 mg PO C (28)

P (28) 2 g PO A (28) 2 g PO A + 200 mg PO C (28)

ENT

30 to 60 minutes before surgery (1 dose)

1. Percentage of patients with severe postoperative pain

A+C>C A+C>P C=P

125

200 mg PO C (20)

P (20) 50 mg PO R (20)

Spinal fusion

60 minutes before surgery (1 dose)

1. Pain scores (verbal analog pain scale) 2. Morphine use during the first 24 postoperative hours

R>C>P

123

200 mg PO C (30)

P (30) 400 mg PO C (33)

ENT

30–45 minutes before surgery

1. Dose of fentanyl required for rescue analgesia in the immediate postoperative period 2. Maximum pain score before rescue with an opioid containing analgesic

400 mg PO C > 200 mg PO C > P

91

200 mg PO C (90)

P (45) 400 mg PO C (151) 50 mg PO R (151) 400 mg PO I (45)

Oral

Postoperatively as soon as moderate to severe pain

1. Total pain relief and sum of pain intensity difference score over 8 hours and 12 hours 2. Patients’ global assessment of study drug at 8 h 3. Time to first dose of rescue medications

R = I > 400 mg PO C > 200 mg PO C > P (R had a longer duration of action than I)

46

200 mg PO C (74)

P (26) 400 mg PO three times a day I (74)

Oral

Postoperatively as soon as moderate to severe pain

1. Onset of pain relief 2. Time to rescue medication

I>C>P

58

200 mg PO C (141)

P (141) 10 mg/ 1000 mg PO H/A (136)

Ambulatory orthopedic surgery

Within 24 hours after surgery (single dose)

1. Time specific pain intensity difference 2. Summed pain intensity difference 3. Time to onset of analgesia 4. Time to first use of rescue medication

C = H/A > P

58

200 mg PO three times a day PRN C (185)

10 mg/1000 mg PO three times a day PRN H/A (181)

Ambulatory orthopedic surgery

Taken three times daily from 8 hours after first dose for up to 5 days (multidose)

1. Maximum pain intensity in the past 24 hours for days 2 to 5 2. Number of doses of study medication taken per day on days 2 to 5

C > H/A

126

400 mg PO preoperatively, then 200 mg PO every 12 hours postoperatively C (40)

P (40)

Spinal fusion

1 hour before the induction of anesthesia and every 12 hours after surgery for 5 days

1. Pain scores (verbal rating scale) 2. Morphine use

C>P

128

400 mg PO preoperatively, then 200 mg PO every 12 hours postoperatively C (40)

P (40)

Spinal fusion

1 hour before the induction of anesthesia and every 12 hours after surgery for 5 days

1. Pain scores (verbal rating scale) 2. Morphine use 3. Chronic donor site pain 1 yr after surgery

C>P

Abbreviations: C = celecoxib; A = acetaminophen; P = placebo; H/A = hydrocodone/acetaminophen; I = ibuprofen; R = rofecoxib; n = number of patients; PO = by mouth; PRN as needed. a

Not all outcome measures are included in this table.

Jonathan S. Jahr, Kofi N. Donkor, Raymond S. Sinatra

Proportion of Patients with First Postoperative Bowel Movement

350 1.0 0.9

Placebo Rofecoxib 50 mg

0.8

74hrs

0.7 0.6 0.5 0.4 0.3 0.2 0.1

90hrs

0.0 0

24

48

72

96

120

Time after Entry in Recovery Room (Hours)

Figure 21.6. Multiple doses of rofecoxib in patients recovering from gynecologic surgery. Rofecoxib group showed a more rapid return to bowel function when compared to placebo group. Sinatra et al.142

voluntarily withdrawn from the U.S. market because of concerns that this COX-2 inhibitor could increase the risk of cardiovascular events.99 Nevertheless, many clinical trials have evaluated the use of rofecoxib in the treatment of acute perioperative pain; therefore, the efficacy of rofecoxib in the treatment of surgical pain is discussed in this section, even though it is no longer in use in the United States (see Table 21.7). The dose of rofecoxib that has been recommended for the management of acute pain is a daily oral dose of 25 to 50 mg (Table 21.7). As discussed in the previous section, the preemptive use of a 50-mg oral dose of rofecoxib was found to be more effective than a 200-mg oral dose of celecoxib in patients undergoing spine stabilization surgery.125 The preemptive use of a 50-mg oral dose of rofecoxib has also been studied in surgical procedures like lumbar disk surgery, arthroscopic knee surgery, lower abdominal surgery, abdominal hysterectomy, urologic surgery, and ENT procedures. In ENT and lumbar disk surgery, the preemptive use of rofecoxib provided a significant analgesic benefit and reduced narcotic consumption when compared to placebo.13,154 The preemptive use of rofecoxib was also shown to be as effective as intravenous ketorolac and more effective with longer duration of postoperative analgesia, and to require less 24-hour need for opioid use than when it is administered postoperatively in patients undergoing arthroscopic knee surgery.80,127 In patients undergoing abdominal hysterectomy, the preoperative administration of oral rofecoxib provided a significant analgesic benefit and decreased opioid requirements in these patient populations.76 Rofecoxib’s use was also shown to provide an equivalent analgesic effect at a reduced cost when compared to that of intravenous ketoprofen after minor urologic surgical procedures.20 In patients undergoing tonsillectomy, the preemptive use of rofecoxib in addition to a 1.5-g oral dose of paracetamol showed an analgesic benefit significantly better than when acetaminophen was used alone.107 In patients who have undergone lower abdominal surgery, the use of a 25- to 50-mg oral sus-

pension of rofecoxib was shown to provide a morphine-sparing effect.147 Rofecoxib has also been studied postoperatively in patients undergoing oral surgery and bunionectomy. In oral surgery, a 50-mg oral dose of rofecoxib was found to have greater analgesic efficacy than oral doses of oxycodone/acetaminophen and acetaminophen/codeine but was less effective when compared to an oral dose of 40 mg valdecoxib.22,23,25,27,54,82 The combination of rofecoxib with acetaminophen in patients undergoing oral surgery has also been shown to have an earlier additive analgesic effect than when rofecoxib was used alone. 22,23,25,27,54,63,82 The postoperative use of rofecoxib have also been found to be more effective than diclofenac in patients who have undergone bunionectomy.25 Buvanendran et al and other studies have shown that the perioperative use of 25- to 50-mg doses of rofecoxib is effective in decreasing postoperative pain and the need for analgesic rescue medications in patients undergoing knee replacement, hernia repair, spine, breast, and orthopedic surgery.18,89,129,131 Sinatra et al142 evaluated the perioperative use of rofecoxib on pain control and clinical outcomes in patients who underwent and are recovering from gynecologic abdominal surgery. In this study, patients who received rofecoxib required 32% fewer intravenous and oral opioids (P = .001) to relieve their pain from days 1 to 5, less sedation, and a 24% reduction in the rate of antiemetic requirement (P = .37) over the first 72 hours postsurgery. The rofecoxib group showed a more rapid return to bowel function (see Figure 21.6) with an earlier mean time to first flatus and first bowel movement compared to that of placebo.142

Use of Valdecoxib and Its Prodrug Parecoxib in Surgical Pain The U.S. FDA initially approved valdecoxib in 2001 for the relief of the signs and symptoms of osteoarthritis and rheumatoid

NSAIDs, COX-2 Inhibitors, and Acetaminophen in Acute Perioperative Pain

351

Table 21.7: Analgesic Efficacy of Rofecoxib Reference

Dose and Route of Rofecoxib (n)

Dose and Route of Comparators (n)

Type of Surgery

Duration/Timing of Dose

154

50 mg PO R (30)

P (30)

ENT

1 hour before surgery

1. Pain scores 2. Intraoperative fentanyl and postoperative diclofenac requirement

R>P

13

50 mg PO R (30)

P (30)

Lumbar disk surgery

24 hours before surgery then 30 minutes before surgery

1. Total dose of morphine requested during stay in the PACU 2. Number of patients reporting high pain scores

R>P

127

preincision dose of 50 mg PO R (20)

Postincision dose of 50 mg PO R (20) P (20)

Arthroscopic knee surgery

Preincision: 1 hour before surgery Postincision: 15 minutes after surgery

1. Pain scores 2. The time to first opioid use 3. 24-hour analgesic use

Preincision R > Postincision R>P

80

50 mg PO R (28)

30 mg IV kr (26)

Arthroscopic knee surgery

R: 30–60 min before surgery Kr: 20 min before end of surgery

1. Proportion of patients reporting pain in the PACU 2. The use of O/A 3. Pain scores 4. Patient satisfaction

R = Kr

76

50 mg PO R (30)

P (30)

Abdominal hysterectomy

1 hour before surgery

1. Pain scores 2. Total and increment tramadol consumption

R>P

20

50 mg PO R (34)

Kp (32)

Urologic surgery

R: 1 hour before surgery Kp: 24 hours after surgery

1. Need for rescue analgesic medication 2. Pain scores

R = Kp

107

50 mg PO R + 1.5 g PO A

P + 1.5 g PO A

Tonsillectomy

1.5 hours before surgery

1. Postoperative pain scores 2. Morphine consumption 3. Intraoperative blood loss

R+A>P+A

147

50 mg PO R (16) (oral suspension)

25 mg PO R (16) (oral suspension) P (16)

Lower abdominal surgery

1 hour before surgery

1. Effort-dependent pain 2. Postoperative morphine requirement

R>P

82

50 mg PO R (90)

5 mg/325 mg O/A (91) P (31)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Total pain relief over 6 and 4 hours 2. Patient’s global assessment of treatment at 6 and 24 hours 3. Onset of analgesic effects

P

22

50 mg PO R (180)

600 mg/60 mg A/COD (180) P (30)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Total pain relief over 6 hours 2. Patient’s global assessment 3. Peak pain relief 4. Duration of analgesic effects

R > A/COD > P

25

50 mg PO R (182)

600 mg/60 mg A/COD (180) P (31)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Total pain relief over 6 hours 2. Patient’s global assessment 3. Peak pain relief 4. Duration of analgesic effects

R > A/COD > P

Outcome Measuresa

Analgesic Efficacy Results

(continued )

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Jonathan S. Jahr, Kofi N. Donkor, Raymond S. Sinatra

Table 21.7 (continued) Dose and Route of Rofecoxib (n)

Dose and Route of Comparators (n)

23

50 mg PO R (121)

50 mg TID D (121) P (63)

Oral surgery

Immediately after surgery

1. Total pain relief over 8 and 24 hours 2. Patient global assessments at 8 and 24 hours

R>D R>P

54

50 mg PO R (82)

40 mg PO V (80)

Oral surgery

Within 4 hours after surgery

1. Onset of analgesia 2. Pain intensity levels 3. Pain relief over 24 hours

V>R>P

28

50 mg PO R (101)

40 mg PO V (99) P (50)

Oral surgery

Within 4 hours after surgery

1. Onset of analgesia 2. Magnitude of analgesic effect 3. Duration of analgesia

V>R>P

63

50 mg PO R (40)

50 mg PO R + 1 g PO A (40) 1 g PO A (20) P (20)

Oral surgery

Postoperatively as soon as moderate to severe pain occurs

1. Pain intensity 2. Pain relief 3. Global evaluation score 4. Use of rescue medications

R+A>R>A> P

43

50 mg PO R (85)

100 mg PO D (85) P (82)

Bunionectomy

Postoperatively on study day 1 and subsequent daily doses from days 2 to 5

1. Total pain relief over 8 hours 2. Sum of pain intensity difference 3. Peak pain relief 4. Peak pain intensity difference

R>D R>P

129

25 mg PO R (50)

P (50)

Total knee arthroplasty

1. Pain score

R>P

18

50 mg PO R (35)

P (35)

Total knee arthroplasty

Daily doses starting 3 days before surgery for 5 days Preoperatively 24 hours before surgery, then 1 to 2 hours before surgery, then daily doses for 5 consecutive days after surgery

1. Postsurgical analgesic consumption 2. Pain scores

R>P

89

50 mg PO R (30)

P (30)

Herniorrhaphy

30 to 45 minutes before surgery, then the morning of the first postoperative day

1. Pain scores 2. Need for rescue analgesics

R>P

131

Perioperatively: 50 mg PO R (180)

Postoperatively: 50 mg PO R (180) P (180)

Spine, breast or orthopedic surgery

Perioperatively: daily doses at leaset 1 hour before surgery then daily doses 3 days after surgery Postoperatively: daily doses for 3 days after surgery

1. Pain score at rest 2. Morphine consumption

R>P

Reference

Type of Surgery

Duration/Timing of Dose

Outcome Measuresa

Analgesic Efficacy Results

Abbreviations: R = Rofecoxib; A = acetaminophen; P = placebo; A/COD = acetaminophen/codeine; V = valdecoxib; R = rofecoxib; O/A = oxycodone/ acetaminophen; D = diclofenac; Kr = ketorolac; Kp = ketoprofen; PACU = postanesthesia care unit; PO = by mouth; PRN as needed. a

Not all outcome measures have been included in this table.

NSAIDs, COX-2 Inhibitors, and Acetaminophen in Acute Perioperative Pain

353

Placebo (n = 55)

Time to Rescue Medication(hrs)

Valdecoxib 20 mg (n = 57) Valdecoxib 40 mg (n = 57)

10

*

22% Required No Rescue Over 24 hrs †

* 8.1 hr

7 hr

5

1.5 hr

*P

0 Placebo

Valdecoxib 20 mg

Valdecoxib 40 mg

0.05 valdecoxib 40 mg and 20 mg vs placebo †P = NS between valdecoxib groups. Desjardins PJ et al Anesthesiology. 97:565; 2002

Figure 21.7. Valdecoxib prior to outpatient surgery (bunionectomy); the figure shows a reduction in opioid dose requirement in the 20- and 40-mg doses of valdecoxib, when compared to that of placebo. Desjardins et al (2002).45

arthritis and for the treatment of primary dysmenorrhea. The U.S. FDA did not approve its use in the management of acute pain.55,99 Valdecoxib was, voluntarily withdrawn from the market for the same reasons as rofecoxib.99 There are, however, many clinical trials that have evaluated the use of valdecoxib and parecoxib for the management of acute surgical pain.18,25,28,43,89,129,131 This section of the chapter documents the evidence available on the efficacy of valdecoxib and parecoxib for use in the management of surgical pain (see Table 21.8). Patients undergoing orthopedic surgery (bunionectomy) were randomized to receive valdecoxib (20 mg), valdecoxib (40 mg), valdecoxib (80 mg), or placebo 45–75 minutes prior to surgery. For the primary efficacy end point of time to rescue medication, patients in the valdecoxib 20 mg, 40 mg, and 80 mg groups experienced significantly better pain relief compared with placebo (P < .05 for all active treatments vs placebo). There was no difference between valdecoxib 20 mg, 40 mg, or 80 mg (see Figure 21.7; 80 mg data not shown) in the median time to rescue medication. Valdecoxib 40 mg and 80 mg provided significantly better pain relief as measured by pain intensity scores compared with placebo through the 24-hour study period. There was no significant difference between valdecoxib groups from the 4-hour assessment onward. By the end of the 24-hour postoperative period, a significantly greater number of patients in each of the valdecoxib groups remained in the study compared with placebo (P < .05 for all active treatments vs placebo).45 As discussed in the previous section, the postoperative use of a 50-mg oral dose of valdecoxib was shown to be a superior analgesic when compared to rofecoxib in patients undergoing oral surgery.54 It was also shown to be equally effective, with a superior duration of analgesia, when compared to oxycodone/acetaminophen.33 In total knee arthroplasty, valdecoxib provided an effective analgesia and was opioid sparing when used in combination with morphine.130 Parecoxib is a water-soluble prodrug of valdecoxib (it is rapidly hydrolyzed in the liver to valdecoxib) and it was developed for parenteral administration. Parecoxib has not been approved for use in the US market, but it is the first injectable COX-2 inhibitor approved for use in Europe for the management of moderate to severe perioperative pain. In an oral surgery pain model, the preemptive use of parecoxib sodium IV doses (20, 40,

and 80 mg) all showed superior analgesic efficacy with opioidsparing effects over placebo with an analgesic ceiling at 40 mg.44 Parecoxib sodium at doses of 20–40 mg has also been shown to be effective in relieving pain and reducing opioid requirements in patients undergoing abdominal surgery and total hip arthroplasty when used postoperatively.90,152 In oral and gynecologic laparatomy surgery, 20- to 40-mg IV doses of parecoxib sodium was shown to be as effective and better tolerated than parenteral ketorolac tromethamine in relieving postoperative pain.12,34 In patients undergoing laparoscopic cholecystetomy, the perioperative use of a 40-mg IV dose of parecoxib followed by a 40-mg oral dose of valdecoxib has been shown to provide greater analgesic efficacy and opioid-sparing benefits than in cases where opioids were used alone.74

Use of Etoricoxib in Postsurgical Pain Although etoricoxib is not available in the US market, it is currently available and in use in some parts of Europe. This section of the chapter evaluates the use and efficacy of etoricoxib in surgical pain (see Table 21.9). In a dose-ranging study that involved patients undergoing dental procedures, a 120mg oral dose of etoricoxib was shown to be the minimal dose required for use in patients experiencing moderate to severe acute post-operative pain.94 The analgesic efficacy of etoricoxib has been compared with that of oxycodone/acetaminophen, codeine/acetaminophen, naproxen sodium, and ibuprofen in oral procedures and in orthopedic surgery.24,63,92,93,121 In patients undergoing oral surgery, the postoperative use of a 120-mg oral dose of etoricoxib was shown to provide superior analgesic effect and a more rapid and long-lasting effect with significantly lesser adverse effects in most of the studies than when compared to oral doses of 10 mg/650 mg oxycodone/acetaminophen, 400 mg ibuprofen, and 60 mg/600 mg codeine/acetaminophen.92,93,94,96 Etoricoxib’s analgesic efficacy was found to be similar to an oral dose of 550 mg of naproxen sodium.93 In patients undergoing knee replacement surgery, the postoperative use of a 120-mg oral dose of etoricoxib was found to have similar analgesic effect as an oral dose of 1100 mg of controlled-release naproxen sodium.121 In all the studies that

354

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Table 21.8: Analgesic Efficacy of Valdecoxib and Parecoxib

Reference

Dose and Route of Valdecoxib or Parecoxib (n)

Dose and Route of Comparators (n)

Type of Surgery

Duration/Timing of Dose

Outcome Measuresa

Analgesic Efficacy Results

44

40 mg PO V (114) 10 mg PO V (56) 20 mg PO V (113) 80 mg PO V (112)

P (112)

Oral surgery or bunionectomy

60 to 75 min before surgery

1. Time to rescue medication 2. Proportion of patients requiring rescue medication 3. Pain intensity 4. Patient’s global evaluation of study medications

80 mg PO V = 40 mg PO V > 20 mg PO V > 10 mg PO V > P

44

20 mg IV PAR (56) 40 mg IV PAR (56) 80 mg IV PAR (56)

P (56)

Oral surgery

30 to 45 min before surgery

1. Time to rescue medication 2. Proportion of patients requiring rescue medication 3. Patients global assessment 4. Pain intensity

PAR > P (analgesic ceiling at 40 mg)

33

20 mg PO V (52) 40 mg PO V (50)

10 mg/1000 mg O/A (51) P (52)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Pain intensity difference 2. Time to onset of analgesia 3. Duration of analgesia

V = O/A > P (V has a superior duration of action)

130

20 mg PO twice a day V + morphine (69) 40 mg PO twice a day V + M (70)

P + M (70)

Orthopedic surgery

Postoperatively as soon as patient can tolerate PO meds, then every 12 hours up to 36 hours

1. Cumulative amount of morphine given over 48 hours 2. Pain intensity 3. Patient’s evaluation of medication

V+M>P+M

152

20 mg IV PAR (19) 40 mg IV PAR (18)

P (18)

Abdominal surgery

Postoperatively at time of first analgesic request, then 12 and 24 hours after surgery

1. Postoperative opioid analgesic requirement 2. Pain scores 3. Pain relief scores

40 mg IV PAR = 20 mg IV PAR > P

90

20 mg IV PAR (67) 40 mg IV PAR (64)

P (70)

Total hip arthroplasty

Postoperatively at time of first analgesic request, then 12 and 24 hours after surgery

1. 2. 3. 4.

Total morphine used Pain relief Pain intensity Time to last dose of morphine 5. Global evaluation rating

PAR > P

34

40 mg IV PAR (51) 40 mg IM PAR (50) 20 mg IV PAR (50) 20 mg IM PAR (51)

P (51) 60 mg IM Kr (51)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Time specific pain intensity difference 2. Time to onset of analgesia 3. Time to use of rescue medication

40 mg IV/IM PAR = Kr > P

12

20 mg IV PAR (39) 40 mg IV PAR (38)

30 mg IV Kr (41) 4 mg IV M (42)

Gynecologic surgery

Postoperatively as soon as moderate to severe pain after discontinuing PCA morphine

1. Onset of analgesia 2. Time to rescue medications 3. Pain intensity difference

40 mg IV PAR = 20 mg IV PAR = 30 mg IV Kr > M>P

74

Perioperatively: 40 mg IV PAR followed by 40 mg PO V (134)

P (129)

Laparoscopic cholecystectomy

Preoperatively: 40 mg IV PAR 30–45 min before induction of anesthesia then 40 mg PO V 6–12 h after PAR: Postoperatively: 40 mg PO daily for days 1–4, then 40 mg PO PRN days 5–7

1. Amount of fentanyl consumed 2. Pain scores

PAR/V > P

Abbreviations: V = valdexoxib; PAR = parecoxib; O/A = oxycodone/acetaminophen; P = placebo; Kr = ketorolac; H/A = hydrocodone/acetaminophen; I = ibuprofen; R = rofecoxib; PO = by mouth; IV = intravenous; IM = intramuscular; M = morphine; PRN = as needed. a

Not all outcome measures have been included in this table.

NSAIDs, COX-2 Inhibitors, and Acetaminophen in Acute Perioperative Pain

have been evaluated, etoricoxib has proved to have superior analgesic efficacy when compared to placebo.24,92,93,94,121 LU M I R AC OX I B

Lumiracoxib is a novel COX-2 inhibitor that is in use in some parts of Europe. It has been described as being distinct from other COX-2 inhibitors and has been shown to demonstrate a 24 hour analgesic efficacy when taken once daily, even though it has a short mean plasma half-life of only 4 hours. Lumiracoxib will not be discussed in detail at this time because of its novel nature and also for the fact that few studies have compared its efficacy with other analgesics.26 S A F E T Y A N D TO L E R A B I L I T Y O F T H E N S A I D S A N D C OX - 2 I N H I B I TO R S

Unless there is a major contraindication for the use of the NSAIDs, they are generally favored for the management of mild to moderate postoperative pain and as adjuncts for use with other analgesics in moderate to severe postoperative pain.2,151 The lack of sedation and respiratory depression, low abuse potential, and little to no interference with bowel or bladder function constitute some of the major advantages associated with the use of the NSAIDs.151 The NSAIDs’ inhibition of the COX-1 enzyme may lead to renal toxicity, platelet dysfunction with bleeding disorders, and gastrointestinal toxicity, including serious complications such as gastroduodenal ulcerations and bleeding.151 As previously stated in this chapter, the COX-2 inhibitors were developed to provide safer alternatives to the nonspecific NSAIDs without compromising efficacy.151 Most of the studies that have been evaluated have shown the efficacy of this class of drugs in postoperative pain management. However, there have been emerging controversies regarding the potential adverse cardiovascular risks associated with the use of the COX-2 inhibitors and whether these compounds truly overcome the perceived limitations associated with the use of the NSAIDs.2,50,150,151 Even among the COX-2 inhibitors, whether the dosing, the duration of drug exposure, and relative degree of selectivity attained may contribute to varying degrees or differences in adverse effects or whether true COX-2 independent effects may be involved, is still not very well established.64

Hematologic and Cardiovascular Effects of the NSAIDs versus the COX-2 Inhibitors The aggregation and hemostasis of the platelets depend on the ability of the platelets to generate thromboxane A2 from prostaglandin H2 . Platelets are known to contain primarily the COX-1 isoform of the cyclooxygenase enzyme but no COX-2.5 The nonselective NSAIDs, capable of inhibiting both COX-1 and COX-2, are therefore known to impair the ability of the platelets to aggregate and therefore increase the risk of bleeding.55 However, several clinical trials have shown that the COX-2 inhibitors do not have much effect on platelets, and so they do not increase the risk of bleeding. 55 In a study that compared the platelet function and bleeding time in elderly and nonelderly volunteers, a 40-mg twice-daily IV dose of parecoxib sodium given for 8 days compared with a 15- to 30-mg intravenous dose of ketorolac given for 5 days

355

was shown to have no effect on platelet function. Ketorolac, however, significantly and profoundly reduced thromboxane A2 in all cases.109 Other studies have also shown that the COX-2 inhibitors like valdecoxib and celecoxib have no effect on platelet function.64,83,84,109 Even though it has been stated and shown in some studies that the nonselective NSAIDs affects platelet aggregation and increases the risk of bleeding,55,64,83,84,109 in most of the studies that were evaluated in this chapter and many other studies regarding the perioperative use of NSAIDs compared to placebo or other control groups, the incidence of bleeding was not significantly different from placebo or the other comparators in most of the NSAIDs that were assessed.123 The current recommendation for the use of celecoxib as a preemptive analgesic in acute postoperative pain is 400 mg followed by 200 mg BID.123 Few other drugs have generated as much attention and controversy as the introduction and withdrawal from general use of rofecoxib followed by valdecoxib in the U.S. market.6 Now, the FDA requires a black box warning stating the possibility of adverse cardiovascular effects to be labeled on all NSAIDs, including the COX-2 inhibitors. It has been hypothesized that the COX-2 inhbitors, in inhibiting COX-2 activity, causes an alteration in the balance between prostacyclin I2 and thromboxane A2 .6,55 Prostacyclin I2 has been shown to be the predominant cyclooxygenase product in the endothelium.6,55 It inhibits platelet aggregation, causes vasodilation, and prevents the proliferation of vascular smooth muscle cells.6,55,64 Therefore, inhibiting prostacyclin I2 ’s effects permits unopposed thromboxane A2 production, which potentiates platelet aggregation, thrombosis, and vasoconstriction.6,55,64 Because data from the rofecoxib gastrointestinal (GI) outcome research study (VIGOR) was published with an 0.4% incidence of myocardial infarction in the rofecoxib group as compared to an 0.1% incidence in the naproxen group,17,106 the discussion about the cardiovascular risk of the COX-2 inhibitors have become very popular. Several clinical, epidemiological, and metaanalysis studies have since demonstrated increased risk of myocardial infarction, heart failure, and hypertension in people who have frequently used rofecoxib in high doses.6,64 However, the decision that led to the withdrawal of rofecoxib from the market was based on data from a 3-year clinical trial that was designed to evaluate the effect of rofecoxib in preventing the recurrence of colorectal polyps in patients with a history of colorectal adenomas. In this study, there was an increased relative risk of confirmed cardiovascular events like stroke and heart attacks beginning after 18 months of treatment in patients taking rofecoxib as compared to placebo.133 There also have been other studies with celecoxib, parecoxib, valdecoxib, and etoricoxib that have shown an increased risk of cardiovascular events like stroke, myocardial infarction, and sometimes hypertension associated with the use of these drugs.5,32,110,149 There are other studies with the COX-2 inhibitors that did not show any significant increase in cardiovascular effects as compared to their comparators.48,97,143 Some have assumed that the cardiovascular effects caused by the COX-2 inhibitors is a “class effect,” whereas others have presented arguments favoring the opinion that the cardiovascular effects of the COX-2 inhibitors would most likely depend on the dosing, the duration of drug exposure, and relative degree of selectivity among the various COX-2 inhibitors.55,64 Most of the clinical trials involving the COX-2 inhibitors and NSAIDs were not specifically designed to address the cardiovascular effects of these drugs

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Jonathan S. Jahr, Kofi N. Donkor, Raymond S. Sinatra

and are underpowered; hence, most of the results are not convincing or conclusive.55,64

Gastrointestinal Toxicity of the NSAIDs versus the COX-2 Inhibitors Prostaglandins play a very important role in maintaining the integrity of the GI mucosa and only COX-1 is present in the normal GI mucosa. The nonselective NSAIDs, which inhibit COX-1 as well as COX-2, are therefore known to induce GI toxicity, and their gastrotoxic effects are known to be one of the most common drug-related serious adverse events in most countries. Its been shown that one in 1200 users of nonselective NSAIDs die from GI bleed within 2 months of starting the drug, 1 of 150 users of nonselective NSAIDs will develop a bleeding complication, whereas 1 in 5 will have an asymptomatic ulcer visible on endoscopy in that time span.55,64 It has been estimated that over 16 500 people of the over 100 000 patients in the United States with NSAIDinduced GI toxicity that are hospitalized because of this adverse effects, result in mortality from GI complications.55,64 The selective COX-2 inhibitors promised fewer gastrotoxic effects but similar efficacy in pain control to that of the nonselective NSAIDs because of their minimum to no influence on the COX-1 isoform.55,64 The COX-2 inhibitors have more or less held their expectation of better GI toxicity compared to that of the nonselective NSAIDs.17,137,143 There are studies that have also shown that even with the short-term use, nonselective NSAIDs are associated with a higher incidence of GI ulcers compared with the selective COX-2 inhibitors and placebo.60

Renal Effects of the NSAIDs versus the COX-2 Inhibitors It is known that prostaglandins play a very important role in renal function by affecting blood flow, glomerular filtration, natriuresis, and antidiuretic hormone secretion.55,115 It has also been very well documented that nonselective NSAIDs inhibit the production of such prostaglandins and cause nephrotoxicity when used alone or in combination with other nephrotoxic agents. This therefore leads to renal complications like acute renal failure, hyperkalemia, water and sodium retention, nephrotic syndrome, edema, hypertension, and interstitial nephritis.55,115 The COX-2 enzyme has been implicated in the maintenance of renal blood flow, the mediation of renin release, and the regulation of sodium excretion.55,115 COX-2 inhibitions may, therefore, briefly decrease urine sodium excretion and hence cause urinary retention or edema in some people and induce mild to moderate elevation of blood pressure.55,115 In cases where considerable intravascular volume depletion and/or renal hypoperfusion have occurred, the use of agents that interfere with COX-2 activity (such as NSAIDs and COX-2 inhibitors) could severely compromise renal blood flow and glomerular filtration rates.55,115 Patients with severe preexisting renal impairment or high-risk patients like those who are volume depleted or are at risk for severe volume depletion should avoid NSAIDs, including COX-2 inhibitor use, or should be closely monitored if they should end up using NSAIDs or COX-2 inhibitors.55,115

Bone and Wound Healing Effects of the NSAIDs versus the COX-2 Inhibitors Some studies have attempted to explain the effects of the NSAIDs on bone and wound healing.66 The mechanism by which the NSAIDs exert their effects on the bone has been attributed to several factors, including inhibition of boneforming cells at the

end-ostial bone surfaces, reduction of immune and inflammatory responses, and inhibition of prostaglandin synthesis.87 Even though the mechanism of action by which the NSAIDs exert their effects is not fully known or understood, many have stated that the COX-2 enzyme most likely plays a significant role in bone healing. Retrospective studies and animal model studies have been used to show that NSAIDs affect bone osteogenesis and bone fusion success rates during bone repair.41,55,59,65 In some of these studies, the investigators demonstrated that even the shortterm use of the NSAIDs could significantly affect spinal fusion.59 There is, however, an 8-week study involving the use of celecoxib, indomethacin, or placebo, in rabbit models that showed that the COX-2 inhibitors do not have a deleterious effect on the healing of intertransverse process fusions in rabbits as compared to indomethacin.87 In summary, the effects of COX-2 inhibition on wound/bone healing are not yet fully understood. U S E O F AC E TA M I N O P H E N I N P O S T S U RG I C A L PA I N

Acetaminophen was first used in medicine in 1883, but gained widespread acceptance only after 1948, when investigators concluded that another popular analgesic drug at that time, acetanilide (discovered in 1886), was toxic. Acetaminophen had already been discovered to be an active metabolite of acetanilide in 1899 (note the derivation for the trademarked version of acetaminophen: N-ace(tyl)-p-aminoph(enol)Tylenol).14,70,117,136 In 1955, McNeil laboratories introduced an elixir for children that contained acetaminophen as its sole active ingredient, and, since then, acetaminophen has become one of the most widely used analgesics of our time and it is currently the active ingredient in over 300 prescription and over-the-counter (OTC) medications.14,86,117,136 Acetaminophen is known to have a well-established safety profile. At recommended doses, it is not associated with the increase incidence of nausea, vomiting, ileus, and respiratory depression associated with opioids or the deleterious gastrointestinal, hematological, renal, and cardiovascular effects associated with the NSAIDs, including the COX-2 inhibitors. Hepatotoxicity is relatively rare, but acetaminophen has been found to have a narrow therapeutic window; therefore, even a modest overdose of the drug has resulted in severe liver damage.9,39,138 Acetaminophen also has a well-established analgesic profile with a proved record in the management of postoperative pain, alone or in combination.27,39,118 The WHO has recommended it to be used as the firstline medication for mild, moderate, or severe pain and to add opioids and other analgesics as the pain remains persistent or increases (see Figure 21.3). This multimodal approach has been adopted in the European Union and has effectively resulted in a 33% decrease in opioid use and its adverse effects. Intravenous acetaminophen (IV APAP) is available in the European Union since 2002 and is marketed by Bristol-Myers Squibb. Cadence Pharmaceuticals acquired the United States and Canadian rights in 2006 and is currently conducting FDA phase 3 trials. Acetaminophen is available in oral, rectal, and intravenous formulations (see Table 21.10). There is also an intravenous prodrug of acetaminophen (propacetamol) that is rapidly hydrolyzed to acetaminophen in the blood by the enzymatic actions of esterases. This section of the chapter focuses on the various acetaminophen formulations (including propacetamol) and their analgesic efficacy in multimodal analgesia in patients undergoing surgical procedures. This section reviews the use of

NSAIDs, COX-2 Inhibitors, and Acetaminophen in Acute Perioperative Pain

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Table 21.9: Analgesic Efficacy of Etoricoxib Dose and Route of Etoricoxib (n)

Dose and Route of Comparators (n)

94

60 mg PO E (75) 120 mg PO E (76) 180 mg PO E (74) 240 mg PO E (76)

P (49) I (48)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Total pain relief over 8 hours 2. Sum of pain intensity difference over 8 hours 3. Patient’s global evaluation 4. Median time to onset of pain relief 5. Peak pain relief 6. Duration of analgesia

120 mg PO E = 180 mg PO E = 240 mg PO E > I>P

24

120 mg PO E (100)

P (25) 10 mg/ 650 mg O/A (100)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Total pain relief over 6 hours 2. Patient’s global assessment of response to therapy 3. Onset, peak, and duration of analgesia 4. Rescue opioid analgesic used

E > O/A > P

92

120 mg PO E (100)

10 mg/650 mg O/A (102) 60 mg/600 mg COD/A(50) P (50)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Overall analgesic effects 2. Total pain relief over 6 hours 3. Patient global evaluation 4. Time to onset 5. Duration of analgesic effect

E > O/A E > COD/A E > P

93

120 mg PO E (50)

550 mg PO N (51) 60 mg/600 mg COD/A(50) P (50)

Oral surgery

Postoperatively as soon as moderate to severe pain

1. Total pain relief over 8 hours 2. Sum of pain intensity difference over 8 hours 3. Patient’s global evaluation 4. Onset, peak, and duration of analgesia

E > P E > COD/A E=N

55

120 mg PO E (50)

1100 mg PO N (51) (day 1 only) P (50)

Orthopedic surgery

Postoperatively as soon as moderate to severe pain

1. Total pain relief over 8 hours 2. Sum of pain intensity difference over 8 hours 3. Patient’s global evaluation at 8 and 24 hours 4. Percentage of patients using rescue medication 5. Time to use of rescue medication

E = N (day 1) E>P (day 1–7)

Reference

Type of Surgery

Duration/Timing of Dose

Outcome Measuresa

Analgesic Efficacy Results

Abbreviations: E = etoricoxib; N = naproxen; COD/A = codeine/acetaminophen; P = placebo; O/A = oxycodone/acetaminophen; PO = by mouth. a

Not all outcome measures listed in literature are included in this table.

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Jonathan S. Jahr, Kofi N. Donkor, Raymond S. Sinatra

acetaminophen in acute pain by mouth and rectal administration and parenteral infusion. For simplicity of understanding, when oral acetaminophen is discussed, the term acetaminophen will be used; when intravenous acetaminophen is discussed, the term paracetamol will be used, although pharmacologically those compounds are interchangeable – just different preparations and vehicle. It will start with meta-analyses and systematic reviews to place the more recent studies into perspective. In 1996, de Craen et al40 performed a systematic review of the literature in the safety and efficacy of acetaminophen/codeine combinations versus acetaminophen alone. This extensive review concluded that there was a small, but significant, difference between the analgesia of acetaminophen alone and acetaminophen with codeine, single-dose studies show a slightly increased analgesic effect when codeine is added to acetaminophen. In contrast, Hyllested et al,70 in a qualitative review, concluded that acetaminophen is a viable alternative to the NSAIDs, especially because of the low incidence of adverse effects, and should be the preferred choice in high-risk patients. It may be appropriate to combine acetaminophen with NSAIDs, but this was not the focus of the review. In a more recent review, Remy et al124 revisited the effects of acetaminophen on morphine side effects and consumption after major surgery in a metaanalysis of randomized controlled trials that led to the conclusion that acetaminophen combined with PCA morphine induced a significant morphine-sparing effect, but did not change the incidence of morphine-related adverse effects in the postoperative period. Since this review, a significant, multicenter, phase 2 trial that involved 150 subjects comparing paracetamol, IV propacetamol, and placebo concluded that paracetamol (1 g), when administered over a 24-hour period in patients with moderate to severe pain after orthopedic surgery, provided rapid and effective analgesia with a very favorable safety and tolerability profile.144 Additionally, paracetamol or propacetamol reduced the need for rescue doses of PCA morphine during the initial 6-hour efficacy evaluation and over the 24-hour evaluation. Intravenous APAP also may also have contributed to fewer adverse events compared to the placebo group, challenging the meta-analysis data discussed earlier in this section.124,144

Oral and Rectal Acetaminophen in Posturgical Pain The use of oral and rectal acetaminophen in multimodal analgesic therapy has been assessed in several surgical procedures, and some of these studies have already been discussed in previous sections, so they will not be discussed in great detail in this section. In patients who underwent open reduction and internal fixation as a result of acute limb fractures, the use of a 1-g oral dose of acetaminophen given every 4 hours (6 g/d) as an adjuvant to morphine PCA was shown to be very beneficial with significant improvement in pain scores, time on PCA, morphine consumption, and patient satisfaction when compared to the use of morphine alone.139 In patients who have undergone abdominal hysterectomy on PCA morphine, the adjuvant use of a 1.3-g dose of acetaminophen given rectally after wound closure, then 8 and 16 hours after surgery, was compared to 50-mg rectal doses of diclofenac or placebo. In that study, the investigators were able to show that the magnitude of the morphine-sparing effect of acetaminophen suppositories were comparable to diclofenac and could be an efficacious adjuvant analgesic in controlling perioperative pain.29 In cardiac surgery, the use of diclofenac alone or its combined use with rectal acetaminophen was also

shown to have significant opioid-sparing effects and improvement in pain relief.49 In patients who have undergone dental surgery, the use of a single postoperative oral dose of 1.5 g of acetaminophen given in combination with a 50-mg dose of rofecoxib (a COX-2 inhibitor) was shown to improve analgesic effect compared to the use of rofecoxib alone in the early postoperative period, but after 3 hours following administration, analgesic efficacy between those analgesics were similar to, but better than, the use of paracetamol as a monotherapy in that particular group of patients.63 Naesh et al107 were also able to show that the preemptive use of a 1.5-g dose of acetaminophen given in combination with a 50-mg dose of rofecoxib resulted in improved analgesic benefit in the early postoperative period in patients undergoing tonsillectomy. A systemic review of randomized controlled trials compared the efficacy and safety of paracetamol with and without codeine in postoperative pain (eg, post dental extraction, postsurgical or postpartum pain). In this analysis, the authors were able to show that the use of acetaminophen alone resulted in significant analgesic effect and, if combined with codeine, there was an additional benefit in analgesia.105 Thus, the evidence shows that for adults, even large doses of rectal acetaminophen may not provide any added benefit over NSAIDs. Pediatric patients may benefit from 30–40 mg/kg of rectal acetaminophen suppositories administered intraoperatively to augment postoperative analgesia. Additionally, the discomfort of placement and negative psychological effects may minimize its use, except in countries (such as Australia), where this practice may be more accepted and commonplace.

Propacetamol in Postsurgical Pain Propacetamol is an acetaminophen prodrug that is supplied as powder to be dissolved in saline or glucose solutions immediately before infusion. It has been shown that the hydrolysis of a 2-g dose of propacetamol is equivalent to 1-g intravenous paracetamol. Propacetamol was frequently used in many European countries during the times when there was no intravenous paracetamol yet available (see Table 21.11).103,145 In oral surgery, the use of a 2-g intravenous dose of propacetamol infused over 15 minutes was shown to be superior over the recommended dose of 1 g in patients reporting moderate to severe pain after surgery.75 Aken et al also showed that in patients who have undergone oral surgery, an intravenous dose of 2 g propacetamol followed by a 1-g dose has a better tolerability and a significant analgesic effect that is indistinguishable from the analgesia that is provided by a 10-mg intramuscular dose of morphine.154 In patients who have undergone knee ligamentoplasty or spinal fusion surgery, a 2-g intravenous dose of propacetamol given every 6 hours as an adjunct to PCA morphine was shown to be useful and safe, with a significant decrease in morphine consumption.42,65 In patients who have undergone total hip replacement or gynecologic surgery, the use of a 2-g intravenous dose of propacetamol as an adjunct to PCA morphine was found to show similar analgesic efficacy to 15–30 mg of an intravenous dose of ketorolac given postoperatively.142,156

Intravenous Acetaminophen (Paracetamol) in Postsurgical Pain Based on samples of clinical trials that have been presented in the previous section, it is obvious that propacetamol has a proved efficacy and general safety when used in surgical

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Table 21.10: Acetaminophen and Propacetamol Preparations and Dosing Brand Name(s)a

Common Adverse Effectsd

Dosage Formsb

Suggested Doses in Acute Painc

Acetaminophen, Tylenol, paracetamol, others APAP, others

Oral capsule: 81 mg, 160 mg, 325 mg, 500 mg, 650 mg Oral elixir: 125 mg/5 mL, 160 mg/5 mL Oral liquid: 160 mg/5 mL Oral powder for solution: 950 mg Oral solution: 325 mg/12.5 mL, 160 mg/5 mL, 81 mg/2.5 mL, 125 mg/3.75 mL, 500 mg/15 mL, 325 mg/5 mL, 500 mg/5 mL, 81 mg/0.8 mL, 160 mg/mL Oral suspension: 160 mg/5 mL, 81 mg/0.8 mL Oral syrup: 160 mg/5 mL Oral tablet: 81 mg, 160 mg, 325 mg, 500 mg, 650 mg Oral tablet, chewable: 81 mg, 160 mg Oral tablet, disintegrating: 81 mg Oral tablet, extended release: 650 mg Rectal suppository: 81 mg, 125 mg, 325 mg, 650 mg

Mild to moderate pain: 650 mg orally every 4 hours as needed, max: 4 gm/day Mild to moderate pain: 650 mg rectally every 4 to 6 hours as needed, maximum of 6 suppositories/24 hours

Rash, gastrointestinal hemorrhage, hepatotoxicity, nephrotoxicity, pneumonitis

Intravenous Paracetamol

Perfalgan, Acetavance

Injection: 10 mg/mL Solution for infusion

Acute pain: 1 gm IV every 4 hours; Max: 4 g/d

Hepatotoxicity

Propacetamol

Pro-dafalgan

No longer on the market

It has been given intramuscularly or Contact dermatitis intravenously in usual doses of 1 to 2 g every 4 hours, up to 4 times daily if necessary, to a maximum dose of 8 g daily, for the treatment of pain

Generic Name

a

Not all brand names are listed. Dosage forms are based on information given in micromedex and/or used in clinical trials. c Doses for acute pain are those that have been suggested in micromedex and/or used in clinical trials. Doses listed do not necessarily apply to all patients, recommended doses in clinical practice should depend on the clinician’s best judgment and should be patient specific. d The table does not give a full list of all the adverse effects that have been reported, only some of the most common adverse events that have been reported in clinical trials are stated in this section. APAP = N-acetyl-p-aminophenol (acetaminophen). b

procedures either alone or as an adjunct to other analgesics. Unfortunately, it is associated with pain at the intravenous injection site or along the vein where its infusion is taking place.103,145 There have also been reports of contact dermatitis in health care professionals handling the drug. This is important, because the drug comes in a powdered form and must be reconstituted into solution before usage; this increases the risk for contact dermatitis and the possibility for errors. Intravenous acetaminophen was recently developed, and this particular formulation does not require reconstitution, which therefore limits the risk of errors that occurs from reconstitution.103,145 It is also not associated with injection site pain or contact dermatitis, and, in the development program, a 1-g dose of intravenous paracetamol has been shown to be equivalent to the 2-g dose of propacetamol (see Table 21.10).103,145 In patients who have undergone oral surgery, complaining of moderate to severe pain, the use of a 1-g intravenous dose of paracetamol was compared to that of a 2-g dose of propacetamol and with placebo. In this study, both active treatment groups showed a comparable efficacy and a significantly longer duration of analgesia and better patients’s global evaluation than when compared with placebo. The incidence of local pain at

infusion sites was found to be significantly less frequent with the intravenous paracetamol group than when compared with propacetamol.103 Sinatra et al144 also assessed the efficacy and safety of a 1-g intravenous dose of paracetamol compared to a 2-g intravenous dose of propacetamol and with placebo in patients undergoing major orthopedic surgery. In this study, both active treatments showed comparable efficacy in pain relief, median time to morphine rescue, and morphine consumption and was significantly different from that of placebo. Drug-related adverse events, which were mostly local site reactions, was significantly lower in the intravenous paracetamol group compared to the propacetamol group (see Table 21.11). S U M M A RY A N D C O N C LU S I O N

The current recommendation for the preemptive use of the NSAIDs is controversial, and it is still not a universally accepted form of managing postoperative pain. However, the studies that have been presented have demonstrated that multimodal regimens that include the NSAIDs are more likely to be effective when used preemptively and continued during the postoperative period. There are studies that have also shown that even

Table 21.11: Use of Acetaminophen in Surgical Pain Dose and Route of Acetaminophen (n)

Dose and Route of Comparators (n)

139

1 g PO every 6 hours A + PCA morphine (28)

63

Analgesic Efficacy Resultsb

Type of Surgery

Duration/Timing of Dose

Outcome Measuresa

P + PCA morphine (33)

Orthopedic surgery

Postoperatively: 1 g acetaminophen or placebo every 4 hours for 72 hours

1. Total morphine consumption 2. Satisfaction with analgesia Pain scores 3. Duration of PCA use 4. Incidence of nausea and sedation

A + PCA morphine > P + PCA mophine

1 g PO A + 50 mg PO R (40) 1 gm PO A + P

P + 50 mg PO R (40)

Dental surgery

Postoperatively: immediately after moderate to severe pain

1. Pain intensity 2. Pain relief 3. Global evaluation score 4. Use of rescue medications 5. Adverse effects

1st 1.5 h: A + R > R >A After 3 hours: A + R =R>A

107

50 mg PO R + 1.5 g PO A (20)

P + 1.5 g PO A (20)

Tonsillectomy

Preoperatively: 1.5 hours before surgery

1. Postoperative pain scores 2. Morphine consumption 3. Intraoperative blood loss

R + A> P + A (early postoperative period)

29

1.3 g PR A + PCA morphine (24)

50 mg PR D + PCA morphine (20) P + PCA morphine (21)

Abdominal Hysterectomy

Postoperatively: immediately after wound closure, then 8 and 16 hours after surgery

1. Pain score 2. Level of sedation 3. Morphine consumption 4. Incidence of vomiting

A=D>P

49

100 mg PR D + 1 g PR Acet (17) 100 mg PR D (17)

1 g PR Acet (20)

Cardiac surgery

Postoperatively, 2 h after surgery: D – every 18 h after surgery for 24 h Acet- every 6 h after surgery for 24 h

5. Visual analog scale pain score 6. Morphine consumption 7. Sedation

D + Acet = D > Acet

75

2 g IV PROP (132) 1 g IV PROP (132)

P (33)

Dental surgery

Postoperatively: immediately after patients report moderate to severe pain

1. Pain intensity 2. Pain relief scores 3. Time to request rescue medications 4. Adverse effects

2 gm IV PROP >1 gm IV PROP (no significant difference in adverse effects)

68

2 g IV PROP followed by 1 g IV (31)

10 mg IM morphine (30) P (34)

Dental surgery

Postoperatively: immediately after patients report moderate to severe pain

1. Pain intensity score 2. Pain intensity difference 3. Pain relief scores 4. Proportion of patients requiring rescue medications 5. Time to request rescue medications

PROP > morphine >P

42

2 g every 6 h IV PROP + PCA morphine (30)

P + PCA morphine (30)

Orthopedic surgery

Postoperatively: immediately after surgery

1. Pain scores 2. Morphine consumption 3. Global efficacy score 4. Adverse effects

PROP > P

65

2 g every 6 h IV PROP for 3 days + PCA morphine (21)

P (21)

Spinal fusion surgery

Postoperatively: every 6 hours for 3 days after surgery

1. Pain relief 2. Opioid analgesic consumption 3. Degree of sedation

PROP > P

142

2 g IV PROP + PCA morphine (57)

15 mg IV K + PCA morphine (28) 30 mg IV K + PCA morphine (27) P (52)

Orthopedic surgery

Postoperatively: on the first morning after major joint replacement surgery

1. Pain intensity difference 2. Pain relief intensity difference 3. Time to onset of analgesia 4. Opioid consumption

PROP = K > P

156

2 gm IV PROP + PCA morphine (87)

30 mg IV K + PCA morphine (89)

Gynecologic surgery

Postoperatively: at tracheal extubation and 6 hours postextubation

1. Total dose of morphine 2. Pain intensity 3. Global efficacy 4. Adverse effects

PROP = K (propacetamol had excellent tolerability results)

103

1 g IV PARA (51)

2 g IV PROP (51) P (50)

Oral surgery

Postoperatively: immediately after patients report moderate to severe pain

1. Pain relief 2. Maximum pain relief 3. Pain scores 4. Adverse effects

PARA = PROP > P

145

1 g IV PARA (49)

2 g IV PROP (50) P (52)

Major orthopedic surgery

Postoperatively: immediately after patients report moderate to severe pain at 6-hour intervals

1. Pain intensity 2. Pain relief 3. Morphine use 4. Adverse effects

PARA = PROP > P

Ref

Abbreviations: A or Acet = oral paracetamol or acetaminophen; P = Placebo; PCA = patient-controlled analgesia; R = rofecoxib; PR = per rectum; D = diclofenac; PROP = propacetamol; PO = orally; IV = intravenous injection; IM = intramuscular injection; K = ketorolac; PARA = intravenous acetaminophen or paracetamol. a b c

Not all outcome measures listed in literature are included in this table. Analgesic efficacy results presented in table are a general summary of author(s)’ conclusions. Data taken from references 17, 20, 21, 27, 50, 51, 89.

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NSAIDs, COX-2 Inhibitors, and Acetaminophen in Acute Perioperative Pain

with short-term use, nonselective NSAIDs are associated with a higher incidence of GI ulcers compared with the selective COX-2 inhibitors and placebo. Patients with severe preexisting renal impairment, or high-risk patients like those who are volume depleted or are at risk for severe volume depletion, should avoid NSAIDs, including COX-2 inhibitor use, or should be closely monitored if they should be treated with NSAIDs or COX-2 inhibitors. The effects of COX-2 inhibition on wound/bone healing are not yet fully understood. Integrating these conclusions with the available data leads to the following recommendations: use of celecoxib as a preemptive analgesic in acute postoperative pain, at the dose of 400 mg. This should be continued postoperatively for up to a week. With regard to adverse effects, most of the clinical trials involving the COX-2 inhibitors and NSAIDs were not specifically designed to address the cardiovascular effects of these drugs and are underpowered; hence, most of the results pertaining to these adverse effects are not convincing or conclusive. Patients with suspected cardiac or renal disease should any avoid long-term use of these drugs without intensive medical monitoring. Also, COX-2 inhibitors should not be assumed to have antiplatelet effects, so all deep vein thrombosis (DVT)/atrial fibrillation prophylaxis must be continued with other medications. This chapter reviewed the relevant pharmacology and clinical trials validating the use of NSAIDs, COX-2 inhibitors, and APAP in perioperative pain. Each class and each particular drug within the class has advantages and disadvantages, but the overriding themes of multimodal therapy, to minimize the adverse effects of opioids, and preemptive analgesia, to minimize the needed doses of opioids, cannot be disputed. The challenge is in the exact regimen to use in a particular case. One strategy is to consider use of the NSAIDs or COX-2 inhibitors preoperatively, because most of these are only available in an oral preparation. These can be continued postoperatively once oral intake has resumed. To this can be added intravenous paracetamol (available in the EU and application applied for in United States), perioperatively, maximizing the dose to 4 g per 24 hours. It can be discontinued when the patient can again take oral medications. Clearly, caution must be exercised in the use of the NSAIDs or COX-2 inhibiors in patients with medical issue that obviate their use, and the same in patients with severe liver disease for the APAP. However, the large majority of patients would experience relief of pain with less opioid use and fewer adverse effects of the opioids. Additional concerns of postoperative bleeding, gastrointestinal adverse effects, and the complicating factors surrounding need for DVT prophylaxis and prevention of pulmonary embolism makes this equation challenging. However, the fact that there is a probability that NSAIDs might have some effects on platelets may make some in this class ideal for pain control and DVT prophylaxis, although this has yet to be studied in large studies designed to look at this specific issue. This may be an advantage over the COX-2 inhibitors, in that they possess little or no platelet aggregation blocking effects and may require separate anti–deep vein thrombosis and antipulmonary embolism therapy that is already prescribed with separate classes of drugs. Future work should focus on use of the NSAIDs and possibly COX-2 inhibitors for perioperative pain, minimizing the use of opioids and benefiting from the possibilities of DVT prophylaxis (or, in the case of COX-2 inhibitors, allowing for separate noninterfering prophylaxis). APAP, with an intravenous form available, may provide immediate perioperative alternatives to opioids and provide pain relief with minimal adverse events, where

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other forms of sedation are required, such as endoscopy, minor dermatologic/plastics procedures, dental procedures, pediatric procedures, and emergency settings, like sprained ankle. In summary, the 3 classes of drugs may in fact serve to make the WHO pyramid, with use of acetaminophen at all levels of pain, with addition of opioids, into a multimodal approach, using NSAIDs and COX-2 inhibitors when patients can take oral medications, and adding the paracetamol for periods when patients are unable to tolerate oral medications. All would likely minimize the perioperative use of opioids and their multiple adverse events.

REFERENCES 1. Akca T, Colak T. The effect of preoperative intravenous use of tenoxicam: a prospective, double-blind, placebo-controlled study. J Invest Surg. 2004;17:333–338. 2. Agency for Health Care Policy and Research. Acute Pain Management: Operative for Medial Procedures and Trauma. Rockville, MD: US Department of Health and Human Services; 1992. Publication 92-0032. 3. Alexander R, El-Moalem HE, Gan TJ. Comparison of the morphine-sparing effects of diclofenac sodium and ketorolac tromethamine after major orthopedic surgery. J Clin Anesth. 2002;14(3):187–192. 4. Angle PJ, Halpern SH, Leighton BL, et al. A randomized controlled trial examining the effect of naproxen on analgesia during the second day after delivery. Anesth Analg. 2002;95:741–745. 5. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355:885–895. 6. Armstrong PW. Balancing the cyclooxygenase portfolio. Cal Med Assn J. 2006;174(11):1581–1582. 7. Aubrun F, Langeron O, Heitz D, et al. Randomized, placebocontrolled study of the postoperative analgesic effects of ketoprofen after spinal fusion surgery. Acta Anesthesiol Scand. 2000;44:934–939. 8. Bandolier: Independent evidence-based healthcare. www. ebandolier.com. Accessed 1/7/2007. 9. Bannwarth B, Pehourcq F. Pharmacologic rationale for the clinical use of paracetamol: pharmacokinetic and pharmacodynamic issues. Drugs. 2003;63:2–5. 10. Barber FA, Gladu DE. Comparison of oral ketorolac and hydrocodone for pain relief after cruciate ligament reconstruction. J Arthros Rel Surg. 1998;14(6):605–612. 11. Barden J, Edwards J, Moore RA, et al. Single dose oral diclofenac for postoperative pain. Cochrane Database Syst Rev. 2004;2:CD004308. 12. Barton SF, Langeland FF, Snabes MC, et al. Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following gynecologic laparatomy surgery. Anesthesiology. 2002;97:306–314. 13. Bekker A, Cooper PR, Frempong-Boadu A, et al. Evaluation of preoperative administration of the cyclooxygenase-2 inhibitor rofecoxib for the treatment of postoperative pain after lumbar disc surgery. Neurosurg. 2002;50:1053–1058. 14. Bertolini A, Ferrari A, Ottani A, et al. Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006;12(3–4):250–275. 15. Blackburn A, Stevens JD, Wheatley RG, et al. Balanced analgesia with intravenous ketorolac and patient-controlled morphine following lower abdominal surgery. J Clin Anesth. 1995;7:103–108. 16. Boccara G, Chaumeron A, Pouzeratte Y, et al. The preoperative administration of ketoprofen improves analgesia after laparoscopic cholecystectomy in comparison with propacetamol or postoperative ketoprofen. Br J Anaesth. 2005;94:347–351.

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22 Perioperative Ketamine for Better Postoperative Pain Outcome Manzo Suzuki

Controlling acute postoperative pain remains a challenge; amelioration of pain affects not only postoperative mobility and mortality, but also the incidence of chronic pain after surgery. Tissue injury from surgery leads to release of inflammatory mediators that activate peripheral nociceptors. Nociceptive information travels thorough A-␦ and C fibers to the spinal dorsal horn and creates a reduction in the threshold for activation in the dorsal horn, which is called central sensitization. N-methylD-aspertate (NMDA) receptors are located presynaptically, and postsynaptically the increase nociceptive pain transmission and play a crucial role in the development of central sensitization. Ketamine, a phencyclidine derivative that possesses a substantial analgesic effect, has been used for intravenous (IV) anesthesia for more than 3 decades. In recent years, hundreds of articles have emphasized the analgesic, preemptive, and antihyperalgesic effects of ketamine.1 However, from the standpoint of improving pain outcome, the clinical use of ketamine is still controversial. Evidence from several studies strongly suggests that the effect of ketamine appears to depend on the type and duration of surgery, impact on nociception by surgical manipulation, type of basic pain treatment, and duration and amount of ketamine administered. By using ketamine effectively, we may reduce the pain score after surgery, decrease morphine consumption, and reduce the incidence of long-term persistent pain after major surgery. In this chapter, I describe the method for effective administration of ketamine to improve outcome with regard to pain.

16 minutes and that in the beta phase 180 minutes. After a single injection of 125 or 250 ␮g/kg, blood concentration of ketamine decreases below 100 ng/mL within 30 minutes. This pattern of change in ketamine concentration is a key point in its effective use, as the change indicates the difficulty in maintaining the blood concentration above 100 ng/mL with a single injection, especially in a narrow range, such as from 100 to 200 ng/mL.

Analgesic and Side Effects of Ketamine Ketamine may produce antinociception through interaction with the spinal ␮-receptor, NMDA receptor antagonism, and descending pain inhibitory pathways.3 The affinity of ketamine for NMDA receptors was shown to be more than one order of magnitude higher than that for ␮-receptors.4 The analgesic effect of ketamine is dose dependent. An analgesic effect alone is present at a blood concentration of 150 ng/mL.5 However, as is well known, the psychedelic side effects of ketamine that are manifested as an emergence phenomenon occur around a blood concentration of 200–300 ng/mL.6,7 These side effects include hypnosis, dreaming, and perceptual feelings. Ketamine at blood concentrations of 50–200 ng/mL has been shown to produce drowsiness. Considering the rapid distribution of ketamine in the alpha phase, the therapeutic range of ketamine as an analgesic without side effects is very narrow. These pharmacokinetics and side effects prohibit us from using ketamine as the sole analgesic. One study demonstrated an analgesic effect of ketamine at a higher dose (>200 ng/mL) during surgery, but this effect was limited to approximately 4 hours after termination of ketamine infusion.8 Changes in blood concentration of ketamine after a single injection, constant infusion, and single injection followed by constant administration are presented in Figure 22.1. It is not difficult to keep the blood concentration of ketamine below 100 ng/mL, especially below 50 ng/mL, because of the slow elimination half-life.

B A S I C P O I N T S F O R K E TA M I N E A D M I N I S T R AT I O N

Pharmacokinetics of Ketamine An understanding of the pharmokinetics of ketamine is very important when examining the literature on the effect of ketamine. Figure 22.1 shows changes in blood concentration of ketamine following either a single injection of 125 ␮g/kg or 250 ␮g/kg.2 The blood concentration of ketamine decreases in 2 phases: rapid distribution (alpha phase) and slow elimination (beta phase), with the half-life in the alpha phase being

Preemptive Analgesic Effect of Ketamine Intraoperative administration of ketamine is used to prevent the development of opioid-induced hyperalgesia. Preemptive 366

Perioperative Ketamine for Better Postoperative Pain Outcome

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Plasma concentration of ketamine (ng/ml) Figure 22.1: Blood concentration of ketamine that potentiates epidural morphine- and bupivacaine-induced analgesia is presented. Group MP (open boxes) and group MK (filled circles) received epidural morphine 2.5 mg and bupivacaine at the end of anesthesia. Group MP received various doses of placebo, whereas group MK received various doses of ketamine. More than 20 ng/mL blood concentration of ketamine significantly potentiates epidural morphine and bupivacaine analgesia. Please note that the pain scores in groups MP and MK before ketamine administration (baseline) were approximately 30 mm (0 00 mm).

analgesia is defined as an antinociceptive treatment begun before surgery to prevent the establishment of central sensitization caused by incisional injury.9 Ketamine had been expected to demonstrate a preemptive effect. However, a recently published quantitative review denied the presence of a preemptive effect by ketamine.10 However, another report demonstrated the preemptive effect of ketamine by showing prevention of hyperalgesia induced by an opioid given during surgery.11 Opioids are routinely administered during surgery for pain control and stabilize hemodynamic control. Animal studies show that NMDA receptor antagonists, such as ketamine, dizocilpine (MK-801), and dextromethorphan suppress the activation of NMDA receptors and inhibit the development of opioid-induced hyperalgesia and opioid tolerance.12,13 There is a possibility that opioid induces hyperalgesia in a dose-dependent manner.14 Results of a study using remifentanil during surgery in humans suggest that ketamine administration prevents the development of opioidinduced hyperalgesia.15

Enhancement of Opioid-Induced Analgesia: Postoperative Infusion of Ketamine Animal studies suggest that an NMDA receptor antagonist can potentiate the antinociceptive properties of opioids.16 Although the results were inconsistent, ketamine coadministered with morphine may provide superior analgesia with a lower incidence of morphine-induced side effects. No study has determined the blood concentration of ketamine required to potentiate IV opioid-induced analgesia. In an investigation of the infusion of ketamine after surgery, the blood concentration was kept over 100 ng/mL.17 However, maintaining the blood concentration at this level often induces hypnosis, and may interfere

with fast recovery, rehabilitation, and discharge (I received complaints from a surgeon when I administered these doses [about 100 ng/mL] of ketamine, thus I determined the blood concentrations of ketamine to potentiate epidural morphine-induced analgesia). The blood concentration of ketamine to potentiate opioid-induced analgesia may vary according to the route of administration and kind of opioid.18,19 The maximal blood concentration may be 100 ng/mL after surgery, which may possibly interfere with rapid recovery and rehabilitation. That these studies failed to demonstrate the efficacy of ketamine in patients who received patient-controlled anesthesia (PCA) morphine indicates that patients who received ketamine infusion displayed significant somnolence induced by both PCA morphine and ketamine infusion.20,21 From these studies, I speculate that patients who received ketamine infusion could not push the delivery button because of sleepiness. Patients who receive ketamine and are awake may feel pain to the same degree as ketamine-untreated patients. The infusion rate is crucial in postoperative ketamine infusion and easily can be changed to maintain patients’ consciousness. As shown in a review article, a dose of ketamine over 30 mg per 24 hours does not result in a dose-dependent morphine-sparing effect.22 This coincides with the results of our study that presented the dose-independent effect of ketamine potentiating epidural morphine-induced analgesia.19 Ketamine can be administered intraoperatively, postoperatively, or both. The timing and amount of administration of ketamine depends on the expectation of the ketamine effect (ie, reduced pain in the postanesthesia care unit [PACU], decreased morphine consumption in the wards, reduced persistent pain), not the expectation of the analgesic effect. We should obtain and maintain this optimal blood concentration at times when we desire an antihyperalgesic effect of ketamine.

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Importance of Dose of Opioid to Provide Analgesia Results of an animal study suggested the ratio between the dose of ketamine or other NMDA receptor antagonists and dose of opioid required to relieve pain.23 The failure of an experimental study to demonstrate a synergistic effect between ketamine and alfentanyl indicates the presence of a specific relationship between dosages of ketamine and opioids.24 We demonstrated that very low-dose ketamine (approximately 20 ng/mL) potentiates epidural morphine and bupivacaine analgesia.19 However, this does not imply that this dose of ketamine potentiates the action of larger doses of morphine or other opioids. We must consider that the patients who received epidural morphine and bupivacaine alone (without ketamine) had a relatively low pain score (VAS < 3). I now speculate that if we administer a larger dose of opioid, a larger dose of ketamine might be required to potentiate or prevent the development of opioid-induced hyperalgesia (Figure 22.1). There seems to be a balance between dosages of opioid and ketamine. The dose of ketamine has limitations because of ketamine-induced side effects. Thus, it is important to obtain a lower pain score by lower dosages of opioid. We must remember that low-dose ketamine potentiates opioid-induced analgesia. Adequate analgesia by an opioid or another agent should be present before administration of ketamine. In the case of postoperative management after highly nociceptive procedures, the use of epidural administration of opioid or concomitant use of epidural local anesthesia, that is, a peripheral nerve block, may be important. P R AC T I C A L A D M I N I S T R AT I O N O F K E TA M I N E I N P E R I O P E R AT I V E P E R I O D

Ketamine Administration for Ambulatory Surgery (Excluding Ear, Nose, and Throat Surgery) Over 60% of surgeries are now performed in an ambulatory setting. Despite improved analgesics and sophisticated drug delivery systems, surveys indicate that over 80% of patients experience moderate to severe pain postoperatively.25 Pain is the most common cause of hospital admissions or emergency room visits after discharge. Ambulatory surgery is performed under general anesthesia using short-acting analgesics (eg, remifentanil, alfentanil) or inhalational or intravenous anesthesia with rapid emergence (eg, sevoflurane and propofol). Some institutions add peripheral nerve block at the beginning of surgery and perform “balanced analgesia” using acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and peripheral nerve block. Because of quick recovery from anesthesia, the patient requires pain medicine soon after the surgery. For slight pain, acetaminophen and/or NSAIDs may be effective; however, for moderate to severe pain, an opioid should be administered. Even though peripheral nerve block was administered, rescue opioids should be given after a relatively highly invasive procedure.26,27 Excess use of opioids induces problems such as nausea and vomiting, which can be another cause for hospital stay. After pain control by IV analgesics, oral pain medication should be started. The purpose of ketamine administration in this type of surgery is prevention of opioid-induced hyperalgesia through administration of opioids during surgery (eg, remifentanil) and potentiation of morphine-induced analgesia in the PACU without delayed recovery from general anesthesia, thus reducing the number of hospital admissions of these patients.

In outpatient surgery, coadministration of ketamine (0.075 mg/kg or 0.1 mg/kg) and morphine (0.1 mg/kg) at the end of surgery resulted in a very high quality of analgesia during PACU phase 1 and phase 2.28 Because no intraoperative fentanyl had been given, the authors speculate that the effect of ketamine may be related to potentiating analgesia in the PACU. Usually, 1–5 ␮g/kg of fentanyl may be given during surgery. After surgery, incremental administration of IV morphine and/or IV NSAIDs may be given. Ketamine (0.1 mg/kg–0.2 mg/kg), given at the induction of anesthesia, may prevent opioid-induced hyperalgesia, and, after the surgery, the ketamine remaining in the body (even though at low blood concentration) may enhance analgesia by morphine administered in the PACU. According to discharge criteria in an ambulatory setting, oral pain medication will be given after pain has been treated to achieve a sufficiently low level that can be treated by oral medication. Beneficial effects of ketamine have been observed even after hospital discharge. Intraoperative ketamine administration (0.15to 0.25-mg/kg bolus) provides a better postoperative outcome in knee arthroplasty, hernia repair, and laparoscopic gynecological surgery, even after discharge.29–31 No study has shown the effect of ketamine combined with peripheral nerve block in ambulatory surgery. Whether ketamine is given during general anesthesia or during “balanced analgesia” using peripheral nerve block, 0.1–0.25 mg/kg of ketamine at the induction of anesthesia may provide beneficial effects and improve pain outcome. Dosage of ketamine can be decided according to the information shown in Figure 22.1. For short procedures (extracting a screw or hard wires, biopsy, etc), 0.1–0.15 mg/kg may be sufficient and, for relatively longer procedures, 0.25 mg/kg can be administered. Peripheral nerve block should be administered so that the postoperative morphine dose can be reduced. In the case of surgery that is unexpectedly completed within a short period, it is possible that the blood concentration of ketamine will remain relatively high at the emergence of anesthesia. Before anesthesia, a benzodiazepine, such as midazolam (1–2 mg), should be given. However, even though benzodiazepine has been administered, hallucination can be evoked when ketamine is provided while the patient is awake.10 With regard to blood concentration after administration of ketamine (0.25 mg/kg), blood concentration will decline to around 20 ng/mL 60 minutes after administration (Figure 22.1). When ketamine is administered at the induction of anesthesia, there is a small possibility of inducing a psychotomimetic side effect.

Remifentanil-Induced Hyperalgesia and Preventive Effect of Ketamine Remifentanil is a newly developed ultra-short-acting opioid. An experimental study indicated that a relatively large dose of remifentanil induces acute opioid tolerance.32 In abdominal surgery, intraoperative infusion of ketamine (0.2 mg/kg/h) prevents high-dose remifentanil- (0.4 ␮g/kg/min) induced hyperalgesia. Area of hyperalgesia and postoperative morphine consumption were reduced by intraoperative ketamine infusion (0.2 mg/kg/h)15 in addition to remifentanil infusion. Low-dose ketamine infusion was shown to enhance remifentanyl-induced analgesia and reduce remifentanil consumption during surgery as well as reduce the degree of hyperalgesia.33 Thus far, the minimum blood concentration of ketamine to prevent hyperalgesia induced by remifentanil or to potentiate remifentanil analgesia

Perioperative Ketamine for Better Postoperative Pain Outcome

has not been determined. However, remifentanil-induced hyperalgesia or tolerance has been observed only when relatively high doses of remifentanil are given. As noted in the next section, in a short procedure such as an ear, nose, and throat surgery (ENT) case, a relatively low dose of remifentanil is given and no anitihyperalgesic effect of ketamine is observed.

Ketamine in Ambulatory ENT Surgery Ear, nose, and throat surgery is also performed in an ambulatory setting. Adult ENT surgery, especially tonsillectomy, is painful. Recently, remifentanil-inhalational anesthesia or remifentanilpropofol anesthesia has been indicated.34 Consequently, the question has arisen as to whether ketamine may be beneficial in ambulatory ENT surgery. However, several clinical studies failed to demonstrate a preemptive, antihyperalgesic, or morphinesparing effect of ketamine.34–36 One reason is that, only a small dose of remifentanil was given, and it may be that the pain pathway during and after surgery is through the pharyngeal nerve, not through spinal gray matter. Although there is no evidence that opioid-induced hyperalgesia is provoked only in spinal gray matter, the spinal cord may play a crucial role in the development of opioid-induced hyperalgesia. I believe there is a small possibility of development of opioid- (remifentanil) induced hyperalgesia in this kind of surgery.

Ketamine as Adjunct to Sedative during Local Anesthesia (MAC Setting) Several minor procedures such as breast biopsy and minor plastic surgery are performed under local anesthesia (monitored anesthesia care, [MAC]). Sedative and supplemental analgesics are used to improve patients’ comfort. Coadministration of ketamine and propofol reduces the incidence of movement of patients at the injection of local anesthetics.37 This combination does not induce respiratory depression. A study by Mortero demonstrated that coadministration of ketamine (0.25 mg/kg/h = 100 ng/mL) and propofol (2 mg/kg/h) reduced pain after discharge and cut down the use of oral pain medication at home, improved mood, and provided earlier recovery of cognitive function.37 High doses of ketamine induce hypnosis and vomiting after recovery, which interferes with quick discharge.38 Ketamine dosages should be limited to subhypnotic and subanalgesic levels (100 ng/mL blood concentration). Bolus administration should be avoided because an MAC setting involves a very short procedure; 0.20–0.25 mg/kg/h (without bolus) is sufficient to improve the postoperative condition after MAC. When propofol is being administered, patient’s vital signs and discomfort should be monitored. Some reports cite administration of a mixture of ketamine and propofol; however, such a mixture could possibly result in a much higher concentration of ketamine38 and ketamine-induced side effects if care is not taken by anesthesiologists to consider the amount of ketamine is being administered (see Figure 22.1[C]). If a ketamine-propofol mixture is administered, a high infusion rate should be avoided (Figure 22.1[C]). Sole administration of ketamine (0.2 mg/kg/h) may be better to avoid ketamine-induced side effects. Monitoring the brain such as by the bispectral index (BIS) or an entropy monitor is commonly used to measure the level of sedation during local anesthesia. During propofol or sevoflurane anesthesia, ketamine administration (0.4–05 mg/kg) paradoxically increases the BIS value.39,40 When a relatively higher dose of

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ketamine has been administered, a possibility of dissociation between the level of sedation and the BIS value is suspected. However, the effect of low-dose ketamine infusion (0.1–0.2 mg/kg/h) on the BIS value during propofol infusion has not been studied.

Ketamine for Patients Admitted after Surgery (Major Orthopedic Surgery, Open Cholecystectomy, Gynecologic Laparotomy) Such surgery is performed on the basis of postoperative admission of the patient, with the patient staying in a hospital for at least 24 hours after surgery. We have two options for the use of ketamine: intraoperative or both intra- and postoperative. Results of a study demonstrating the beneficial effect of ketamine administration (0.15 mg/kg) before surgical incision or at the end of anterior cruciate ligament repair suggest that even a single injection of this dose of ketamine has a morphine-sparing effect or prevents opioid-induced hyperalgesia from the opioid given during surgery, but this dose of ketamine does not reduce the pain score after surgery.41 Intraoperative and postoperative ketamine infusion (100 and 50 ng/mL blood concentration, respectively) combined with continuous femoral nerve block reduces postoperative morphine consumption.42 Both of these studies emphasized that patients who received ketamine had superior knee flexion with less pain during rehabilitation. Even if there is no reduction in pain immediately after surgery, reduction in pain during the subacute phase and facilitation of rehabilitation may be beneficial. Ketamine should be administered 0.1–0.15 mg/kg before surgical incision followed by 0.15 mg/kg/h during surgery and 0.05–0.1 mg/kg/h after surgery. I N T R AV E N O U S P C A

PCA with opioid is a popular method of delivering postoperative pain relief. Coadministration of ketamine and morphine may provide synergistic analgesia and reduce the incidence of opioid-induced side effects. For effective analgesia and avoidance of side effects, the ratio of morphine to ketamine may be important. Sveticic et al43 investigated the optimal ratio of morphine and ketamine and the lockout interval to obtain the synergistic effect of both drugs. Possibly, the best combination of morphine with ketamine is a ratio of 1:1, and a lockout interval of 8 min after spinal or hip surgery is recommended. This was not a randomized controlled study, but the pain score after surgery was less than 3 and morphine consumption after surgery was approximately 3 mg/h. However, in a randomized controlled trial of major abdominal surgery, the pain score and morphine consumption did not differ between patients who were coadministered ketamine and morphine, and those who were only given morphine via PCA; the pain score in both groups was more than 3 and more than 3 mg/h of morphine was delivered via PCA. Cognitive function was worse in those coadministered these agents. Coadministration of ketamine and morphine after a major procedure may increase the possibility of ketaminerelated side effects such as somnolence because of high doses of both drugs44 ; with such coadministration, there is the possibility that the ketamine blood concentration may reach an unexpected level. Coadministration of morphine and ketamine (1:1) has a limited possibility of improving pain control in low invasive procedures. The effect of coadministration of ketamine

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and morphine via PCA has been demonstrated in very minor invasive procedures.45

K E TA M I N E F O R M A J O R S U RG E RY

Major surgery, including upper abdominal surgery, thoracotomy, and breast surgery, induces high nociceptive input from a broad section of spinal nerve and visceral components. Inappropriate pain management after such surgery induces dramatic changes in peripheral and central pain processing; that is, pain occurs that does not require further noxious stimulation, socalled secondary hyperalgesia. Both peripheral and central pain sensitization increases postoperative pain, disability from pain, and impaired rehabilitation. Early ambulation and movement to reduce the incidence of pulmonary complications lead to a dynamic or effort-dependent pain. Consequently, after these procedures, high doses of opioids may be administered intravenously or epidurally. The purposes of ketamine administration for these procedures are to (1) reduce pain, facilitate rehabilitation, and lessen the possibility of pulmonary complications; (2) lessen the dose of IV opioid and the incidence of opioidrelated side effects; and (3) reduce the incidence of opioidinduced hyperalgesia and decrease the incidence and severity of postoperative persistent pain.

Administration of Ketamine for Postoperative Pain Management after Major Abdominal Surgery Maneuvers for major abdominal surgery include nociception for a broad section of spinal and supraspinal nerves. Completion of such surgery takes from a few to several hours and high nociception persists during this interval. Consequently, high doses of opioid may be given during surgery. Ketamine should be administered continuously during and after surgery. Aida et al46 demonstrated that relatively low doses of ketamine (blood concentration = 120 ng/mL) during surgery combined with epidural morphine infusion produced superior postoperative analgesia and reduced epidural morphine consumption postoperatively compared with epidural morphine alone. In a study in which ketamine was infused only after surgery, the pain score was not reduced in patients receiving ketamine infusion compared with patients treated with PCA morphine alone.47 Only morphine consumption is reduced in ketaminetreated patients.47,48 Katz et al49 did not demonstrate a preemptive effect of low-dose ketamine (=60 ng/mL) coadministered with fentanyl in a short- and long-term postoperative period. An animal study indicated the possibility of a competitive relationship between ketamine and fentanyl in ␮-opioid receptors.18 Epidural administration of morphine is preferable, because it has a 4 times higher potency than intravenous morphine. It is preferable that intravenous ketamine infusion and epidural morphine be given at the beginning of induction of anesthesia.

P R E V E N T I O N O F P O S TO P E R AT I V E LO N G - T E R M P E R S I S T E N T PA I N

Long-term persistent pain has gained attention as a postoperative adverse outcome.50 Activation of spinal NMDA-receptors

through C-fiber input generated by tissue trauma has a crucial role in central sensitization and evokes persistent pain. Perioperative pain management is signified as having an important role in preventing the development of long-term persistent pain.51 From the standpoint of opioid-induced hyperalgesia, reduction in the amount of postoperative opioids may also contribute to a reduction in long-standing persistent pain. Preventive analgesia is a perioperative pain management strategy to avoid development of such pain. The hypothesis that intraoperative low-dose ketamine will reduce both short-term and long-term postoperative pain has been proposed. Some studies have shown such beneficial effects of ketamine administration, whereas others have not. De Kock et al52 showed that intraoperative ketamine infusion of 100 ng/mL, but not a lower dose (=50 ng/mL), reduced postoperative morphine consumption in surgical patients who had received epidural anesthesia with bupivacaine-sufentanilclonidine. Also, they found that a significant reduction in the amount of morphine leads to a reduction in residual pain 1 year after the surgery. The importance of the basic pain regime in addition to the administration of low-dose ketamine was noted by Lavand’home et al.53 They found that when comparing ketamine infusion as an adjunctive to epidural analgesia with that as an adjunctive to intravenous opioid, the latter provides a better analgesic outcome. For a significant preemptive (preventive = avoidance of persistent pain) effect of ketamine in major surgery, basic pain management is important. Epidural anesthesia using local anesthetics and opioid, especially morphine, may be best combination. K E TA M I N E I N F U S I O N F O R T H O R AC I C S U RG E RY

Maneuvers for thoracotomy involve cutting ribs, retracting the pleura and chest wall, and placing an indwelling intercostal trocar in VATs. These manipulations damage intercostal nerves directly and activate C-fiber afferents, which may cause a significant change in peripheral and central nervous systems. Chronic pain after thoracotomy is believed to be of neuropathic origin.54 Even after completion of surgery, an inflammatory mediator around the skin incision may initiate the development of peripheral and central sensitization. Chronic postthoracotomy pain syndrome is defined as pain that recurs or persists along a thoracotomy scar at least 2 months following a surgical procedure.55 The incidence is 44% to 67%, but the pain is severe only in 25% of those patients. Patients who developed chronic postthoractomy pain had expressed the presence of severe pain after surgery. Management of acute pain is important to prevent the development of chronic postthoracotomy pain.56 Epidural analgesia is the mainstay of postthoracotomy pain management.57,58 Long-term use of ketamine after surgery may be beneficial to reduce the incidence of chronic postoperative pain.59 However, respiratory complications immediately after surgery are worrisome, and efforts should be made to prevent such complications. Dosages of opioid and ketamine should be limited as much as possible while still treating the pain. The blood concentration of ketamine required to potentiate epidural morphine and bupivacaine analgesia is 20–30 ng/mL. Intra- and postoperative infusion of very low-dose ketamine (20 ng/mL) combined with epidural morphine and ropivacaine resulted in a lower pain score and few patients required rescue pain

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Time after surgery Figure 22.2: The effect of low-dose ketamine (0.05 mg/kg/h, filled circles) with epidural morphine (3 mg/d) and ropivacaine 0.15% (3 mL/h) is presented. When basic pain treatment is adequate (open box) and very low-dose ketamine is sufficient to potentiate analgesia (filled circles), the pain score of the ketamine-treated patients is nearly zero, whereas that of the ketamine-untreated patients is 3.

medication after surgery. This low dose may be effective only when the pain is relatively relieved by epidural analgesia (VAS < 3–4 without ketamine; Figure 22.2).59 Low-dose ketamine infusion may decrease the pain score (Figure 22.2). Patients who received low-dose ketamine infusions had a lower pain score even 3 months after surgery than those who did not receive such infusions (Figure 22.3). Considering the relatively smooth change in ketamine blood concentration through changes in the infusion rate (Figure 22.3[A]), we can administer ketamine at a relatively high infusion rate and change the infusion rate at the end of surgery. Thus, I advocate an infusion rate for ketamine of 0.2 mg/kg/h during surgery and to change the rate to 0.05 mg/kg/h at the end of surgery. We are using an epidural infusion pump for ketamine because of its low price and ease of portability (Figure 22.3[B]). We are using an infusion pump during surgery followed by use of a disposable epidural infusion pump.

E P I D U R A L A D M I N I S T R AT I O N O F K E TA M I N E

Although there is a high possibility of psychotomimetic side effects induced by intrathecal administration of ketamine, the direct analgesic effect or enhancement of epidural morphineinduced analgesia by epidural ketamine administration has been investigated.60,61 Ketamine administered in the epidural space moves smoothly into the systemic circulation. Although the plasma half-life of ketamine administered in the epidural space is longer than that of ketamine administered intravenously, the dose and method of administration (injection or infusion) should be decided according to nociceptive input and length of surgery. Sole administration of ketamine (1 mg/kg) into the epidural space brings about preemptive analgesia and a morphine-sparing effect in thoractomy.63 Coadministration of ketamine and morphine continuously into the epidural space provides analgesia superior to that of morphine alone.

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In addition, multimodal analgesia by epidural bupivacaine, morphine, and ketamine provides better pain relief. Although the mechanism of the antagonism of spinal NMDA receptors by epidural administration of ketamine is not known, smooth movement of epidurally administered ketamine into the systemic circulation suggests that epidural ketamine possesses both spinal and supraspinal effects. Dosage of ketamine administered into epidural space is from 5% to 10% that of intravenously administered dosages (0.25 mg/kg/d). Higher doses of epidural ketamine may induce a psychotomimetic side effect. K E TA M I N E F O R A M P U TAT I O N

Incidence of phantom limb pain after amputation is reported to be 49% to 88%.64 Its origin is believed to be neuropathic. Because long-term persistent pain is related to the pain just after the surgery, which is called stump pain, a question arises about

the use of ketamine to prevent phantom limb pain.65 Some reports show the effect of ketamine infusion to treat already established phantom limb pain.66 Only one study, in which relatively high doses of ketamine were administered during and after surgery under general anesthesia, denies the contribution of ketamine infusion to prevent the development of phantom limb pain.67 C O N C LU S I O N

How to use perioperative ketamine effectively is described. There is variety in how much ketamine should be used and how it can be used. Its usage depends on nociception and length of the surgical maneuver, and what we expect from its use. An important point is adequate analgesia through basic pain management. Ketamine can be a good adjunct to relatively well-treated pain, but it should not be used as rescue for inadequate analgesia.

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Image to understand the balance between nociception and the effect of ketamine • Nociception • Dose of opioid

Anti-hyperalgesic of ketamine

Increased nociception and/or increased dose of opioid may reduce the anti-hyperalgesic effect of ketamine

Panel B

No mixture ketamine and propofol Example Ketamine and propofol mixture Ketamine(10 mg/ml)*5 ml+propofol (10 mg/ml)*45 ml =ketamine(1 mg/ml)+propofol(9 mg/ml) Example: patient of 60 kg, 3 ml/kg/hr infusion 18 ml/hr=ketamine 18 mg/hr=0.3 mg/kg/hr In case of 5 ml/kg/hr infusion 30 ml/hr=ketamine 30 mk/kg/hr=0.5 mg/kg/hr According to panel A, 0.5 mg/kg/hr of ketamine infusion makes blood concentration of 200 ng/ml at 90 minutes. Thus in this mixture, 5 ml/kg/hr is maximum rate. Infusion rate of mixture should be considered according to possible ketamine administration rate.

Panel F

Important points for when to withdraw the effect of ketamine • Higher dose of ketamine does not induce high quality of analgesia • Avoid higher dose of opioid as possible • Multimodal analgesia • Adequate analgesia by basic pain regime

Panel C

Ketamine for ambulatory surgery For short procedure (length of surgery 0.5-1h)

Intraoperative ketamine infusion Intraoperative administration of ketamine Ketamine should be administered by infusion pump. Ketamine injection 0.5 mg/kg followed by 0.2-0.25 mg/kg/hr (terminateat the end of surgery). Co-administer epidural morphine (3 mg followed by 1 mg/hr) + bupivacaine 0.5 % 5-10 ml incremently) during surgery. Postopertaive administration of epidural morphine and bupivacaine by PCEA or infusion (set to deliver epidural morphine 510 mg/day and bupivacaine 0.0675%-0.125%, 3-5 ml/hr)

Panel G

Ketamine 0.1-0.15 mg/kg at anesthesia induction

fentanyl

For relatively long procedure (length of surgery 1-2 h) Ketamine 0.2-0.25 mg/kg at anesthesia induction

Postoperative ketamine infusion fentanyl

Panel D

Ketamine is NOT recommended for  Ear, nose, and throat surgery, and maxillofacial surgery 

Use as co-administrator with opioid via patient controlled analgesia (PCA)

Panel E

Postoperative ketamine infusion Using multi rate setting epidural infusion pump. Select flow rate from 2, 3 and 5 ml/hr. Example Weight=60 kg. Primary infusion rate 3 ml/hr for 70 hr. Ketamine infusion 0.15 mg/kg/hr. (60 ng/ml) Total amount of infusion: 3*70=210 ml Ketamine 70 (hr)*60 (kg)*0.15=630 mg ; 63 ml Mixture is 63 ml of ketamine (10 mg/ml)+147 ml of saline As shown in Panel A, even after a 5 hour infusion of ketamine, reduction in rate of infusion reset to low blood concentration level within 1 hour. Thus, using multirate pump we can easily change the dose of ketamine when the patients were somnolence.

Panel H

Perioperative Ketamine for Better Postoperative Pain Outcome

REFERENCES 1. Schmidt RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82:111–125. 2. Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth. 1981;53:27–30. 3. Pekoe GM, Smith DJ. The involvement of opiate and monoaminergic neuronal system in the analgesic effects of ketamine. Pain. 1982;12:57–73. 4. Smith DJ, Azzaro AJ, Zaldivar SB, Palmer S, Lee HS. Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines. Neuropharmacology. 1981;20:392–396. 5. Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics and analgesic activity of ketamine in humans. Br J Anaesth. 1981;53:27–30. 6. Suzuki M, Tsueda K, Lansing P, et al. Midazolam attenuates ketamine-induced abnormal perception and thought process but not mood changes. Can J Anesth. 2000;47:866–874. 7. Bowdle TA, Radant AD, Cowley DS, et al. Psychedelic effects of ketamine in human volunteers: relationship to steady-state plasma concentrations. Anesthesiology. 1998;88:82–88. 8. Bilgin H, Ozcan B, Bilgin T, et al. The influence of timing of systemic ketamine administration on postoperative morphine consumption. J Clin Anesth. 2005;17:592–597. 9. Kissin I. Preemptive analgesia. Anesthesiology. 2002;93:1138–1143. 10. Elia N, Tramer MR. Ketamine and postoperative pain- a quantitative systemic review of randomized trials. Pain, 2005;113:61– 70, 11. Royblat L, Korotkoruchko A, Katz J, et al. Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg. 1993;77:1161–1165. 12. Trujillo KA, Akil H. Inhibition of opiate tolerance by noncompetitive N-methyl-D-aspertate receptor anatagonist. Brain Res. 1994;633:178–188. 13. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995;62:259–274. 14. C´el`erier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats. Anesthesiology. 2000;92:465–472. 15. Jory V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103:147–155. 16. Baker AK, Hoffman VLH, Meert TF. Dextromethorphan and ketamine potentiate the antinociceptive effects of ␮- but not ␦or ␬-opoid agonists in a mouse model of acute pain. Pharmacol Biochem Behav. 2002;74:73–86. 17. Stabhaug A, Brevik H, Eide PK, Kreuen M, Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressors of central sensitization to pain following surgery. Acta Anaesthesiol Scand. 1997;41:1124– 1132. 18. Hoffman VLH, Baker AK, Vercauteren MP, Adriaensen HF, Meert TF. Epidural ketamine potentiates epidural morphine but not fenanyl in acute nociception in rats. Eur J Pain. 2003;7:121– 130. 19. Suzuki M, Kinoshita T, Kikutani T, et al. Determining plasma concentration of ketamine that enhances epidural bupivacaineand-morphine-induced analgesia. Anesth Analg. 2005;101:777– 784. 20. Ilkjaer S, Nikolajsen L, Hansen TM, Wernberg M, Brenum J, Dahl JB. Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Br J Anaesth. 1998;81:707–712.

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21. Edwards ND, Fletcher A, Cole JR, Peacock JE. Combined infusions of morphine and ketamine for postoperative pain in elderly patients. Anesthesia. 1993;48:124–127. 22. Bell RF, Dahl JB, Moore RA. Kalso E. Peri-operative ketamine for acute-post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005;49:1405–1428. 23. Price DD, Mayer DJ, Mao J, Caruso FS. NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage. 2000;S7–S11. 24. Sethna NF, Liu M, Gracely R, Bennett GJ, Max MB. Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects. Anesth Analg. 1998;86:1250–1256. 25. Shang AB, Gan TJ. Optimising postoperative pain management in the ambulatory patient. Drugs. 2003;63:855–867. 26. Ben-David B, Schmaleberger K, Chelly JE. Analegsia after total knee arthroplasty: is continuous sciatic blockade needed in addition to continuous femoral nerve blockade? Anesth Analg. 2004;98:747–749. 27. Mcnamee DA, Parks L, Milligan KR. Post-operative analgesia following total knee replacement: an evaluation of the addition of an obturator nerve block to combined femoral and sciatic nerve block. Acta Anaesthesiol Scand. 2002;46:95–99. 28. Suzuki M, Tsueda K, Lansing PS, Tolan MM, et al. Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg. 1999;89:98–103. 29. Menigaux C, Guinard B, Fletcher D, Sessler DI, et al. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg. 2001;93:606–612. 30. Palvin DJ, Horvath KD, Palvin EG, Sima K. Preincisional treatment to prevent pain after ambulatory hernia surgery. Anesth Analg, 2003;97:1627–1632. 31. Kwok RFK, Lim J, Chan MTV, Gin T, Chiu WKY. Preoperative ketamine improves postoperative analgesia after gynecologic laparoscopic surgery. Anesth Analg. 2004;98:1044–1049. 32. Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmeltz M, Sch¨uttler J. Differential moduration of remifentanil-induced analgesia and postinfusion hyperalgesia by s-ketamine and clonidine in humans. Anesthesiology. 2003;99:152–159. 33. Guinard B, Coste C, Costes H, et al. Supplementing desfluraneremifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesia requirements. Anesth Analg. 2002;95:103– 108. 34. Ganne O, Abisseror M, Menault P, et al. Low-ketamine failed to spare morphine after a remifentanil-based anaesthesia for ear, nose and throat surgery. Eur J Anaesth. 2005;22:426–430. 35. Lebrun T, Elstraete ACV, Sandefo I, Polin B, Pierre-Louise L. Lack of a pre-emptive effect of low-dose ketamine on postoperative pain following oral surgery. Can J Anaesth. 2006;53:146–152. 36. Elstraete ACV, Lebrun T, Sandefo I, Polin B. Ketamine does not decrease postoperative pain after remifentanil-based anaesthesia for tonsillectomy in adults. Acta Anaesth Scand. 2004;48:756–760. 37. Mortero RF, Clark LD, Tolan MM, et al. The effect of a small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition and pain. Anesth Analg. 2001;92:1465–1469. 38. Shyamala B, Michail A, Melissa S, Thomas W, Anthony I. The use of ketamine-propofol combination during monitored anesthesia care. Anesth Analg. 2000;90:858–862. 39. Hirota K, Kubota T, Ishihara H, Matsuki A. The effects of nitrous oxide and ketamine on the bispectral index and 95% spectral edge frequency during propofol-fentanyl anaesthesia. Eur J Anaesth. 1999;16:779–783. 40. Hans P, Dewandre PY, Brichant JF, Bonhomme V. Comparative effects of ketamine on bispectral index and spectral entropy

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41.

42.

43.

44.

45.

46.

47.

48.

49.

50. 51. 52.

53.

Manzo Suzuki of the electroencephalogram under sevoflurane anaesthesia. Br J Anaesth. 2005;94:336–340. Menigaux C, Fletcher D, Dupont X, et al. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg. 2000;90:129–135. Adam F, Chauvin M, Manoir B, et al. Small-dose ketamine infusion improves postoperative analgesia and rehabilitation after total knee arthoroscopy. Anesth Analg. 2005;100:475–480. Sveticic G, Gentilini A, Eichenberger U, Luginb¨ul M, Curatolo M. Combinations of Morphine with ketamine for patient controlled analgesia. A new optimization method. Anesthesiology. 2003;98:1195–1205. Reeves M, Lindholm DE, Myles PS, Fletcher H, Hunt JO. Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: a double-blinded randomized controlled trial. Anesth Analg. 2001;93:116–120. Javery KB, Ussery TW, Steger HG, Colcrough GW. Comparison of morphine and morphine with ketamine for postoperative amalgesia. Can J Anaesth. 1996;43:212–215. Aida S, Yamakura T, Baba H, Taga K, Fukuda S, Shimoji K. Preemtive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy. Anesthesiology. 2002;92:1624– 1630. Guillow N, Tanguy M, Seguin P, Branger B, Campion JP, Mall´edant Y. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg. 2003;97:843–847. Adriaenssen G, Vermeyen KM, Hoffman VLH, Mertens E, Adriaensen HF. Postoperative analgesia with i.v. patient-controlled morphine: effect of adding ketamine. Br J Anaesth. 1999;83:393– 396. Katz J, Schmid R, Snijdelaar DG, Coderre TJ, McCartney CJL, Wowk A. Pre-emptive analgesia using intravenous fentanyl plus low-dose ketamine for radical prostatectomy under general anesthesia dose not produce short-term or long-term reductions in pain and analgesic use. Pain. 2004;110:707–718. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. Anesthesiology. 2000;93:1123–1133. Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol. 2006;19:551–555. De Kock M, Lavand’homme P, Waterloos H. ‘Balanced analgesia’ in the perioperative period: is there a place for ketamine? Pain. 2001;92:373–380. Lavand’homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective

54. 55. 56.

57.

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63.

64.

65. 66.

67.

preventive analgesia in patients undergoing major digestive surgery. Anesthesiology. 2005;103:813–820. Rogers ML, Duffy JP. Surgical aspects of chronic postthoracotomy pain. Eur J Cardiothorac Surg. 2000;18:711–716. Erdek MA, Staats PS. Chronic pain and thoracic surgery. Thorac Surg Clin. 2005;15:123–130. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain. 1996;12:50–55. Tippana E, Nilsson E, Kalso E. Post-thoracotomy pain after thoracic epidural analgesia: a prospective follow-up study. Acta Anaesthesiol Scand. 2003;47:433–438. S¸ent¨urk M, Ozcan PE, Talu GK, et al. The effects of three different analgesia tecvhniques on long-term postthoracotomy pain. Anesth Analg. 2002;94:11–15. Suzuki M, Haraguchi S, Sugimoto K, et al. Low-dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology. 2006;105:111–119. Tan PH, Kuo MC, Kao PF, Chia YY, Liu K. Patient-controlled epidural analgesia with morphine or morphine plus ketamine for post-operative pain relief. Eur J Anaesthsiol. 1999;16:820–825. Chia YY, Liu K, Liu YC, Chang HC, Wong CS. Adding ketamine in a multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic consumption. Anesth Analg. 1998;861:1245–1249. Pedraz JL, Lanao JM, Calvo MB, Muriel C, Haern´andez-Arbeiza J, Dominguez-Gil A. Pharmacokinetic and clinical evaluation of ketamine administered by i.v. and epidural routes. Int J Clin Pharmacol Ther Toxicol. 1987;25:77–80. Ozyaclin NS, Yucel A, Camlica H, Dereli N, et al. Effects of preemptive ketamine on sensory changes and postoperative pain after thoracotomy: comparison of epidural and intramuscular routes. Br J Anaesth. 2004;93:356. Kooilman CM, Pijkstra PU, Geertzen JHB, Elzinga A. Schans CP. Phantom pain and phantom sensations in upper limb amputations: an epidemiological study. Pain. 2000;87:33–41. Nikolajsen L, Jensen TS. Phantom limb pain. Br J Anaesth. 2001;87:107–116. Nikoljsen L, Hansen CL, Nielsen J, et al. The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain. 1996;67:69–77. Hayes C, Armstrong-Brown A, Burstal R. Peroperative intravenous etamine infusion for the orevention of persistent postamputation pain: a randomized, controlled trial. Anaesth Intensive Care. 2004;32:330–338.

23 Clinical Application of Glucocorticoids, Antineuropathics, and Other Analgesic Adjuvants for Acute Pain Management Johan Raeder and Vegard Dahl

The opioids are among the oldest of pain relievers known to mankind, and they remain the cornerstone for acute pain management in patients with moderately severe to severe symptoms. Their benefits include a rapid onset of action, no upper limit of efficacy, many modes of administration, and low cost. Well-known side effects such as nausea, vomiting, pruritus, constipation, and respiratory depression limit their use and may impose significant morbidity. Most opioids have a high degree of first-pass metabolism in the liver making oral dosing unpredictable. Opioid-induced sedation and anxiolysis may be of benefit in some situations; but these effects are unreliable and some patients may experience excessive obtundation, sleep apnea, airway obstruction, confusion, and impaired cognition. Whereas opioids may be titrated to effectively relieve pain at rest, they are not as efficient at controlling incident pain during mobilization. This limitation may be problematic in settings where patients require physiotherapy or physical activity during rehabilitation and recovery. Further, the opioids may disturb the natural pattern of sleep, with reduced fraction of REM sleep after dosing and catch-up, and restless nights later on. Although tolerance and dependency are well-recognized problems with continued opioid use, the development of hyperalgesia or reduced threshold for discomfort from pain stimuli has only recently become recognized as a clinical concern. Such hyperalgesia has been reported after just a few hours of exposure. Opioids also have negative effects on the immune system, which may be unfavorable for debilitated patients in intensive care settings, and they do not seem to protect against development of chronic pain in the same way as some other analgesics may do.

minimize tissue injury and prevent or reduce the inflammatory and neuropathic stimulation. Administration of nonopioid analgesics/adjuvants can reduce inflammatory responses and peripheral neuropathic sensitization, thereby minimizing nociceptive pain and opioid dose requirements. Prophylactic, preventative measures designed to minimize tissue injury (noninvasive surgery) and inflammation (nonsteroiday antiinflammatory drugs [NSAIDs] and other anti-inflammatory agents) are important in this context. The importance of gentle and minimally traumatic surgery should also be mentioned; for example, endoscopic procedures are associated with significantly less tissue injury and are generally less painful than open invasive surgery. Also, nonpharmacological measures to further reduce tissue damage, inflammation, and nerve stimulation should be provided, particularly when the pain-provoking process is ongoing. Examples are limb elevation, compression, and localized cooling to reduce inflammation and edema. Analgesics have variable sites of activity and can interact with receptors, local and humoral mediators in injured tissues, or on nerves and nerve endings that transmit nociceptive stimuli to the central nervous system (Figure 23.1). Analgesics are also effective to modulate the pain impulse at the level of the spinal cord and also at cortical level. This chapter will focus on the role of glucocorticoids, antineuropathics and other analgesics as nonopioid analgesics.

G LU C O C O RT I C O I D S

Overview The glucocorticoids are naturally occurring hormones, with a diurnal variation in circulating levels with mobilization and increased circulating levels during trauma and stress (Figure 23.2). Typically about 25–50 mg of cortisone is secreted during a normal 24-hour period.1 The clinical analgesic effect of stress hormones have long been acknowledged,2,3 for instance, during combat situations where the pain threshold seems to be significantly elevated, possibly partly from glucocorticoids and other

P R I N C I P L E S F O R E M P LOY I N G N O N O P I O I D A NA LG E S I C S

Acute pain reflects potential or established tissue damage. It is now recognized that acute pain is mediated by peripheral nociceptors, which are stimulated by traumatic and inflammatory mechanisms. The best way to treat acute pain is to

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Table 23.1: Why Administer Nonopioids Analgesics and Analgesic Adjuvants Opioid sparing Fewer opioid-induced side effects Constipation Nausea Respiratory depression Sedation Sleep apnea Sleep disturbance Pruritus Improved analgesia Opioids less effective during movement/mobilization Delayed and restrictive opioid dosing in clinical practice Impact on pain mechanisms Blocking wind-up, sensitization, hyperalgesia Limiting development of chronic pain?

stress hormones. It has also been shown that animals with elevated levels of endogenous glucocorticoids experience less pain than others.4 Although the mechanism of action of most analgesics has been elucidated, many were first used empirically, and their

efficacy was never tested in large-scale controlled trials. In this regard, therapeutic benefits associated with glucocorticoids have not been studied as other newer analgesic drugs have been studied for regulatory approval. At the present time, there is little incentive for the pharmaceutical industry to develop patents and market higher priced glucocorticoid drugs. Also, the fear of side effects and the lack of exact knowledge of their analgesic mechanisms have limited the introduction of this class into routine clinical use. However, this lack of interest may be challenged as ongoing research is performed on membrane-bound glucocorticoid receptors and more selective and potentially safer steroid agonists.5 Potential analgesic benefits of glucocorticoids are outlined in Table 23.2.

Effect Mechanisms Glucocorticoids act by binding to a class of nuclear receptors (corticosteroid receptors). On binding to the receptor transfer (chaperone) protein, the drug-receptor complex diffuses into the nucleus of the cell and binds to deoxyribonucleic acid (DNA), initiating production of proteins and enzymes with subsequent clinical effects (Figure 23.3).6–8 Traditional pharmacokinetic parameters are not appropriate for describing glucocorticoid pharmacodynamics, because genetic activation is associated with significant latency to effect. For this reason, onset is typically delayed, with maximum glucocorticoid effects observed after 3–4 hours or more.8–10 For the same reason, the duration of clinical effect is prolonged and does not correlate with plasma

Figure 23.1: Neural and humoral mechanisms underlying pain perception and central sensitization. The central nervous system is sensitized by (1) neural transmission of noxious impulses and (2) humoral transmission of noxious mediators, including cytokines, interleukins, TNF-␣, and prostanoids. Neural transmission can be attenuated by neural blockade, epidural analgesia, and antineuropathic agents, whereas administration of NSAIDs, COX-2 inhibitors, and glucocorticoids may reduce local inflammation and humoral induced aspects of central sensitization.

Analgesic Adjuvants for Acute Pain Management

Table 23.2: Corticosteroid Clinical Actions Anti-inflammatory Antiedema Analgesia Antiemesis Antipyretic Euphoria Alertness Increased energy Restless Increased appetite

concentrations of drugs. In general, effects on cellular processes will continue for hours to days, despite complete clearance of drugs from plasma. Some direct cellular membrane effects of glucocorticoids have also been suggested.5 The rapid membrane stabilization from glucocorticoids during anaphylactoid reactions and a study by Romundstad et al,11 showing analgesic effect within 1 hour of administration, are clinical supportive of these non-DNAmediated effects of glucocorticoids.

Molecular Actions of Glucocorticoids The family of steroid molecules includes potent hormones necessary for normal homeostasis and growth of the human body.3

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The glucocorticoids have virtually no sex hormonal effects, but some of them may still have a slight mineral-corticoid effect (Table 23.3), resulting in renal sodium and water retention.12 There are also some reports of increased blood sugar levels, especially in diabetic patients.13 The major effects of the glucocorticoid subclass of steroid hormones are linked to the inflammatory response, including inhibition of inflammatory gene expression and stimulation of anti-inflammatory gene expression. Important mediators include cyclooxygenase 2 (COX-2) inhibition,14 TNF inhibition, and leukocyte inhibition, both in the peripheral injured tissue, as well as in the spinal dorsal horn and central nervous system. As a part of this general anti-inflammatory action, glucocorticoids also have direct effects on blood capillaries, with decreased permeability and reduced vasodilatation. A general anti-inflammatory action may be very important for pain reduction per se by reducing local tissue pressure and limiting the release of potent pain mediators. The glucocorticoids have also been shown to have direct effects on pain neurons and receptors. They reduce neuropeptide release, inhibit signal transmission in C fibers, and stimulate the secretion of endogenous endorphins.

Clinical Actions of Glucocorticoids The well-known clinical effects of glucocorticoids include antiinflammation, antiedema, antiallergic, and antipyrexia. Also analgesia and antiemetic effects15 are well documented, although the mechanisms, especially of antiemesis, is less well understood. The glucocorticoids frequently induce a slight feeling of euphoria and alertness (Table 23.2).16 The patient may sometimes describe a sensation of more “energy” when these drugs are used and also increased appetite may be beneficial in this setting. However, there are also reports of restlessness, dysphoria,

21

CH2OH

CH2OH

20

C=O 18

HO

12 11

19

CH3

1

9

D 14

2 10

A

B

4

OH

CH3

HO

16

CH3 15

8 7

5

3

O

17

C13

C=O OH

CH3

6

O

(a) Hydrocortisone (cortisol)

(b) Prednisolone CH2OH

O CH2OCC2H5 C=O HO

C=O CH3

HO

O

OH CH3

OCC2H5 CH3

CH3

CH3

F CL O CH3

O

(c) Beclomethasone dipropionate

(d) Dexamethasone

Figure 23.2: The chemical structures of glucocorticoids and other steroid hormones.

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Table 23.3: Steroid Pharmocokinetic/Dynamic Characteristics Half Life (hours)

Drug

Equivalent Dose (mg)

Anti-Inflammatory Potency

Mineral Corticoid Potency

Na+ Retaining Potency

Short acting Hydrocortisone

8–12

20

1

1

1

Cortisone

8–12

25

0.8

0.8

0.8

Prednisolone

18–36

5

4

0.8

0.8

Prednisone

18–36

5

4

0.8

0.8

Methylprednisone

18–36

4

5

0.5

0.8

Triamcinolone

18–36

4

5

0

0

36–54

0.75

25

0

0

Intermediate

Long acting Dexamethasone

Note: Endogenous cortisone production: 25–50 mg/d ≈ 1–2 mg dexamethasone. Modified from from: Salerno A, Hermann R. J Bone Joint Surg. 2006:88:1361–1372.12

H 1.Cytoplasmic Receptor [R]

T

H 2. Surface receptor

R T

H

R T

Cell Membrane

DNA

Nuclear Membrane

H: Steroid Hormone R: Receptor T: Transfer Protein

Figure 23.3: Cellular sites of steroid activity. The corticosteroid nuclear receptor requires many steps and significant time (hours to days) to initiate effects. Steroid hormones (H) cross the cell membrane and bind to a cytoplasmic receptor (R). A transfer protein (T) binds to the receptor hormone complex and guides it to the nuclear membrane. The transfer protein then decouples from the receptor, and the receptor hormone complex attaches to and influences specific genetic targets (DNA). Inhibition of inflammatory gene expression and stimulation of anti-inflammatory expression is mediated by selective synthesis of m-RNA and specific proteins/enzymes. Direct steroid effects at the cell membrane occur sooner (minutes to hours).

Analgesic Adjuvants for Acute Pain Management

Table 23.4: Steroid Side Effects Dermatological

Endocrine

Skin thining

Diabetes

Alopecia

Adrenal-pituitary insufficiency

Hirsuitism Acne Striae Bone

Gastrointestinal

Osteoporosis

Gastritis

Avascular necrosis

Peptic ulcer disease Bowel perforation

Muscle Myopathy Renal

Neuropsychiatric Euphoria Dysphoria

Fluid volume shifts

Psychosis

Hyperkalemia

Insomnia

Cardiovascular

Reproductive

Hypertension

Amenorrhea

Cardiomyopathy

Infertility

Immunological Increased risk of infection Herpes zoster

and even rare cases of abrupt psychosis17 when glucocorticoids are used in the postoperative setting. Less postoperative shivering have been observed and a lower incidence of cardiac arrhythmias has been demonstrated in some but not all studies.16 With prolonged use of these drugs there is a very long list of negative effects, from a generalized reduction in tissue growth, decreased cellular activation, and wound healing. The clinical manifestations may be wound dehiscence, nonunion of fractures, gastric ulceration and perforation, skin vulnerability and wound formation, and poor infection control. Also hormonal side effects may develop, such as moon face, sexual hormone dysfunction, mental disturbances, and hyperglycemia. Adverse events associated with long term glucocorticoid exposure are outlined in Table 23.4.

Clinical Analgesic Action The postoperative analgesic effect of glucocorticoids has been well documented2,3,9,11,18–24 Compared with other analgesics, the onset of clinical effect is generally delayed. In our experience, no analgesic effect is evident during the first 4 hours following administration of dexamethasone (16 mg) to patients recovering from breast surgery. This correlates with previous reports of delayed onset of effect. Aasboe et al9 were not able to demonstrate any analgesic effect from bethamethasone (12 mg) until 3 hours postoperatively. In a laparoscopic surgical trial, Coloma et al10 found that the antiemetic effect of dexamethasone was

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more pronounced after discharge than in the immediate 3 hours postoperatively. Alternatively, Romundstad et al21 reported that the onset of postsurgical analgesia provided by intravenous (IV) methylprednisolone (125 mg) was evident at 60 minutes after administration.21 This is in accordance with experimental and clinical evidence suggesting that glucocorticoids may have rapid and direct, nongenomic actions on cellular membranes.8 The duration of analgesia of a single dose of IV glucocorticoids may be prolonged. Romundstad and coworkers11 found that a single dose of methylprednisolone (125 mg) provided measurable analgesic effects for 3 days. Similarly, Bisgaard et al20 reported that a single dose of dexamethasone (8 mg) significantly reduced pain intensity up to 1 week following laparoscopic surgery. The plasma elimination half-life of dexamethasone is only about 6 hours,25 thus there seems to be ongoing drug effects for a significant period after drug clearance from the plasma. The optimal dose of a glucocorticoid for analgesia has not been established in double blind placebo controlled trials. Similarly the effective dose of dexamethasone for the prevention of post operative nausea and vomiting ranges from 2.5 to 8 mg.26,27 For augmentation of analgesia, a dose of dexamethasone (4 mg) resulted in less inhibition of prostanoids and less effective analgesia after dental surgery than ketorolac (30 mg).28 Bisgaard et al20 reported that an 8-mg dose of dexamethasone was sufficient for pain relief. Dexamethasone has also been tested out for local application as endoalveolar powder or local infiltration in wisdom tooth surgery.29 However, the dose used was 4–10 mg, and a systemic effect cannot be ruled out in this experimental design. In another dental surgery study, 8 mg dexamethasone was found to be more efficient than 4 mg, but increasing the dose to 16 mg provided no further improvement in pain relief.30 The dose of glucocorticoid used in the studies from Romundstad’s group11,21 is more generous, as the 125-mg methylprednisolone dose they employed is equivalent to 25 mg of dexamethasone.12 Olstad and Skjelbred31 also reported that 84 mg methylprednisolone administered over 4 days was effective for postdental surgery pain. Although glucocorticoids have been shown to inhibit the COX-2 enzyme system, much like NSAIDs, they also have hormonal effects and act on a variety of other enzyme systems. Thus, it is of interest to elucidate how the analgesic effect compares with other analgesics in placebo-controlled models: Olstad and Skjelbred31 studied the effect of betamethasone versus paracetamol during a 4-day study and found a tendency of paracetamol to be more analgesic during the 3–4 hours after administration, whereas betamethasone was best during days 3 and 4. Romundstad et al found that the analgesic effect of a single prophylactic 125-mg dose of methylprednisolone was equivalent to parecoxib (40 mg) during a 6-hour study period, with significantly less nausea and sedation.21 These authors also evaluated the effectiveness of methylprednisolone (125 mg) versus ketorolac (30 mg) given for postoperative pain. They found that both drugs provided equivalent and effective analgesia during the first 24 hours. Patients treated with ketorolac experienced a more rapid onset of analgesia, whereas those treated with methylprednisolone required significantly less rescue analgesics during postoperative days 2 and 3.11 An important question that must be answered is whether the glucocorticoids provide measurable analgesic effects when given alone and whether they provide additive analgesic effects when administered with other analgesics.18,32,33 In Bisgaard’s et al study,20 the analgesic effect of dexamethasone (8 mg) was

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in addition to a regimen of local wound anesthesia, paracetamol, and ketorolac. These analgesics were also given to the placebo patients. Similarly, in the study performed by Romundstad and colleagues,21 the analgesic effect of a glucocorticoid was in addition to that provided by local anesthesia, paracetamol, and codeine.19 Coloma et al supplied ketorolac and local anaesthesia to all patients for baseline analgesia. Several studies have been designed to test the specific analgesic effects of a glucocorticoid plus an NSAID or COX-2 selective inhibitor (coxib). In one such study of postdental surgery pain, Bamgbose et al23 added dexamethasone (8 mg) to diclofenac and reported improved pain score at 48 hours with the combination. In a similar clinical model, Moore et al34 found that dexamethasone (10 mg) added to rofecoxib (50 mg) provided superior pain relief for up to 24 hours than either drug administered alone.35 Lin and coworkers24 found that patients treated with the combination of prednisolone (10 mg) plus diclofenac experienced significant reductions in gingival swelling following dental surgery.24

Other Clinical Effects and Side Effects Glucocorticoids may also have beneficial effects on postoperative nausea and vomiting (PONV),15,36 alertness, appetite, and mood.16 Potential negative effects include hyperglycemia,13 flushing, restlessness, impaired wound healing, gastrointestinal ulceration, and increased infection risk.37 Increased alertness has also been described20,38 and may result in potential benefits in more rapid clear-headed recovery and discharge. Adverse effects are unlikely following single-dose administration but may increase with repeated doses.21,36,38 In a meta-analysis of side effects after single-dose administration by Henzi et al,36 no significant side effects were demonstrated in the 17 studies of 941 patients receiving dexamethasone. Even more impressive is the absence of side effects revealed in the meta-analyses of a much higher dose of methylprednisilone (ie, 15–30 mg/kg) used for chest trauma care.37 In more than 2000 patients from 51 single studies, the only significant effect found was an improvement of pulmonary function with glucocorticoid.37 However, there have been scattered reports of psychotic reactions after a single, high-dose administration of glucocorticoids.17,39 Also, in a study of dexamethasone (10 mg), a mean 32% increase in postoperative blood sugar was noted, although no placebo group was included.13

Glucocorticoids The glucocorticoids have an postoperative analgesic effect with delayed onset of 1–4 hours and prolonged duration for at least 1–3 days after a single IV dose. The analgesic peak potency seems to be comparable to the effects provided by optimal doses of NSAIDs and paracetamol. The combination of a glucocorticoid plus NSAIDs provides additive anti-inflammatory effects and analgesia. In addition, the glucocorticoids may offer a safe and useful substitute for patients with known contraindications to NSAIDs (asthma, allergy, renal failure, bleeding tendency). There seem to be no differences in the effect of different glucocorticoids, although very few comparative studies on equipotent doses of different drugs have been done. From a theoretical point of view, dexamethasone may be the most appropriate choice. This drug has no mineralocorticoid effect and has the most prolonged duration of effect after a single dose.12 The opti-

mal dose of dexamethasone that can be recommended remains unclear and varies according to the location and severity of the surgery. With dexamethasone, reliable analgesic effects have been demonstrated with 8–16 mg after surgery of moderate invasiveness; however, it remains to be determined whether higher doses may be more effective and more long lasting, especially because there are minimal adverse events even with very high doses.37 There is a need for studies examining the effects of glucocorticoids after major surgery and large-scale studies to unearth any possible rare side effects, with better sensitivity and statistical power. M E M R A N E S TA B I L I Z I N G D RU G S : A N T I N E U RO PAT H I C S

Calcium Channel Blockers: Gabapentin and Pregabalin Pregabalin and gabapentin are ␥ -aminobutyric acid (GABA) analogs with antiepileptic, analgesic, and anxiolytic activities. Pregabalin was developed as a follow-up compound to gabapentin and is the S-enantiomer of racemic 3-isobutyl GABA. Pregabalin has a more predictable dose-effect relationship, a more prolonged duration of effect, and an improved sideeffect profile. Pregabalin has demonstrated efficacy at doses 2 to 4 times lower than gabapentin and seems to have a higher affinity to the binding site at the ␣2 -␦ subunit. Pregabalin and gabapentin work by modulating the presynaptic release of exitatory neurotransmitters like glutamate, substance P, and norepinephrine. They bind selectively to the ␣2 -␦ subunit of voltage-sensitive calcium channels.40 The action of these compounds seems to be restricted to neurons and they have minor effects on blood pressure and heart rate.41 Gabapentin and pregabalin modulate the release of sensory neuropeptides but only under conditions corresponding to inflammation-induced sensitization of the spinal cord. Gabapentin has a well-established role in the treatment of chronic pain conditions,42 especially in neuropathic pain such as postherpetic neuralgia and diabetic neuropathy.43 Pregabalin has also shown to be effective in alleviating pain in chronic, neuropathic pain conditions.44–46 Pregabalin and gabapentin have also been shown to have analgesic, antineuropathic, and opioid-sparing effects in acute pain. Although acute pain is predominately nociceptive in nature, prolonged central sensitization with some degree of hyperalgesia will occur following trauma, thus there is a rational reason for administering gabapentin and pregabalin in acute pain. Further, surgical trauma commonly involves damage to small nerve fibers and neurons, which also explains the activity of these agents in acute pain and their potential efficacy during the initial development of neuropathic pain. In a systematic review of randomized controlled trials, a single dose of gabapentin (1200 mg or less) given preoperatively significantly reduced pain intensity and opioid consumption for the first 24 hours after surgery.52 Time to first request for rescue analgesia was also prolonged in subgroups receiving 1200 mg. Multiple dosing preoperatively and/or continued use postoperatively did not reduce VAS scores further. Gabapentin also reduced postoperative pain and vomiting; the mechanism probably reflects the significant reduction in opioid consumption.47 In a study of gabapentin alone (1800 mg) or in combination with rofecoxib for 3 days after hysterectomy, the combination of was superior to any of the drugs alone or

Analgesic Adjuvants for Acute Pain Management

placebo. However, at this dose sedation was more frequent in the gabapentin groups.48 Thus far, few studies have been published on acute pain treatment with pregabalin. In a molar extraction dental pain model, 300 mg of pregabalin given after surgery significantly reduced postoperative pain as measured by pain relief and pain intensity difference. A 300-mg dose was more efficacious than 50 mg pregabalin. Pregabalin was comparable to ibuprofen (400 mg) and significantly superior to placebo.49 Side effects such as dizziness, somnolence, and vomiting were more frequent in the 300-mg group. Reuben and coworkers50 found that pregabalin (150 mg) given preoperatively and repeated after 12 hours reduced pain and opioid consumption after spinal fusion surgery. They also found that the combination of pregabalin plus the selective COX2 inhibitor celecoxib (200 mg) provided even better analgesia, reduced the need for IV patient-controlled anesthesia (PCA) morphine by 70%, and was associated with fewer side effects than placebo or either drug alone.50 In conclusion, a preoperative dose of either 1200 mg gabapentin or 150 mg pregabalin will reduce postoperative pain intensity and opioid consumption with few side effects. The reduction in opioid dose requirement might decrease associated side effects like nausea and vomiting. The combination of pregabalin plus a nonsteroidal anti-inflammatory drug seems advisable as it would block both neuropathic and inflammatory components of acute pain.

Sodium Channel Blockers: Lidocaine and Mexilitine Sodium channels are universally located on neurons and nerve fibers, being responsible for the propagation of an action potential along the cell membrane. A complete reversible block of these channels can stop the nerve impulse, which is thought to be the major mechanism for the common use of local anesthetics. For obvious reasons, a complete and generalized sodium channel block, as may be accomplished by the tetrodotoxin of the Japanese puffer fish, may be lethal. However, there are also sodium channels in the periphery that are resistant to this toxin, and these have been shown to be of importance in conditions of neuropatic pain.51 Systemic low concentrations of lidocaine, and the oral analog mexilitine, act on these channels. They have been shown to be efficient analgesics in neuropatic pain syndromes, such as diabetic neuropathy52 and reflex sympathetic dystrophy syndrome.53,54 Action on receptors of G-protein type and N-methyl-D-aspartic acid (NMDA) type have been suggested as the analgesic mechanisms of these drugs.55 The prolonged analgesic effect is thought to be caused by inhibition of spontaneous impulse generation in injured nerves and ganglion neurons proximal to injured nerve segments. Efforts to produce drugs that act more specifically on the tetrodotoxin channels are ongoing,56 but so far clinical trials have not been published. However, there are some studies showing significant effects on postoperative pain from intravenous lidocaine administration.51,55,57,58 Although the clinical analgesic effect seem to be modest, it was significant and opioid sparing when added to paracetamol and NSAID.55 Two studies have shown that continuous infusion of lidocaine improves bowel function after surgery,51,59 Kaba et al55 have recently shown that the use of systemic lidocaine facilitates acute rehabilitation after laparascopic surgery. Nevertheless, many questions

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regarding optimal use of these agents and this analgesic principle remain unanswered. For example, what is the optimal dose of lidocaine? What is the optimal timing and duration of infusion? Will other local anesthetics be good alternatives? What is the potential of using oral alternatives (ie, mexilitine) instead or in addition? Will new, more specific, drugs have better clinical potential? ␣ 2 - A D R E N E RG I C R E C E P TO R AG O N I S T S

The ␣2 -receptor agonists have sedative, anxiolytic, analgesic, and hemodynamic properties.32 They decrease sympathetic tone and attenuate the neuroendocrine and hemodynamic response to anesthesia and surgery. They reduce opioid and anesthetic requirements in the perioperative setting and provide measurable analgesia. In humans, ␣2 adrenoceptors are located in the dorsal horn of the spinal cord and in several areas of the brain. There are at least 3 different subtypes of the ␣2 -adrenergic receptor, 2A, 2B, and 2C. Different subtypes may mediate antinociception and sedation separately and be a target for further drug refinement in this class.60 Sedation is one major effect or side effect of ␣2 agonists, and dexmedetomidine has recently been approved by the Food and Drug Administration (FDA) for use as a sedative in the intensive care units. For specific pain treatment the use of high doses of ␣2 agonists is limited by their sedative/anesthetic properties, probably by action in the locus coerileus. Sedation after epidural administration of clonidine reflects a substantial systemic absorption. The current ␣2 agonists used in pain management are clonidine, tizaninidne, dexmedetomidine, and epinephrine. These compounds have different partial agonist properties; dexmedetomidine with a selectivity ratio of 1600:1 for ␣2 :␣1 , clonidine with 200:1, and epinephrine with 1:1. New agonists like radolmidine with high ␣2 selectivity are currently being investigated in animal models. They have a better pharmacokinetic profile with less rapid distribution within the central nervous system and may have a potential of analgesia with less central nervous side effects.61 Intrathecally administered ␣2 agonists produce antinociception in much lower doses than when administered systemically, thus indicating that the main site for analgesia is in the neuraxis.62 Clonidine is used as a coanalgesic in neuraxial blockades.62 When administered epidurally or intrathecally, ␣2 agonists have synergistic action with opioids. An epidural bolus administration of the combination of fentanyl and clonidine will reduce the analgesic dose of each component by approximately 60%.68 Clonidine will also enhance and prolong the effect of local anesthesia intrathecally.64,65 Epinephrine is widely used as an epidural adjunct for postoperative pain relief, the effect being known for more than 50 years.66 A mixture of 1 ␮g/mL epinephrine, together with 2 mg/mL bupivacaine and 1 ␮g/mL fentanyl, is well documented for synergistic epidural pain relief with minor incidence of motor block or hemodynamic instability.67 Dexmedetomidine and other agonists also have analgesic properties when administered systemically. Dexmedetomidine at dose ranges from 0.5 ␮g/kg IV to 2.5 ␮g/kg intramuscularly (IM) or orally results in significant analgesia with few side effects.5,6 Dexmedetomidine is also highly efficacious when adminstered intrathecally or epidurally in animal models, but its use spinally in humans is still experimental.

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Local administration of ␣2 agonists at the site of trauma seems to have analgesic properties,68,69 possibly by a reduction in norepinephrine release in the terminal nerve endings. There is also evidence of additional analgesia when added to local anaesthesia in peripheral nerve blocks or intravenous regional anaesthesia.62,70 In acute pain treatment, the use of ␣2 -receptor agonists either in low dose systemically or as an adjuvant epidurally or intrathecally is highly beneficial. Its synergistic action with opioids and local anesthesia will reduce the doses needed of each drug, thus reducing the possible side effects. The development of less lipidsoluble agonists and a better understanding of the different subtypes of the ␣2 receptors will probably result in an extended use of selective ␣2 agonists. OT H E R A NA LG E S I C A D J U VA N T S

Cannabinoids The discovery of the cannabinoid receptors, CB1 and CB2 and their endogeneous ligands, has resulted in an extensive research and the development of several cannabinoid receptor agonists and antagonists. Numerous animal studies have demonstrated analgesic and antihyperalgesic properties of both plantderived and synthetic cannabinoids. Cannabinoids produce antinociception in acute pain models in animals.71 However, the number of clinical trials investigating their acute analgesic effect on humans is limited and the results are mixed. Nabilone, a synthetic cannabinoid, had no or negative effect on pain scores in patients undergoing major surgery.72 In a multicenter dose escalation study, 10–15 mg of an oral cannabis extract (cannador) resulted in a dose-related reduction in rescue analgesia requirements in a postoperative pain model.73 Buggy et al74 found no effect of 5 mg tetrahydrocannabinol in a double-blinded, placebo-controlled study in women after hysterectomy. Drowsiness and cardiovascular events such as tachycardia, bradycaria, and hypotension are known possible side effects of cannabinoids.75 In conclusion, further studies are needed to evaluate the possible beneficial role of cannabinoids in the acute pain setting.

Nicotine As pain generation and mediation may be inhibited by acetylcholine action, there has been some interest into looking at the antinociceptive effect of different cholinergic agonists.76,77 Nicotine has been one potential agonist candidate, readily available in tablets and skin pads. It has been shown that regular nicotine users (ie, smokers) may have more postoperative pain than nonsmokers,78,79 especially when they have to abstain from smoking.80 In a study of uterine surgery, Flood and Daniel81 showed that a single dose of nasal nicotine just after end of uterine surgery resulted in lower pain scores during 24 hours, without any side effects. However, thus far few studies have been done on nicotine analgesia in the clinical setting.

Neostigmine Another analgesic is to enhance endogenous acetylcholine levels by using neostigmine.82 Neostigmine is an inhibitor of the acetylcholinesterase enzyme, thus providing higher concentra-

tions of acetylcholine in the synaptic area. One problem that has limited the exploitation of this analgesic mechanism has been the high incidence of nausea that results from neostigmines’ activity in the brainstem emesis center. Nausea is most prominent when neostigmine is given intrathecally, whereas epidural or peripheral administration is associated with a gradual doseresponse curve for emetic side effects.83 Neostigmine provides useful analgesic effects with epidural or caudal routes of administration, whereas the analgesic effects of intra-articular and intravenous administration are not universally apparent.83–86 It has also being questioned whether there is any physiologic reason to believe in a role of acetylcholine in pain mechanisms outside the central nervous system,87 suggesting that any effect seen from topical administration may be a central one.

Magnesium A magnesium ion plug normally maintains the NMDA receptor ion channels in the resting state. Dissociation of magnesium ions is believed to be a mandatory first step that activates these NMDA receptors and enhances pain transmission and sensitization. Receptor antagonists such as ketamine block NMDA activation; however, another way to limit activity is to rapidly replace the magnesium ion block by having increased concentrations of magnesium in the extracellular environment. Indeed, there are numerous clinical studies showing that infusion of magnesium in the perioperative phase has an additive analgesic action.88–92 There are several negative studies as well.93,94 Positive effects have been demonstrated after various types of surgery: gynecological, prostate, cardiac, ear/nose/throat, and cholecystectomy. Typically, 20–50 mg/kg magnesium sulfate is given slowly by the start of anesthesia, followed by infusion of 10–20 mg/kg/h for up to 1–3 days. In a dose-finding study Seyhan et al90 found 40 mg/kg bolus followed by 10 mg/kg/h for 4 hours to be the optimal dose, with no more analgesia by doubling the infusion rate. Some studies have also shown prolonged (ie, until next morning) postoperative efficacy by utilizing a single bolus dose, without the need for infusion.92,95 Topical administration has also been shown to be safe and effective in patients recovering from knee surgery96 and intravenous regional anesthesia.97 In one study looking specifically on magnesium in addition to ketamine for tonsillectomies, there was no analgesic effect of either drug nor of the combination.93

Nonpharmacological Approaches Nonpharmacological measures may be valuable supplements in the treatment of acute pain. Acupunture and transcutaneaus electrical nerve stimulation (TENS) have been scientifically proven for analgesia. Psychoprophylaxis (ie, preoperative psychological preparation for a surgical procedure) is also an interesting option in the nonpharmacological approach to optimal pain treatment. Thorough communication with information, both by the surgeon and anesthetist, about the surgical procedure, anesthesia technique, and pain treatment reduces anxiety and stress. It has been known for decades that psychoprophylaxis reduces the need for postoperative analgesics.98 In a more recent study, Doering et al99 investigated the use of the preoperative presentation of a videotape showing a patient undergoing total hip replacement surgery. This prophylactic procedure significantly reduced the

Analgesic Adjuvants for Acute Pain Management

Table 23.5: A Balanced Approach to Postoperative Pain Medication Preoperatively Paracetamol (1.5–2 g orally; 40–50 mg/kg children) Coxib/NSAID orally Pregabalin/gabapentin Perioperatively Local anesthesia, when possible Dexamethasone (8 mg IV) (paracetamol + NSAID/coxib if not given pre-op) Postoperatively, in hospital Continue local anesthetic infusion Fentanyl if needed Top-up dose of ketorolac Continue pregabalin/gabapentin Continue paracetamol every 6 hours At home, phase I: Paracetamol (1 g × 4) NSAID/Coxib (× 1–3, depending on drug) If needed, oxycodone (fast or slow release) on top At home, phase II Paracetamol NSAID/coxib, if needed

perioperative anxiety level and the need for postoperative analgesic medication in patients undergoing hip surgery. T H E C L I N I C A L A P P L I C AT I O N O F N O N O P I O I D S : P U T T I N G I T A L L TO G E T H E R

Unlike opioids, most nonopioid analgesics and adjuvants have a maximal ceiling effect and a delayed onset of action. Further, there is evidence to suggest that many of these drugs, especially local anesthetics, ketamine, NSAIDs/coxibs, and glucocorticoids, have a preemptive or preventive effect,100 thus there is rationale to administer these agents as early as possible prior to or during exposure to trauma. In this section we have not included most of the “new” analgesic options described above. This is mainly because of lack of extensive documentation of clinically relevant additive effect on top of established multimodal care, but also because of incomplete documentation on optimal dosing and risk of rare side effects. These issues may change rapidly during the next few years. Also, there may be good reason to encourage clinicians to test out some of these modalities, especially in patients where standard opioid-based regimens prove to be suboptimal. Preferably, such testing should be done in controlled studies, to contribute to the development of sound, scientific knowledge on practical use of these agents. We have included the glucocorticoids in our basic regimens, as we feel the evidence is adequate for making general recommendations. The optimal dose and duration of a ketamine infu-

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sion needs to be resolved. With the calcium blockers, systemic local anesthetics, and cannabinoids we think the evidence generally is too sparse at the moment to justify general recommendations.

Acute Postoperative Pain The cornerstones are paracetamol/acetaminophen and NSAIDs/ coxibs to all patients, unless contraindicated, and local anesthesia whenever feasible; in all wounds and even better as dedicated nerve or plexus blocks (Tables 23.5 and 23.6).

Preoperatively Paracetamol and an NSAID/coxib should be given 1 hour or more prior to a procedure to ensure an empty stomach before anesthetic induction and systemic absorption. Oral paracetamol/acetaminophen should be administered as a 1- to 2-g dose for average adults; in case of body weight less than 60 kg or age above 70 years the dose should be reduced to 1.5 g. Paracetamol is also available in the European Union (EU) as a rapidly disintegrating tablet. The rapidly disintegrating tablets have a peak serum concentration as soon as 27 minutes after ingestion compared with 45 minutes for ordinary tablets.105 Rectal administration of paracetamol/acetaminophen should be reserved in cases of noncompliance or nonaccessability of the oral route. The rectal administration of acetaminophen has a delayed onset of action with lower, delayed peak plasma levels. In the pediatric population the initial dose is 50–60 mg/kg. NSAIDs, such as diclofenac (50 mg), naproxen (500 mg), or ibuprofen (800 mg), should also be given orally at least 1 hour before surgery; again, dose reduction should be undertaken in small adults and elderly patients (>70 years). In children, ibuprofen or diclofenac are licensed down to 1 year of age in many countries, with a typical dose being 15–20 mg/kg (ibuprofen) or 2–3 mg/kg (diclofenac). As the coxibs seem to carry no more cardiovascular risks than most traditional NSAIDs, such as diclofenac or ibuprofen, the threshold for using a coxib instead of NSAID should be rather low. The potential advantage of the coxibs in the perioperative period is their lack of effect on platelets. Celecoxib is well documented in starting dose of 400 mg followed by 200 mg twice daily. In the EU, etoricoxib is approved for use and doses of 120 mg can provide up to 24 hours of safe and effective analgesia in uncompromised patients. If oral medication preoperatively is not feasible or practical (eg, too short time delay before start of anesthesia, gastric suction needed), the starting dose of IV paracetamol or NSAID (ie, ketorolac or parecoxib in case of coxib) may alternatively be given IV shortly after induction of anesthesia. Intravenous paracetamol/acetaminophen is readily available and widely administered in the EU. It is undergoing final FDA trials and is not currently available for use in the United States. There are reasons to believe that the IV paracetamol starting dose also should be 2 g instead of the recommended 1-g dose commonly used. For ketorolac or parecoxib the starting dose will typically be 30 and 40 mg, respectively. Parecoxib is not available in the United States. Peroperatively, Early Phase After establishment of the IV line in the OR, certainly glucorticoids are recommended to be administrated as early as possible because of their slow onset of clinical action. However, injection

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Table 23.6: Present Status of Nonopioid Adjuvants in Acute Pain Drug (class)

Effect on Acute Pain

Paracetamol

+

Documentation on Dosing

Documentation on Clinical Usefulness

Toxic with overdose

++

++

Side Effects

Toxicity

Few

NSAID

++

Some

Low

++

+++

Coxib

++

Few

Low

+

++

++

Few

Cardio/CNS toxicity

++

+++

0 → many

Chronic use

?

+

Local anesthesia a

Glucocorticoids

+ (+)

Gabapentin/pregabalin

(+)

Few

Cardiovascular

+

+

IV lidocaine (mexilitine)

(+)

Few

Dose dependent

(+)

(+)

Ketamine

++

Psychogenic

Small

(+)

+ (?)

Magnesium

Dose dependent

Cardiovascular

?

(+)

␣2 block

+

Some

Dose dependent

+

+

Cannabinoids

+

Psychogenic

Low

?

?

Some

Cardiovascular

?

?

Nausea

Dose dependent

?

?

Nicotine Neostigmine

(++)

+/? +

Key: ? = questionable/unknown; + = positive; ++ = very positive; ( ) = disputed or controversial. a

Glucocorticoids have a slow, but definite effect on acute pain, with no side effects after single dose and numerous effects with continued use.

of the common solvent in the dexamethasone preparations may result in perineal and genital itching. For this reason, dexamethasone, in typical doses (8 mg for minor surgery, 16 mg for major surgery in adults, and 0.25–0.5 mg/kg in children), is best given after induction or slowly injected after start of sedation in awake patients receiving regional anesthesia. If the surgeon approves of the use of local anesthesia infiltration prior to the initiation of surgery,100 Lidocaine (5–10 mg/mL) has a rapid onset and, with epinephrine added, the duration is moderately prolonged and hemostasis is improved. Nevertheless, bupivacaine (2.5 mg/mL) is the preferred agent for prolonged postoperative analgesia (up to 10–15 hours). Care should always be taken to avoid high doses and systemic toxicity. If a dose of more than 40 mL (of the 2.5 mL/mg solution) is needed, the infiltration should be with the less toxic levobupivacaine (2.5 mg/mL) or ropivacaine (2–5 mg/mL) instead. If high doses of remifentanil are used intraoperatively (ie, more than 0.3 ␮g/kg/min or plasma target of more than 7–8 ng/mL for more than 2–3 hours), there are data suggesting development of postoperative hyperalgesia, possibly by NMDA receptor activation. The best documented way of blocking this hyperalgesia is to employ a low-dose infusion of ketamine (ie, 1–2 ␮g/kg/min) perioperatively and for some hours postoperatively. There is also evidence to suggest that general anesthesia with potent inhalational agents or nitrous oxide will attenuate remifentanil hyperalgesia. Also perioperative administration of NSAIDs or coxibs may also blunt this hyperalgesia.

Postoperatively in the PACU/Hospital In this phase, there will be an IV line for drug administration and qualified nurses caring for the patients, thus allowing for individualized care of the patient. Still, medications with paracetamol (1 g every 6 hours in adults; 25–30 mg/kg every

6 hours in children) and NSAID/coxib (prescription doses and intervals) should be used as baseline, prophylactic medications. In case of pain, an extra IV dose of ketorolac should be considered (see previously), also if parecoxib was given peroperatively a repeated dose may be considered after 4–6 hours. When patients are still in pain, add small, titrated doses of opioid. Fentanyl (1–2 ␮g/kg) is a good routine opioid; with a fairly rapid onset of action within 3–4 minutes and limited duration of action, there is reduced risk of overdosing and subsequent nausea or somnolence. Recent evidence suggests that oxycodone may be a better alternative for visceral pain, because of some action on the ␬-receptors in addition to primary ␮-receptor effects.

Postoperatively at Home or without IV Access at Hospital Ward/Hotel Whereas the glucocorticoids are recommended only as a single dose preoperatively with potential effect for 2–3 days, the dosing of paracetamol and NSAID/coxib should be repeated on a round the clock basis throughout this phase of recovery. Typically, NSAIDs or coxibs may be dosed for 1, 3, 5, or 10 days based on expected duration of pain after the procedure in question, whereas paracetamol should be used for the whole period of postoperative pain, extending up to 1–2 weeks or more. If additional analgesia is needed, oral oxycodone is an effective alternative. Sustained release oxycodone in an appropriate dose may be useful for moderate to severe pain supplemented with immediate release oxycodone for breakthrough.

Other Types of Acute Pain Many of the same principles and drugs as used for postoperative acute pain should be valid in other contexts of acute pain;

Analgesic Adjuvants for Acute Pain Management

such as occupational trauma, sports injury, neurologic pain, inflammatory pain, and so on. However, these conditions are usually not planned or predicted, so the option of pretreatment is usually not applicable. Still, the concept of rapid and adequate relief of pain with a multimodal nonopioid regimen is valid. The indication for an IV line should be considered; although impractical and painful for insertion, it may be necessary if the pain is severe with subsequent stop or delay in gastric emptying, making the oral route unpredictable. Nonpharmacological measures should also be in focus; the ICE principle (from sports medicine) may apply to all kind of pain caused by external trauma: I = cooling via ice, ice-spray, or cold water C = compression; elastic bandage, taping and also other measures of keeping the injuried place immobilized to avoid edema, hematoma, and further tissue injury E = elevation; mostly to reduce the edema and pressure but also to facilitate venous blood drainage. Oral paracetamol, possibly in a rapidly disintegrating formula, may be a primary drug option, supplemented with an NSAID whenever paracetamol is judged to have insufficient analgesic effect alone. In case of bleeding or hematoma formation, there is a good theoretical rationale for using a coxib instead, although there are no good clinical studies available justifying this selection. When there is an inflammatory component to the pain mechaonism (eg, gout, dysmenorrheal, animal bite, infection), NSAIDs can be useful not only as an analgesic but also as a means to reduce the edema and inflammatory process causing the pain. Finally, glucocorticoids may be added in cases where prolonged analgesic/anti-inflammatory effects are required. An alternative to IV dexamethasone may be oral prednisolone in a 50– to 100-mg dose. If the pain is caused by an infection, steroid should probably be withheld; however, the appropriate use of antibiotics or antiviral drugs (eg, with herpes) is important as both adjuvant and causal therapy. Specific neurologic acute pain, such as migraine and neurogenic pain, are beyond the scope of this chapter but specific pain medications are available and should be employed for these conditions.

C O N C LU S I O N S

This chapter introduced several analgesic options commonly employed in the EU that may be considered for use in patients receiving multimodal analgesic regimens for acute pain management. The guiding principal is to reduce opioid dosing for acute pain as much as possible by using nonopioids and adjuvants in maximum tolerable doses, in a stepwise fashion, according to intensity of the pain stimulus. In a clinical context, single perioperative doses of glucocorticoid, paracetamol/acetaminophen, and ␣2 -␦ antagonists should be considered and administered in appropriate patients. In combination with standardized regional analgesia, NSAIDs or COX-2 inhibitors, and limited doses of opioid, the overall quality of pain management, rehabilitation, and return to functionality can be optimized while patient safety is maintained.

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39. Ferris RL, Eisele DW. Steroid psychosis after head and neck surgery: case report and review of the literature. Otolaryngol Head Neck Surg. 2003;129:591–592. 40. Zareba G. Pregabalin: a new agent for the treatment of neuropathic pain. Drugs Today (Barc). 2005;41:509–516. 41. Fink K, Dooley DJ, Meder WP, et al. Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology. 2002;42:229–236. 42. Fehrenbacher JC, Taylor CP, Vasko MR. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain. 2003;105:133–141. 43. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev. 2005;CD005452. 44. Bennett MI, Simpson KH. Gabapentin in the treatment of neuropathic pain. Palliat Med. 2004;18:5–11. 45. Dworkin RH, Corbin AE, Young JP, Jr, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebocontrolled trial. Neurology. 2003;60:1274–1283. 46. Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, doubleblind, multicentre, placebo-controlled trial of flexible- and fixeddose regimens. Pain. 2005;115:254–263. 47. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain: a systematic review of randomized controlled trials. Pain. 2006;126:91–101. 48. Gilron I, Orr E, Tu D, et al. A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movementevoked pain after abdominal hysterectomy. Pain. 2005;113:191– 200. 49. Hill CM, Balkenohl M, Thomas DW, et al. Pregabalin in patients with postoperative dental pain. Eur J Pain. 2001;5:119–124. 50. Reuben SS, Buvanendran A, Kroin JS, Raghunathan K. The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesth Analg. 2006;103:1271– 1277. 51. Groudine SB, Fisher HA, Kaufman RP, Jr, et al. Intravenous lidocaine speeds the return of bowel function, decreases postoperative pain, and shortens hospital stay in patients undergoing radical retropubic prostatectomy. Anesth Analg. 1998;86:235– 239. 52. Jarvis B, Coukell AJ. Mexiletine. A review of its therapeutic use in painful diabetic neuropathy. Drugs. 1998;56:691–707. 53. Challapalli V, Tremont-Lukats IW, McNicol ED, et al. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev. 2005;CD003345. 54. Kalso E. Sodium channel blockers in neuropathic pain. Curr Pharm Des. 2005;11:3005–3011. 55. Kaba A Laurent SR, Detroz BJ, et al. Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy. Anesthesiology. 2007;106:11–18. 56. Akada Y, Ogawa S, Amano K, et al. Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats. Eur J Pharmacol. 2006;536:248– 255. 57. Koppert W, Weigand M, Neumann F, et al. Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery. Anesth Analg. 2004;98:1050–1055. 58. Fassoulaki A, Patris K, Sarantopoulos C, Hogan Q. The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesth Analg. 2002;95:985–991.

Analgesic Adjuvants for Acute Pain Management 59. Rimback G, Cassuto J, Tollesson PO. Treatment of postoperative paralytic ileus by intravenous lidocaine infusion. Anesth Analg. 1990;70:414–419. 60. Buerkle H, Yaksh TL. Pharmacological evidence for different alpha 2-adrenergic receptor sites mediating analgesia and sedation in the rat. Br J Anaesth. 1998;81:208–215. 61. Xu M, Kontinen VK, Kalso E. Effects of radolmidine, a novel alpha2 -adrenergic agonist compared with dexmedetomidine in different pain models in the rat. Anesthesiology. 2000;93:473– 481. 62. Singelyn FJ, Dangoisse M, Bartholomee S, Gouverneur JM. Adding clonidine to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block. Reg Anesth. 1992;17:148–150. 63. Eisenach JC, D’Angelo R, Taylor C, Hood DD. An isobolographic study of epidural clonidine and fentanyl after cesarean section. Anesth Analg. 1994;79:285–290. 64. Bonnet F, Brun-Buisson V, Saada M, et al. Dose-related prolongation of hyperbaric tetracaine spinal anesthesia by clonidine in humans. Anesth Analg. 1989;68:619–622. 65. Liu S, Chiu AA, Neal JM, et al. Oral clonidine prolongs lidocaine spinal anesthesia in human volunteers. Anesthesiology. 1995;82:1353–1359. 66. Priddle HD, Andros GJ. Primary spinal anesthetic effects of epinephrine. Curr Res Anesth Analg. 1950;29:156–162. 67. Niemi G, Breivik H. Adrenaline markedly improves thoracic epidural analgesia produced by a low-dose infusion of bupivacaine, fentanyl and adrenaline after major surgery. A randomised, double-blind, cross-over study with and without adrenaline. Acta Anaesthesiol Scand. 1998;42:897–909. 68. Davis KD, Treede RD, Raja SN, et al. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain. 1991;47:309–317. 69. Gentili M, Juhel A, Bonnet F. Peripheral analgesic effect of intraarticular clonidine. Pain. 1996;64:593–596. 70. Memis D, Turan A, Karamanlioglu B, et al. Adding dexmedetomidine to lidocaine for intravenous regional anesthesia. Anesth Analg. 2004;98:835–840. 71. Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol. 2001;63:569–611. 72. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006;53:769–775. 73. Holdcroft A, Maze M, Dore C, et al. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology. 2006;104:1040–1046. 74. Buggy DJ, Toogood L, Maric S, et al. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106:169–172. 75. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia. 2004;59:440–452. 76. Decker MW, Rueter LE, Bitner RS. Nicotinic acetylcholine receptor agonists: a potential new class of analgesics. Curr Top Med Chem. 2004;4:369–384. 77. Vincler M. Neuronal nicotinic receptors as targets for novel analgesics. Expert Opin Investig Drugs. 2005;14:1191–1198. 78. Creekmore FM, Lugo RA, Weiland KJ. Postoperative opiate analgesia requirements of smokers and nonsmokers. Ann Pharmacother. 2004;38:949–953. 79. Woodside JR. Female smokers have increased postoperative narcotic requirements. J Addict Dis. 2000;19:1–10. 80. Marco AP, Greenwald MK, Higgins MS. A preliminary study of 24-hour post-cesarean patient controlled analgesia: postopera-

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24 Nonpharmacological Approaches for Acute Pain Management Stefan Erceg and Keun Sam Chung

Pain is defined by the International Association for the Study of Pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage.1 It is a subjective experience that develops differently for each individual through life experiences. The pathophysiological mechanisms of pain and sites of pain processing are continually being elucidated and are discussed in other chapters of this textbook. Concepts underlying pain perception include the following: peripheral and central sensitization, higher cortical recognition/interpretation, descending inhibition, and sympathetic responses. A basic understanding of these concepts is the key to better appreciating traditional and nontraditional analgesic techniques. With the now widely accepted multimodal approach to pain management, our focus must expand to include techniques beyond the strictly Western-based pharmacologic approach to the treatment of pain. A fine balance should be achieved between the use of pharmacologic management and nontraditional nonpharmacologic techniques. Observations made during the 1980s found the approach to analgesia needed to be reexamined. The success of the World Health Organization (WHO) in setting guidelines for pain management was based on the administration of appropriate pharmacologic agents for each level of pain severity. The WHO analgesic ladder provided an impetus for the use of opiate analgesics as the foundation of pain management. This goal was successfully met as evidenced by the fact that opioid sales in the United States, recorded in morphine equivalents, increased from 76,747.0 mg in 1999 to 134,792.7 mg in 2002.2 It should not be forgotten that the WHO guidelines clearly supported the use of nonopioid analgesics and nonpharmacologic techniques; however, these options are rarely used in optimal fashion. Opioid monotherapy is associated with significant annoying and occasional life-threatening adverse events. Opioids produce dose-dependent respiratory depression because of impairment of the respiratory center’s capnic drive. The medullary cough center may also be affected by opioid usage, leading to increased risk of aspiration. Opioids, such as morphine and fentanyl, are associated with confusion, cognitive dysfunction, increased sedation, and respiratory depression. Such morbidity

is particularly troublesome in elderly patients, and may increase morbidity and interfere with activities of daily living. The gastrointestinal effects of morphine and its cousins appear to be dose related and quite varied. Gastrointestinal motility and genitourinary dysfunction often develop from the use of opioid medications. Lower esophageal sphincter relaxation increases the risk for aspiration, whereas the increased tone combined with the decreased propulsive activity of the bowel often leads to constipation. By far, one of the most undesirable effects of opioids involves their activity at the chemoreceptor trigger zone that produces a high risk for nausea and vomiting. Opioid analgesics are also frequently diverted and abused. The Drug Abuse Warning Network published a report in 2006 with data collected from a national sample of general, nonfederal hospitals emergency department (ED) visits. Of the nearly 1.3 million ED visits, the nonmedical use of prescription pharmaceuticals such as opiates, benzodiazepines, and muscle relaxants accounted for nearly half a million. In fact, 31.9% of these visits involved the nonmedical abuse of opiates3 (Table 24.1). The National Survey on Drug Use and Health report, published in the same year by Substance Abuse and Mental Health Services Administration, further highlights the methods used to obtain pharmaceuticals for nonmedical purposes, at least by young adults aged 18–25 years. Although the vast majority of cases indicated that the drug in question was obtained free from a friend or relative (53%), the second most common source of nonmedically abused prescriptions were obtained from a physician (12.7%) (Figure 24.1).4 Regardless of the resource used by individuals to obtain the medications, the stark reality of opiate abuse remains. A final complication associated with opioid analgesics is termed opioid-induced hyperalgesia (OIH). This well-accepted hyperesthetic phenomenon results in a paradoxically increased sensitivity to painful stimuli. OIH may be differentiated from the development of tolerance by progressive increases in pain intensity despite adequate advancement in dosing. The etiology of OIH is undoubtedly multifactorial; however, researchers have strongly implicated a central role for NMDA receptor activation.5 391

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Table 24.1: Emergency Department Visits Involving the Nonmedical Use of Opiates Estimated Visits

95% Confidence Interval

Drug

Number

Percentage

Lower Bound

Upper Bound

Opiates/opioids Hydrocodone/combos Oxycodone/combos Methadone

158,281 42,491 36,559 31,874

31.9

131,292 31,831 28,964 23,752

185,270 53,151 44,154 39,996

Note: Data adapted from the Drug Abuse Warning Network reports of approximately one-half million emergency department visits involving nonmedical use of prescription pharmaceuticals in 2004.

N O N P H A R M AC O LO G I C T H E R A P Y

If our goal is to provide the most effective form of treatment with the least number of associated risks, we must integrate all of our methods of analgesia. Just as the use of multiple classes of analgesic drugs reduces the dosage and side effects of each drug, inclusion of adjuvant nonpharmacologic analgesic techniques could further diminish cumulative analgesic dose, thereby increasing patient safety. Moreover, the majority of nonpharmacologic techniques are predominantly side effect free. Decreasing our exposure should also reduce the incidence of annoying and life-threatening adverse effects, decrease risks of opioid diversion and abuse, and lower the prevalence of opioid induced hyperalgesia. The beneficial contribution provided by nonpharmacologic analgesics should not be overlooked. Many nonpharmacologic analgesic techniques were spawned from Eastern medicine practices and have yet to gain wide acceptance in the Western medical world. However, it is a burgeoning component of alternative medicine, becoming quite popular with patients. The largest impediments to the incorporation of these techniques in the field of pain management include unfamiliarity, production pressure, and lack of well-developed studies to prove their validity. Unfortunately, because of the nature of many of these interventions, standard Western study models are often difficult to design. Holistic medicine is one of the uniting themes throughout a large proportion of the proposed mechanisms for many of today’s most popular nontraditional, nonpharmacologic anal-

gesics. It is a concept that focuses on the patient as the sum of his or her parts. All of the different parts of the body, including the mind, are interconnected. Pathology involving one part of the body, consequently, will affect other parts of the body. Therefore, to properly treat a patient, one must view the patient as a complex milieu. No form of analgesia illustrates this concept better than the practice of acupuncture. Beyond the concept of holistic medicine, the fields of acupuncture, acupressure, moxibustion, cupping, transcutaneous electrical nerve stimulation (TENS), and percutaneous electrical nerve stimulation (PENS) (electroacupuncture) have additional similarities. Although acupuncture, acupressure, and moxibustion all developed from ancient, Eastern Asian folk medicine practices; TENS and PENS had a more Western development with its early progenitors found in practices dating back to ancient Grecian times. The underpinning that connects all of these therapies involves the use of subnoxious to noxious stimuli at discrete locations to produce counter irritation and a state of heightened analgesia. AC U P U N C T U R E

Acupuncture was probably first used more than 3000–4000 years ago. The Huang Di Nei Jing (The Yellow Emperor’s Classic of Internal Medicine), initially compiled approximately 400–100 BC, is one of the earliest texts to describe the technique of acupuncture.6,7 Since its inception, it has grown in popularity with more than 10 million treatments annually in the United

10 1.3 2.9 From A Friend Or Relative

3.8

Prescriptions From One Doctor 4.8

Bought From A Friend Or Relative Bought From A Drug Dealer 53

10.6

Took From A Friend Or Relative Acquired In Another Way Prescriptions From More Than One Doctor Unknown Source

12.7

Figure 24.1: Percentages of reported method of acquiring prescription pain medicines for nonmedical use in the past year for 18- to 25-year-olds.

Nonpharmacological Approaches for Acute Pain Management

393

Figure 24.2a: Acupuncture meridians and areas of therapeutic effect for the torso (adapted with permission from Shmuel Halevi).

States.8 The modern-day embracement of this practice appears to owe thanks to the governmental support, it received under the regime of Mao Zedong in the late 1940s and early 1950s. The practice spread in earnest to Western countries approximately 20 years later, with the growth of US international politics. Its popularity appears to have blossomed out of various reports indicating its effectiveness for surgical anesthesia. Currently, the practice of acupuncture has become so highly regarded, that the Food and Drug Administration (FDA), National Institutes of Health (NIH), and WHO have all given their stamp of approval for its use.6 Acupuncture is based on an overall theme of interconnectedness. The philosophy postulates that one energy source permeates the universe and all things within it. This flow remains in a state of perpetual balance between the forces of yin and yang. The energy flow, or qi, travels along pathways known as

meridians. In fact, the body is composed of a series of meridians interconnecting the various parts of the body and in continuance with the rest of the universe. Fourteen traditional meridians have been described along with more than 360 specific acupuncture points. If any obstruction should occur along one of the body’s meridians, the qi will no longer flow and pathology will develop. (Figures 24.2[a] and 24.2[b] illustrate meridians and areas of treatment for the torso and head.) Various acupuncture points between these meridians exist on the body, and it is here that the application of needles has its effect. Stimulation of these points is achieved through continual or periodic twirling or flicking of the needles to produce afferent stimuli. The acupuncture points are stimulated to relieve the blockage obstructing the flow of qi through the body. Once this is achieved, balance is returned, and symptoms subsequently resolve.6,8 Acupuncturists verify accurate placement of needles

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Figure 24.2b: Meridians of the face and neck (adapted with permission from Shmuel Halevi).

by the presence of cutaneous hyperemia (de qi phenomenon), which is believed to be mediated by local and humorally released mediators (Figure 24.3). From its early introduction into Western medicine, clinical researchers have found it difficult to comprehend the mystical nature of acupuncture and have sought to prove or disprove the validity of this technique. Fortunately, the situation has been improved through the keen interest of the Western medical community. Various acupuncture enthusiasts have attempted to explain its mechanism of action; however, only a few of these proposals appear to have withstood the test of time. In 1965, Melzack and Wall introduced the gate control theory, and it was subsequently used to explain a possible mechanism for acupuncture’s analgesic qualities.9 According to their theory, noxious stimulation of A-␤ sensory fibers sends afferent impulses to the dorsal horn of the spinal cord that inhibit the transmission of pain impulses along the smaller A-␦ and C fibers. This theory, along with others, proposed that neural pathways instead of mysterious meridians were involved. This then provided the necessary scientific basis to encourage greater acceptance of acupuncture in the Western world.

Building on this theoretical base, more recent studies have started to explore the neurohumoral contributions of acupuncture. Based on the observation that analgesia produced by acupuncture has a slow onset that outlasts the period of stimulation, humoral mechanisms have been proposed. Early studies in animals, and later in humans, using opiate antagonists have clearly provided evidence to support the hypothesis that acupuncture is at least partially attributable to the release of endogenous opioids.10–12 Mayer’s team explored the effectiveness of acupuncture after exposure to naloxone, an opioid-specific antagonist. Although their subjects experienced approximately 27% improvement in their pain threshold, these effects were virtually negated after administration of naloxone.13 Elevation of ␤-endorphins were also noted in a cohort of males undergoing major abdominal surgery. The results were noted after only 5 minutes post stimulation, but it is somewhat difficult to ascribe them to only acupuncture therapy.14 Unfortunately, the researcher had exposed the treatment group to both acupuncture and TENS; however, most experts believe these two forms of counter irritation likely have similar mechanisms.

Nonpharmacological Approaches for Acute Pain Management

Figure 24.3: Example of the de qi phenomenon, a hyperemic reaction used by acupuncturists to verify accurate placement of needles.

Other investigators have also remarked on possible endorphin-related effects of acupuncture; however, this research has not been without its detractors. Apparently, some researchers have found no correlation between acupuncture therapy and the levels of certain endogenous opioids. Tempfer et al15 found in their study, of 80 matched prenatal females, no significant increase in ␤-endorphin levels relative to controls despite the reduction in labor duration. Although their study supports the use of acupuncture during labor, the mechanism by which it works is brought into question. It would seem difficult to ignore the possible contribution of endogenous opioids, because tolerance and opioid antagonism have both been reported with the use of acupuncture. However, it is difficult to make this assumption in light of published findings to the contrary. It may simply be because of the methodology of studies performed or, more likely, it is a mystery that has yet to be fully uncovered. More research continues to explore the possibility that other endogenous opioids or neurotransmitters may be involved in the analgesic response to acupuncture therapy. Some studies have postulated highly complex interaction between numerous central nervous system (CNS) pathways and various neural and humoral transmitters. One recommended review article of such studies published in 1987 attempts to dissect through the nearly insurmountable literature on this topic. After careful review, one can surmise that numerous CNS loci are linked to acupuncture-induced analgesia and that a number of various endorphins (met-enkephalin, dynorphins, ␤-endorphins, etc) and neurotransmitters (serotonin and norepinephrine) serve as signals between these systems.12

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Recent advancements in brain imaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have led to a deeper exploration into the possible mechanisms at work in acupuncture-induced analgesia. Multiple studies have identified purported complex neural systems involved in acupuncture analgesia. These studies have implicated areas such as the hypothalamus, cerebellar vermis, arcuate cingular cortex (ACC), prefrontal cortex, periaqueductal grey, hippocampus, and somatosensory areas I and II as being involved. Although it is recognized that placebo intervention may stimulate some of these brain regions, the degree of stimulation and locale specificity does differ.16,17 Although many researchers have proposed different tantalizing explanations for acupuncture’s mechanism, no definitive conclusion has yet been made. The mechanism is likely a combination of the aforementioned pathways. Recently, a more eclectic and unified theory on acupuncture’s mechanism has been proposed. The noxious stimulus of needles stimulates type I, II, and A-␦ afferent nerves, whose impulses reach the anterolateral tract of the spinal cord, producing an increased release of enkephalins and dynorphins. These endogenous opioids then block the ascension of additional pain signals along the spinothalamic tract. Furthermore, acupuncture needles also activate descending inhibitory pathways via increased activity of both norepinephrine and serotonin. Finally, acupuncture stimulates the pituitary-hypothalamic complex, leading to an increased release of ␤-endorphins.6 It is likely a complex interplay of neural and humoral mechanisms that produce the analgesic properties of acupuncture therapy. NIH, WHO, and the FDA have endorsed, regulated, and permitted compensation for the practice of acupuncture for certain maladies. However, this path to acceptance has not been unhindered. Unfortunately, the plethora of studies performed, to date, have uncovered many conflicting results and conclusions. According to some authors, this is because of a placebo effect or the difficulty in designing appropriate studies to adequately test acupuncture’s proposed analgesic properties. Nevertheless, today acupuncture is regarded as having greater analgesic effects than can be accounted for by placebo.10 Some authors even account for the benefits of placebo effect, while clearly showing an improvement on placebo analgesic effect with the inclusion of acupuncture.11 These results find continuing support with more recent studies using PET and fMRI to identify significant differences between the central neural pathways stimulated or inhibited by acupuncture in comparison to sham acupuncture.16,17 Undoubtedly, this is an area of research that will provide further elucidation of not only the efficacy of acupuncture but also its etiology. Acupuncture has found its greatest support in the treatment of both acute and chronic pain syndromes, yet its application in postoperative analgesia has yet to be fully embraced. Some small advances have been made with the NIH Consensus Development Panel’s (NIHCDP) support for the clinical efficacy of acupuncture for the relief of postoperative dental pain.18 Only recently, the clinical practice of postoperative acupuncture analgesia yielded quality research to support its use. AC U P U N C T U R E F O R P O S TO P E R AT I V E PA I N

A well-designed clinical trial by Kotani and colleagues19 evaluated the effectiveness of acupuncture for postoperative pain. This

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Morphine (mg)

35 30 25 Acupunture

20 15

No Acupunture

10 5 0 1

2 3 4 Post-Operative Days Figure 24.4: Postoperative daily consumption of morphine in patients after upper abdominal surgery. Only days 2 through 4 were deemed statistically significant. (Adapted with permission from Kotani et al, 2001.)19

randomized double-blinded controlled trial used both subjective and objective end points to elucidate the effectiveness of acupuncture in the relief of pain. It explored the use of acupuncture versus sham/control for postoperative analgesia in patients undergoing lower and upper abdominal surgery. The control group was designed to prevent the common bias produced by the placebo effect, as the needles were positioned, but never inserted in the control group. All patients received standardized anesthesia as well as identical postoperative analgesic orders. Although initial pain ratings were similar on postop day one, a significant improvement over the control group was noted on day two in the acupuncture group. Moreover, the consumption of morphine analgesia postoperatively was reduced by 50% in the acupuncture group on days 1–419 (Figures 24.4 and 24.5). Their objective measurements of plasma cortisol and epinephrine concentrations revealed a greater increase in the control group relative to the treatment group. These studies provide both strong subjective and objective data for the effectiveness of acupuncture in postoperative pain control. A common theme found in many acupuncture analgesia trials is a lack of improvement in verbal or visual pain intensity scores. Too often, when used as sole end points, these results can be misleading. When taken together with pharmacologic analgesic consumption, an obvious trend is seen. This is no more clearly illustrated than in the work by Lao et al20 in study published in 1999 that showed, despite insignificant differences in subjective

pain reporting, there was a very significant improvement in analgesic consumption, time to first pain medication request, and duration of pain-free period among the acupuncture group. Furthermore, they compared acupuncture therapy to sham acupuncture, which did not require the insertion of needles. The results, of Lao’s work, were recently echoed in an article published by Usichenko and colleagues in the Canadian Medical Association Journal in early 2007. The study involved a much larger sample of patients using acupuncture and noninvasive sham acupuncture. Once again, the results showed that analgesic medication consumption was lower in acupuncture patients, despite no difference in patient reported pain scores.21 Another important aspect of both of these clinical trials was the fact that both employed a certified, licensed acupuncturist, which unfortunately has been an overlooked variable in earlier studies. These two articles helped to eliminate the confounder that any noxious counterstimulus, regardless of its physical location, can produce an analgesic-like effect. Acupuncture, unlike some of the other modalities of nonpharmacologic analgesia discussed in this chapter, has succeeded in garnering enough attention to stimulate rigorous investigation into its effectiveness and physiologic basis. Fortunately, this interest has translated into significant evidence to support acupuncture’s postoperative analgesic properties. Similar interest appears to be producing resurgence in other forms of nonpharmacologic analgesia as well.

Morphine (mg)

35 30 25 Acupunture

20 15

No Acupunture

10 5 0 1

2

3

4

Post-Operative Days Figure 24.5: Postoperative daily consumption of morphine in patients after lower abdominal surgery. Only days 2 through 4 were deemed statistically significant. (Adapted with permission from Kotani et al, 2001.)19

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Figure 24.6: Two examples of commercially available and approved TENS devices.

T R A N S C U TA N E O U S E L E C T R I C A L N E RV E S T I M U L AT I O N

TENS and PENS are two therapeutic modalities similar to acupuncture that have been receiving considerably more interest over recent years. As mentioned earlier in this chapter, these modalities were likely borne out of ancient Greek medicinal practices. However, they appear to have matured along with acupuncture in Eastern medical practices. Both techniques are based on the practice of counter-irritation and probably have similar if not identical mechanisms. A large number of approved TENS devices are available on the market, with many different capabilities. Two representative units are displayed in Figure 24.6. The units come in a variety of shapes/sizes and with buttons/switches to adjust stimulation parameters. All include a pulse generator, an amplifier, and electrodes. The pulse generator/amplifier is about the size of a small radio and generally comes with a carrying case that can be worn on a belt. The signal produced by the pulse generator can be manually amplified to overcome the impedance among the electrodes, subcutaneous tissues, and peripheral nerves. Therapeutic effectiveness is individualized by the patient and practitioner by adjusting the amplitude of the current from 0 to 50 mA. Other variables that influence efficacy include the pulse width (generally 50–250 ␮sec) and frequency or number of impulses per second (hertz). Frequencies greater than 100 Hz are perceived as “buzzlike” and most patients prefer rates of 30–60 Hz. In acupuncture-like TENS, patients generally prefer higher amplitude/low frequency (1–2 Hz), which is perceived as a “ticking” stimulus. Investigation into the etiology of TENS-induced counterirritation seems to have progressed along a tract parallel to that of acupuncture. Early studies focused on the contribution of endogenous on TENS- and PENS-mediated analgesia. Studies by both Pomeranz and Chiu11 and Mayer et al10 clearly demonstrate the analgesic reversing effect of naloxone on animals and humans receiving electroacupuncture (EA).10,11 In fact, recent literature shows the ability of naloxone to cancel the inhibitory effect of electroaccupunture on sympathetic cardiovascular reflexes, as well.22,23 Objective results, such as increased levels of endorphins in cerebral spinal fluid of subjects exposed to low-frequency EA, have been reported.22 Given the quality of these results, it is difficult to rule out the role of endogenous opioids in electrical counter-irritation techniques.

Investigators began to theorize early that more than one mechanism could be involved in the analgesia produced by electrical counter-irritation. By using other neural and humoral transmitter inhibitors, researchers have shown that other substances are involved in the analgesic properties of PENS and TENS. Serotonin is one such hormone. It has been implicated in the development of analgesia with the use of high-frequency electroacupuncture. The reversal of EA’s analgesic effect by parachlorophenylalanine and not naloxone gives the impression that high-frequency EA and low-frequency EA may have somewhat different mechanisms.24,25 A few more recent studies appear to confirm this assertion. Naloxone-reversible analgesia is seen in both high- and low-frequency EA. However, the reversibility appears to be complete only in the low-frequency group, whereas the high-frequency group undergoes only partial reversibility.25 Further research may have even implicated the specific opiate receptors involved in both low- and highfrequency TENS. Animals studies focusing on the ventral rostral medulla, an area of the brain believed to contain a dense supply of opiate receptors, have shown some fascinating results in regard to both ␮- and ␦-opiate receptors. Through the use of naltrindole, a ␦2 -receptor antagonist, and naloxone, researchers are believed to have found a predominant role for ␦2 -opiate receptors with the use of high-frequency TENS. Low-frequency TENS, once again, appears to be mediated through ␮-receptors.26 Enough evidence currently exists to produce a fairly persuasive argument for supraspinal endogenous opiate activity as at least one of the mechanisms of electrical counter-irritation therapies. However, a fair number of studies do raise the question as to what the other mechanisms might be. A recent randomized controlled trial using both acupointspecific locations as well as remote dermatomes provided positive results with only the classical acupuncture points. The authors claim this clearly indicates that production of endogenous opioids cannot be the only mechanism by which percutaneous neuromodulation therapy (PNT) operates. Their presumption is based on the belief that endogenous opiates will be released by any noxious stimulus regardless of its location on the human body. Instead, they postulate roles for direct spinal pain-modulating pathways, neural gating mechanisms, and even placebo responses. On the basis of this trial, one may also conclude not only that the frequency may play a critical role in PNT analgesia, but also that the physical location of the applied

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Throracotomy Gastrectomy Rectal surgery L4, crest of ilium

Hysterectomy

Figure 24.7: TENS electrode pad placement for several types of surgical incisions. Electrodes are generally applied in the operating room by the surgeon or anesthesiologist on completion of the procedure. The electrodes are placed parallel to incision, approximately 2 cm from the edge of the wound, and covered with sterile dressing. (McCaffery M, Beebe A. Pain: a clinical manual for nursing practice. St Louis, MO: Mosby; 1989.)

stimulus is also critical for its effectiveness.27 The only reality one may be certain of, in regard to the mechanism of electrically applied counterirritant analgesia, is that a final story has yet to be written. Undoubtedly, additional studies will continue to elucidate the mechanism of this analgesic therapy and it will likely be a composite of many, if not all, of the aforementioned proposals. The efficacy of electrical counter-irritation as a postoperative analgesic modality has, like its cousin, only recently begun to receive support from the Western medical world through the development of well-designed clinical studies. For optimal effectiveness, stimulating electrodes should be closely applied parallel to the surgical incision (Figure 24.7). Many studies clearly report significant improvement in analgesia through the reduction of pharmacologic analgesic requirements28–32 (Figure 24.8). Reductions of up to 61% in morphine requirements have been recorded in some trials.28 In fact, significant differences have been seen in total opiate consumption as well as time to first analgesic request.28,29 One study found that the use of TENS lengthens the time of analgesic request from 38 ± 18 minutes to 581 ± 86 minutes after video-assisted thoracoscopy procedures29 (Table 24.2).

Interestingly, either the effect on subjective patient-reported pain scores were not end points in some of these studies or no significant benefit was observed. As previously mentioned, if patients report similar levels of pain relief, yet their pharmacologic analgesic consumption differs, then one may conclude a significant effect has taken place. Some researchers, however, further stipulate that the level of relief seen with either pharmacologic or nonpharmacologic means must be significantly different to that of a strict noninterventional control group. Constructing trials with this parameter in mind is somewhat impractical, as noninterventional control groups are commonly considered unethical. A few authors further refine their outcomes to indicate that the therapeutic effect of TENS and PENS may occur only in specific subsets of postoperative patients. It has been asserted that only patients suffering from either mild or moderate levels of discomfort and pain may receive significant relief through the use of electrical counterirritation therapies.29 A growing amount of evidence suggests that TENS and PENS are useful, yet underappreciated, forms of analgesia. Their acceptance has been seen in a wide array of chronic painrelated maladies, but they have yet to achieve a foothold in the

Minutes

200 150 Placebo

100

TENS

50 0 Muscle Sparing Thoracotomy

Costotomy

Sternotomy

Procedure Figure 24.8: Improved analgesic effects as indicated by lengthened time to first postoperative analgesic request (adapted with permission from Benedetti et al 1997).29

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Table 24.2: Significant Improvements in PCA Demands and Morphine Consumption in Both High and Low Frequency TENS Compared with Controlsa Control Group Time to first postoperative dose of pethidine (minutes) PCA demands in the first 24 hours 1–8 hours 8–16 hours 16–24 hours Total dosage in 24 hours Morphine delivered (mg) 1–8 hours 8–16 hours 16–24 hours Total morphine in 24 hours a

Sham EA

Low-Frequency EA

High-Frequency EA 28.1 ± 13.8

10.6 ± 5.9

18.0 ± 7.9

27.9 ± 12.3

9.0 ± 3.6 8.2 ± 5.3 3.2 ± 2.4 20.5 ± 9.2

7.0 ± 3.6 5.8 ± 3.8 3.3 ± 2.1 16.1 ± 7.4

5.1 ± 4.0 4.0 ± 2.6 2.6 ± 2.1 11.7 ± 7.1

16.1 ± 7.1 15.5 ± 9.4 6.5 ± 4.8 38.1 ± 16.0

12.9 ± 6.6 10.8 ± 7.7 6.6 ± 4.1 30.2 ± 14.4

9.2 ± 7.1 7.6 ± 5.4 5.0 ± 4.2 21.8 ± 14.7

3.3 ± 3.2 2.8 ± 2.1 1.8 ± 1.6 7.9 ± 5.9 6.1 ± 5.9 5.4 ± 3.8 3.5 ± 3.2 15.0 ± 10.7

Adapted with permission from Lin et al (2002).28

realm of postoperative analgesia. Their efficacy as an adjunct to pharmacologic medicines has been shown after a wide range of operative situations, from thoracic surgery to gynecological procedures.28,32 Their relative absence of any significant side-effect profile further strengthens the argument for their inclusion in appropriately selected populations of postoperative patients. Moreover, the usage of TENS and PENS therapies may enable practitioners to decrease their reliance on pharmacologic agents, thereby reducing the subsequent side effects/risks of those medicines. With a thorough review of the literature, one is quickly confronted with various parameters that may affect the quality of analgesia provided by electrically induced counterirritation therapies. Amplitude and frequency of the electrical stimulus, location of the applied contacts, duration of therapy, temporal onset relative to surgical procedure, surgical procedure performed, number of interventions, level of expertise of the practitioner, and patient demographic, seem to all play an integral role in the success of not only TENS and PENS but also acupuncture. These variables undoubtedly create hurdles for researchers to overcome in the design of their clinical trials. However, in controlling for and standardizing these variables we will be able to develop a better model to support the usage of these therapies for the treatment of acute, chronic, and postoperative pain.

M AG N E T I S M

Magnetic therapy is a burgeoning business in the field of analgesia. It has generated a lot of public interest with annual sales in the billions of dollars.33 It has been postulated that all materials organic or inorganic possess a potential to be affected by magnetic forces. The very nature of atomic structure with its balance of positive and negative forces makes magnetic therapy a very intriguing proposition. After all, if animals are capable of using electromagnetic fields as means of orientation and navigation, is it not possible that magnetic fields may be involved in other areas of life? 34 Some researchers ascribe potential opioid pathway modulation to the use of magnetic field therapy. Unfortunately, the literature has yet to bear any conclusive evidence of analgesic properties of this type of therapy in humans. Application of magnet therapy is depicted in Figure 24.9. As with many other nonpharmacologic antinociceptive techniques, many variations of magnetic therapy exist. In basic terms, magnetic therapy may be applied in either a static or dynamic fashion. These terms describe the use of solid magnets and exposure to magnetic fields, respectively. Furthermore, the location of the applied magnets, the duration of contact, and their strength may affect their efficacy. Magnetic fields also may vary in their frequency, orientation, and duration.

Figure 24.9: Examples of static magnet application via wraps to the shoulder and lower back.

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A recent randomized double blinded study reported little benefit in the use of static magnet therapy in the postoperative population. It utilized solid magnets placed around incisional sites for 2 hours postoperatively with the outcome measures of verbal pain scale scores and opioid requirement. Their study revealed no benefit in either outcome relative to the sham control group.33 Unfortunately, the availability of additional credible RCTs using static magnetic therapy are minimal at best. Our literature search did locate numerous studies on the analgesic/antinociceptive effect of magnetic field therapy. However, articles pertaining to the use of magnetic fields in humans are lacking, although some of the initial studies are promising. Initial trials in this area incorporated the use of relatively simple forms of magnetic field application. Recent studies have begun to explore the effect of much more complex magnetic field patterns and their effect on living subjects. Martin et al35 investigated the effect of complex magnetic burst field application on electrical and thermal noxious stimuli in rats. The results of their trial showed that after 30 minutes of exposure to burst field magnetic therapy that a level of analgesia equivalent to 4 mg/kg of morphine was produced.35 Moreover, the administration of naloxone to their test subjects appeared to abolish this improvement in latency duration. Therefore, they concluded that the use of magnetic fields was associated with an analgesic response, which is most likely mediated, the endogenous endorphin pathways. Whether this form of intervention may be suitable for humans and has any sustainability has yet to be adequately explored. A more recent study36 explored the effect of low-frequency magnetic fields on tail flick latency periods with the additional outcome measure of endorphin, substance P, and serotonin levels in the brain. Another unique feature of the study is the use of continuous low-frequency magnetic therapy over a period of 14 days. Their findings did reveal a positive effect on tail flick latencies of approximately 5 seconds, but only on days 3 and 4. The effect did not carry over the entire 14-day period. Elevated levels of ␤-endorphins, serotonin, and substance P were also noted.36 Their data appear to provide some validity to the analgesic effects of magnetic therapy. In addition, it also seems to indicate a more complex integrated mechanism for this proposed form of analgesia, resembling that of the other forms of nonpharmacologic analgesia. Magnetic field therapy, although fascinating, has not yet matured to the point where it can be actively supported as a modality of postoperative analgesia. Some of the aforementioned studies do indicate a promising future for this field; however, not enough conclusive evidence has been produced. Until the appropriate studies in humans have been performed, this form of therapy will remain investigational. Moreover, a practical, clinical application of this therapy appears to be difficult to implement. T H E R A P E U T I C TO U C H A N D M A S S AG E

Massage, osteopathic manipulations, chiropractic manipulations, and therapeutic touch (TT) are some of the various physical activities believed to be capable of providing significant pain relief. Each of these techniques involves human to human contact that may provide physical stimulation or relaxation as well as psychological benefits not often described in Western medical literature. Such qualities may attest to the usefulness of these therapies or raise a degree of suspicion regarding their benefit

over placebo therapies. None of these therapies illustrates this point any more than the field of therapeutic touch. Therapeutic touch is a practice sometimes mistakenly referred to as the laying of hands, used to achieve a heightened state of well-being. Practitioners of therapeutic touch describe it as assessing and redirecting patients’ energy field via the movements of one’s hands across the body as the patient maintains a state of meditation.37 Images of divine intervention and uptempo eulogies often spring forth with just the thought of such lines of therapy. Is there any scientific basis for this line of therapy, or are there any substantial studies to prove the efficacy of these practices? The practice of therapeutic touch was developed in earnest by Kunz and Krieger in 1972. Unlike the religious practice of the laying of hands, no overlying religious context or physical contact is necessarily used. Not unlike ancient Eastern acupuncture, TT is thought by some to be based on the concept of unitary human beings. This theory attempts to describe a series of energy fields that are intertwined with each other between humans and their environment. The practice of therapeutic touch is designed to help regulate the proper ebb and flow of energy between the patient and his or her environment.37 Similarly to acupuncture, any disruption of the natural energy flow between the patient and the environment may produce a painful experience. Some supporters of therapeutic touch have described the experience of pain to be partially potentiated by a negative physiological response to stressful stimuli. The autonomic nervous system reacts to noxious stimuli by producing a fight or flight response that leads to elevations in blood pressure and heart rate as well as generalized skeletal muscle tension. The platform, thus far, seems reasonable. After adequately assessing the energy field by the passing of his hands above the patient, a practitioner then redirects the energy to depleted areas restoring the overall flow. Although the concepts of TT seem to mimic those of other forms of nonpharmacologic analgesia, no detailed scientific explanation has been provided. Obviously, this is a fundamental weakness for this form of therapy to gain acceptance in the Western medical world; however, this does not by any means indicate that it has no beneficial effect. Therapeutic touch simply has not received the level of attention and investigation necessary to conclusively support its use. As to the efficacy of this mode of analgesia, very few clinical trials have been developed to draw strong support in the field of postoperative analgesia. The majority of articles on TT have been simple case reports describing potential positive effects after the use of therapeutic touch. Of the few randomized clinical trials performed, the level of methodological errors is high.38 Understandably, TT would be a difficult practice to standardize, particularly with no detailed mechanism yet elucidated; however, basic study constructs such as standardized anesthesia, acceptable end points, and minimization of other confounders should be achievable. Until adequate and repeatable trials are published, no declaration of acceptance for this form of therapy can be made in the area of postoperative analgesia. Massage therapy is a long-standing practice designed to help alleviate physical and psychological tension, stress, and discomfort. The mechanism behind it has also yet to be elucidated, but some speculate it works through the physical stimulation of afferent receptors to modify either ascending pain transmission or descending inhibitory pain pathways. Its use has become very widespread, and is even incorporated into the sports medicine programs, rehabilitation programs, and various other forms of

Nonpharmacological Approaches for Acute Pain Management

Figure 24.10: Osteopathic manipulation of the back (with permission from Vickers and Zollman 1999).62

occupational therapy. Unfortunately, as a means of postoperative analgesia, massage therapy has yet to yield a substantial collection of supporting studies. During our literature review only a few well-performed clinical trials were unearthed. As with many other nonpharmacologic forms of analgesia, study design is fraught with difficulty in providing a suitable control group. If one uses no intervention, the possibility of placebo effect can be far too strong of a confounder. Sham interventions are undoubtedly the correct form of control group to choose; however, designing the sham group is extremely difficult. Significant attempts have been made to eliminate the uncertainty that plagues nonstandardized interventions. Using mechanical massage devices instead of human touch helps to ensure that the intervention being studied is uniform between patients. Results of this are fairly convincing, showing significant reductions in not only analgesic consumption but also subjective pain reporting scores. Although these positive findings are most notable during postoperative days 2–5, no significant difference has been found in the duration of hospital stay.39 Whether this form of therapy could be regarded as cost effective in a postoperative setting has not been determined. The results, however, are still intriguing, if only from an academic standpoint. Other studies, unfortunately, contest these results. Some clinical trials have found little to no benefit in the use of massage therapy in the postsurgical setting. A recent, randomized controlled trial exploring the benefits between massage therapy and simple pharmacologic intervention failed to uncover any significant benefits to massage over the short postoperative period.40 Moreover, no alterations in objective measures, such as autonomic vital signs or serum cortisol levels, were detected. The study, however, contained some significant flaws in its design. By failing to incorporate sham controls, the role for a placebo effect cannot be ruled out. Also, these patients began with very low reported pain score levels. Any significant benefit seen with such low baseline scores would be difficult to assess.40 This particular form of therapy may yet become used more as a postoperative analgesic adjunct; however, until sufficient scientific data to warrant its acceptance is provided, it cannot be recommended as such. In fact, until cost-benefit analyses are performed, it is unlikely to be incorporated into common practice, despite any future positive results. Osteopathic manipulation (OMT) is a form of treatment championed by osteopathic medical schools and practitioners

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alike. Once again, osteopathic medicine uses a holistic approach to provide medical therapy for a vast array of ailments. The underlying basis of osteopathic medicine involves the concept of the body as a sum of its parts. A derangement to any of its parts produces a structural abnormality that leads to suffering. Particular focus is placed on the musculoskeletal system, which makes up about two-thirds of the body. Osteopathic physicians (DO) believe that symptoms often develop from underlying musculoskeletal problems that may be relieved through the use of osteopathic manipulative therapy (Figure 24.10). Similar, perhaps, in some ways to massage and chiropractic therapy, osteopathic manipulation utilizes a hands-on technique to apply pressure, stretching, and resistance to joints and muscles. Through these exercises, the DO hopes to alleviate tension and pain to restore the body’s natural function. Critical to the success of OMT is the relief of underlying discomfort and pain. The application of this therapy to postoperative pain has been investigated through the use of randomized, controlled clinical trials. Many studies conclude that manipulations may be used as successful adjuncts to standard pharmacologic analgesics. The development of a surgically amenable illness is often accompanied by the physiological derangements of inflammation, musculoskeletal tension, and heightened responses to pain. These processes are undoubtedly partial justification for the use of preemptive analgesia. Not only should you avoid the development of such conditions after an invasive surgical procedure, but many of these symptoms may exist secondary to the development of the very pathology that requires surgical intervention.41 Consequently, with improved analgesia, rehabilitation will be hastened and hospital stay will subsequently be decreased.42 When comparing the use of OMT to sham treatment, results have shown reduced blood morphine concentrations, indicating a decrease requirement for opiate analgesics among those supplemented with manipulations.41 Results such as these seen in patients after total abdominal hysterectomies are quite impressive. The reason is that objective measures are reported, instead of patient reported use of narcotics, which helps to eliminate reporting bias. Other studies have found success with the use of osteopathic-like practices of pressure friction and stretching techniques for thoracotomy patients who were unable to find satisfactory relief with the use of oral analgesics. The small study of postthoracotomy patients showed reductions in visual analog pain scores from 10 to as little as 2.43 As with trials performed on the use of electrical counterirritation, benefits are seen in reduced reliance on pharmacologic agents. Like TENS/PENS, this does not necessarily translate into significant reductions in subjectively reported pain scales; however, reductions in opioid dose requirements observed with OMT attest to its analgesic benefits. Despite the growing success of this school of medicine, the dearth of literature regarding the use of osteopathic manipulative therapy for postoperative analgesia is surprising. Further studies showing repeatable benefits, performed after different surgical operations and among different demographics, will, of course, provide additional confirmation and support for the use of OMT as a postoperative nonpharmacologic analgesic. HYPNOSIS

Many forms of nonpharmacologic therapy rely on physical contact to produce alterations or to modulate the pain pathway. Other techniques focus on the use of the mind and senses to

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produce a heightened state of analgesia. Hypnosis is loosely defined as an altered state of awareness. This may include a highly suggestible state and an intensely relaxed state of being. Hypnosis may be achieved through both pharmacologic and nonpharmacologic means. The term hypnosis frequently is used in a generic sense without differentiating among various subgroups such as therapeutic suggestion and mental imagery. Hypnosis, mesmerism, therapeutic suggestion, mental imagery, and relaxation techniques have been used to assist in surgical procedures well before the development of the pharmacologically based practice of anesthesia. These techniques, however, have since been relegated as mystical practices that are incapable of matching the effectiveness of modern-day pharmacologic agents. Whether these techniques are difficult to employ, effective only in select populations, or inadequate as sole anesthetic therapies should not deter a capable practitioner from using these methods to augment their patient’s medical therapy. The decision to use any of these techniques should be based solely on the anticipated beneficial effect it may achieve in the patient in question. No consensus currently exists on the possible mechanisms underlying the effects of hypnosis. It is likely a central neurological process involving higher center interpretation of stimuli. In regard to analgesia, it may involve a reinterpretation of a noxious stimulus to no longer be recognized as harmful or it may involve the interference of the transmission of such noxious stimuli to the conscious mind. With the advent of functional imaging techniques such as PET and fMRI, more light is being shed on possible avenues of activity within the brain during hypnosis therapy. Regions of the brain noted to show increased activity during noxious stimulation include both thalami and caudate nuclei. The left insula and anterior cingulate cortex are also implicated through detection of increased cerebral blood flow. Hypnosis appears to affect cerebral blood flow, primarily in the anterior cingulate cortex (ACC). Therefore, it is reasonable to assume that the ACC plays a key role in the analgesic effects seen with hypnosis.44 Furthermore, it has been postulated that this area may be specifically linked to the affective response to painful stimuli. As to whether there are any beneficial effects, with the use of hypnosis therapy, the literature is conflicting at best. Depending on the particular mode of hypnotic therapy used, there are as many studies to indicate positive, as well as negative, results. Presurgical relaxation therapy has been found to provide significant decreases in postoperative analgesic requirements as well as reduced hospitalization.45 However, these results were not replicated in a recent study by Gavin et al. The single blinded randomized controlled trial compared postoperative pain intensity scores and opioid usage after lumbar and cervical spine surgery. They found that morphine dose requirements were in fact higher in the relaxation group.46 Trials involving patients receiving hypnosis are somewhat more promising than those involving relaxation therapy. Unfortunately, study design is less than optimal as many claim that for hypnotherapy to be successful, patients must be susceptible. This often prevents the random allocation of the intervention being studied. Moreover, the nature of the intervention often precludes the ability to create blinded patients. Regardless, a number of well-designed cohort studies have produced good results with the use of hypnosis for control of intraoperative and postoperative analgesia. Hypnosis has been used as a primary anesthetic technique during thyroid and various forms of plastic surgery. In fact, it has been found to be more effective than midazolam/alfentanyl combinations for plastic surgery. One

Belgian study produced results showing a median alfentanyl consumption of 10.2 ␮g/kg/h when hypnosis was used compared to 15.5 ␮g/kg/h without it. The intensity of subjective pain reporting was also notably less in the hypnosis group during, as well as after, surgery.47 Self-induced hypnotic states have also been used during radiologic procedures. Intraoperative requirements for midazolam and fentanyl were reduced by half in the hypnosis treatment group compared to controls.48 A novel study of hypnosis during orthopedic hand surgery also produced complementary results with the use of hypnosis. Using standardized hypnotic scripts, the patients achieved improved analgesia over a 3-day postoperative period. Moreover, the investigatory team measured not only subjective intensity pain scale scores, but also subjective affective pain scale scores. In other words, the patients were asked to qualify their pain intensity in terms of how tolerable that particular level of pain was. The results indicated a more demonstrable improvement in affective pain scores compared to pain intensity scores.49 Such results provide clues that hypnosis may not simply alter nociceptive transmission, but, instead, may affect the way our higher centers interpret the signal. Some proponents indicate that children may be the best demographic in which to employ hypnosis. Given that children are much more suggestible than adults, it is reasonable to assume they may more easily be placed into a state of hypnosis. Although I have not uncovered a comparative study between adult and children populations, the use of hypnosis in children has provided as promising results as those in adults. One recent randomized control trial resulted in decreased pharmacologic analgesic consumption when hypnosis was given preoperatively.50 Unfortunately, conclusions regarding the effectiveness of therapeutic suggestion are, once again, less convincing. While in combination with strict hypnotic therapy, therapeutic suggestion has produced substantial improvements over controls.47 However, these improvements in pain scores and narcotic usage have not necessarily been repeated with the use of only therapeutic suggestion. In fact, multiple well-designed randomized control trials have failed to show any improvement over control groups with the use of therapeutic suggestion.51–53 Therapeutic suggestion comes in two flavors, intraoperative and preoperative. These two forms of interaction rely on different levels of consciousness or memory. It is believed that intraoperative awareness may in some ways be a function of implicit memory. Implicit memory occurs on a subconscious level, which the patient is not aware of during its formation but is able to recall at a later time. Explicit memory is the type of memory with which most of us are familiar. Although the concept of implicit memory has been suggested, no definitive proof has yet been provided to validate its existence. However, some of these studies provide hints of its existence with proper identification of cues related to the suggested material. Despite the questionable capability of the human mind to comprehend intraoperative applied aural stimuli, therapeutic suggestion has not been shown to be of significant benefit in either a preoperative or intraoperative setting.53 Without the use of a hypnotic state, therapeutic suggestion appears to be an insufficient means of analgesia to recommend based on the current literature. MUSIC THERAPY

Another form of therapy, designed to incorporate higher center sensory input to modulate pain perception, is music therapy.

Nonpharmacological Approaches for Acute Pain Management

Music therapy has been widely studied as an adjuvant to the pharmacologic therapy for the treatment of both pain and anxiety. In fact, many authors have theorized that it is music’s effect on anxiety levels that leads to its beneficial effects on pain. Music may provide a useful distraction to help lure a patient away from focusing on his or her pain. It can provide a calming sensation that may help diminish the level of muscular tension a patient experiences, thereby attenuating aggravating factors that would lead to higher levels of pain.54 As mentioned, the studies utilizing this nontraditional, nonpharmacologic form of analgesia have been less than ideal. Only recently has there been a push for more standardization to adequately evaluate the effectiveness of music therapy. Nilsson, et al.55 have attempted to provide some standardization in the type of music therapy provided. Based on studies initially reported by Unestahl in 1970 and White in 2000, their conclusion was that for music therapy to be beneficial, it must produce a sense of relaxation. They propose that this is best achieved by using soft, instrumental melodies with slow flowing rhythms that duplicate a pulse rate of 60–80 beats per minute. This conclusion has been echoed by other authors, who theorize that this form of music stimulates the autonomic production of endorphins by the pituitary gland.56 Yet another study, published in 1999, demonstrated that the usage of binaural beats to produce hemispheric synchronization markedly reduces the fentanyl requirements of patients under general anesthesia.57 Whether these musical parameters are correct remains to be borne out in further studies, as other investigators believe the greatest effect of music on one’s state of mind is achieved through patients’ own musical selection.58,59 It may be that the empowerment given to patients to select their own musical ambience might increase their level of control, therein reducing their level of anxiety. Unfortunately, there is no current consensus on what type of music is best suited to help reduce pain in the postoperative period.55 Regardless, standardization of the musical intervention should be a primary goal of additional studies to ensure that results of any future research may be comparable. With comparable investigations, more weight will be lent to this form of intervention as a useful adjunct in the treatment of postoperative pain. Nilsson, et al.55,60 have also explored other qualities of music therapy, which will undoubtedly help standardize the intervention. Their work on the timing of music therapy has produced results that indicate no difference between the implementation of music intraoperatively or postoperatively. This, of course, relies on acceptance of the concept of implicit memory. In light of their results, it appears that music therapy may not work solely by providing a distracting stimulus. However, music as a nonpharmacologic analgesic does not lose any ground as an effective therapy on this basis; the etiology of its effect is simply brought into question. Overall, many of the studies we reviewed showed significant reductions in either subjective reported pain scale scores and/or reductions in the use of opiates. The use of both subjective and objective outcomes is important in the evaluation of the effectiveness of nontraditional analgesic interventions. Standardization of anesthetic technique and exclusion/inclusion criteria are other areas of study design that give these articles particular robustness. The possible beneficial effects of music therapy far outweigh the cost of implementing such techniques, and with a lack of any adverse effects, it seems reasonable for this form of therapy to be added to any postoperative patients analgesic regimen.

403

Table 24.3: Use of Complementary Medicine Worldwide Gathered from Surveys Taken from 1987 to 1996a

Country

Seeing a Practicioner

Using Any Form of Complementary Treatment

United Kingdom Australia United States Belgium France Netherlands West Germany

10.5% in past year 20% in past year 11% in past year 24% in past year No data 6%–7% in past year 5%–12% in past year

33% ever 46% in past year 34% in past year 66%–75% ever 49% ever 18% ever 20%–30% ever

a

Adapted with permission from Zollman and Vickers (1999).62

C O N C LU S I O N S

We reviewed the most commonly used nontraditional, nonpharmacologic analgesic techniques; however, those discussed are by no means all inclusive. Numerous other nonpharmacologic techniques exist and are in the process of being studied. Undoubtedly, more analgesic therapies will be developed in the future as well. To become accepted as viable medical techniques, each must be shown to produce effective results with equal or less risk relative to current methods of analgesia. These techniques must also be practical and cost-effective to employ. Some of the aforementioned therapies qualify on the basis of these criteria and should be incorporated into daily practice as either monotherapy or as nonpharmacological adjuvants to conventional analgesic therapy. Others have failed to meet sufficient criteria to be recommended for use as common postoperative analgesic remedies. Their current failure, however, does not necessarily mean they cannot one day be refined or shown to be successful adjuncts to a growing armamentarium of nonpharmalogic analgesic treatments. Patient acceptance of nonpharmacologic methods of analgesia appears to be growing far more quickly than the clinicians’ willingness to practice it. A recent prospective study found that various alternative nonpharmacologic techniques for pain management were used by between 13% and almost 60% of patients.61 The British Medical Journal has published a wide array of articles exploring the use of complementary medicine. One such article, using compiled data from other studies published from 1987 to 1996 (Table 24.3), also found the use of complementary medicine to range between 18% and 75%, depending on the geographical setting.62 With the provision of various complementary nonpharmacolog, anxiolytic, and analgesic techniques, patients have been noted to not only utilize them, but also to experience a heightened sense of well-being with a decreased reliance on intravenous opioid use. An apparent divide among the research community, the clinical practice community, and patients appears to exist. Additional research is necessary. However, enough research exists for the limited use of some of these techniques. Yet, most of these techniques have failed to gain widespread acceptance in the Western medical world. With the growing desire among patients to explore the use of nonpharmacologic adjuncts, the medical community should be encouraged to oblige. The provision of

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improved objective and subjective analgesia while reducing the reliance on pharmacologic agents clearly upholds the principle cornerstone of multimodal analgesia.

APPENDIX

TENS Contraindications and Precautions ■

■

■

■

■

■

■

■ ■

Electrodes should not be placed over the carotid sinuses (anywhere on the front of the neck should be avoided). Stimulation in this area can cause hypotension and risk of laryngeal spasm. Electrodes should not be placed over areas that are numb or have altered sensation. There is a risk of skin irritation and sensation signals will not be sent back to the brain. Electrodes should not be placed over bony prominences, broken or irritated skin, varicose veins, or directly over open wounds or recent scars. They should not be placed transcerebrally (on each temple), on the front of the neck (because of the risk of acute vasovagal induced hypotension), or on or near the trigeminal nerve if the patient has a history of herpes zoster. There is a significant risk that TENS will interfere with the action of a cardiac pacemaker if the electrodes are applied above the waist and clearance from a cardiologist is recommended. TENS is safe for use in pacemaker patients who require use of electrodes below the waist. For patients with impaired comprehension and/or who are unable to use the TENS machine, a partner/caregiver may take responsibility following education and instruction in use of TENS. Pregnancy – manufacturers do not recommend use of TENS in pregnancy. Although there is no research to support the claim that TENS could cause miscarriage, it would not be ethical to presume it does not. Advice and approval should be sought from patient’s obstetrician prior to application. Epilepsy – it is unclear whether TENS can induce seizures because of the electrical activity. Patients with epilepsy can have a trial under supervision and if beneficial take TENS home to use when another person is present. The TENS unit should not be activated for long periods, as there is an increased risk of sensitizing skin. The patient should be aware there is a small risk of sensitivity to the electrodes.

REFERENCES 1. Merskey H, Bogduk N, eds. IASP Task Force on Taxonomy: Classification of Chronic Pain. 2nd ed., Seattle, WA: IASP Press; 1994. 2. Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in the united states. Pharmacoepidemiol Drug Saf. 2006;15:618–627. 3. Vickers A, Zollman C. ABC of complementary medicine. the manipulative therapies: Osteopathy and chiropractic. BMJ. 1999;319:1176–1179. 4. The NSDUH report patterns and trends in nonmedical prescription pain reliever use: 2002 to 2005, 2007. 5. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104:570–587.

6. Chernyak GV, Sessler DI. Perioperative acupuncture and related techniques. Anesthesiology. 2005;102:1031–1049; quiz 1077–1078. 7. Lin YC. Perioperative usage of acupuncture. Paediatr Anaesth. 2006;16:231–235. 8. Bueno EA, Mamtani R, Frishman WH. Alternative approaches to the medical management of angina pectoris: Acupuncture, electrical nerve stimulation, and spinal cord stimulation. Heart Dis. 2001;3:236–241. 9. Wall P, Melzack R, eds. Textbook of Pain. Edinburgh: Churchill and Livingstone; 1984. 10. Mayer DJ, Price DD, Rafii A. Antagonism of acupuncture analgesia in man by the narcotic antagonist naloxone. Brain Res. 1977;121:368–372. 11. Pomeranz B, Chiu D. Naloxone blockade of acupuncture analgesia: endorphin implicated. Life Sci. 1976;19:1757–1762. 12. He LF. Involvement of endogenous opioid peptides in acupuncture analgesia. Pain. 1987;31:99–121. 13. Stoelting RK. Opiate receptors and endorphins: Their role in anesthesiology. Anesth Analg. 1980;59:874–880. 14. Kho HG, Kloppenborg PW, van Egmond J. Effects of acupuncture and transcutaneous stimulation analgesia on plasma hormone levels during and after major abdominal surgery. Eur J Anaesthesiol. 1993;10:197–208. 15. Tempfer C, Zeisler H, Heinzl H, Hefler L, Husslein P, Kainz C. Influence of acupuncture on maternal serum levels of interleukin8, prostaglandin F2alpha, and beta-endorphin: A matched pair study. Obstet Gynecol. 1998;92:245–248. 16. Dhond RP, Kettner N, Napadow V. Do the neural correlates of acupuncture and placebo effects differ? Pain. 2007;128:8–12. 17. Shen J. Research on the neurophysiological mechanisms of acupuncture: Review of selected studies and methodological issues. J Altern Complement Med. 2001;7(suppl 1):121–127. 18. Mayer DJ. Acupuncture: an evidence-based review of the clinical literature. Annu Rev Med. 2000;51:49–63. 19. Kotani N, Hashimoto H, Sato Y, et al. Preoperative intradermal acupuncture reduces postoperative pain, nausea and vomiting, analgesic requirement, and sympathoadrenal responses. Anesthesiology. 2001;95:349–356. 20. Lao L, Bergman S, Hamilton GR, Langenberg P, Berman B. Evaluation of acupuncture for pain control after oral surgery: A placebocontrolled trial. Arch Otolaryngol Head Neck Surg. 1999;125:567– 572. 21. Usichenko TI, Lysenyuk VP, Groth MH, Pavlovic D. Detection of ear acupuncture points by measuring the electrical skin resistance in patients before, during and after orthopedic surgery performed under general anesthesia. Acupunct Electrother Res. 2003;28:167– 173. 22. Ho WK, Wen HL. Opioid-like activity in the cerebrospinal fluid of pain patients treated by electroacupuncture. Neuropharmacology. 1989;28:961–966. 23. Chao DM, Shen LL, Tjen-A-Looi S, Pitsillides KF, Li P, Longhurst JC. Naloxone reverses inhibitory effect of electroacupuncture on sympathetic cardiovascular reflex responses. Am J Physiol. 1999;276:2127–2134. 24. Cheng RS, Pomeranz B. Electroacupuncture analgesia could be mediated by at least two pain-relieving mechanisms; endorphin and non-endorphin systems. Life Sci. 1979;25:1957–1962. 25. Lee JH, Beitz AJ. Electroacupuncture modifies the expression of c-fos in the spinal cord induced by noxious stimulation. Brain Res. 1992;577:80–91. 26. Kalra A, Urban MO, Sluka KA. Blockade of opioid receptors in rostral ventral medulla prevents antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS). J Pharmacol Exp Ther. 2001;298:257–263.

Nonpharmacological Approaches for Acute Pain Management 27. White PF, Craig WF, Vakharia AS, Ghoname E, Ahmed HE, Hamza MA. Percutaneous neuromodulation therapy: Does the location of electrical stimulation effect the acute analgesic response? Anesth Analg. 2000;91:949–954. 28. Lin JG, Lo MW, Wen YR, Hsieh CL, Tsai SK, Sun WZ. The effect of high and low frequency electroacupuncture in pain after lower abdominal surgery. Pain. 2002;99:509–514. 29. Benedetti F, Amanzio M, Casadio C, et al. Control of postoperative pain by transcutaneous electrical nerve stimulation after thoracic operations. Ann Thorac Surg. 1997;63:773–776. 30. Bjordal JM, Johnson MI, Ljunggreen AE. Transcutaneous electrical nerve stimulation (TENS) can reduce postoperative analgesic consumption. A meta-analysis with assessment of optimal treatment parameters for postoperative pain. Eur J Pain. 2003;7:181– 188. 31. Gejervall AL, Stener-Victorin E, Moller A, Janson PO, Werner C, Bergh C. Electro-acupuncture versus conventional analgesia: A comparison of pain levels during oocyte aspiration and patients’ experiences of well-being after surgery. Hum Reprod. 2005;20:728–735. 32. Hamza MA, White PF, Ahmed HE, Ghoname EA. Effect of the frequency of transcutaneous electrical nerve stimulation on the postoperative opioid analgesic requirement and recovery profile. Anesthesiology. 1999;91:1232–1238. 33. Cepeda MS, Carr DB, Sarquis T, Miranda N, Garcia RJ, Zarate C. Static magnetic therapy does not decrease pain or opioid requirements: A randomized double-blind trial. Anesth Analg. 2007;104:290–294. 34. Prato FS, Robertson JA, Desjardins D, Hensel J, Thomas AW. Daily repeated magnetic field shielding induces analgesia in CD-1 mice. Bioelectromagnetics. 2005;26:109–117. 35. Martin LJ, Koren SA, Persinger MA. Thermal analgesic effects from weak, complex magnetic fields and pharmacological interactions. Pharmacol Biochem Behav. 2004;78:217–227. 36. Bao X, Shi Y, Huo X, Song T. A possible involvement of betaendorphin, substance P, and serotonin in rat analgesia induced by extremely low frequency magnetic field. Bioelectromagnetics. 2006;27:467–472. 37. Samarel N. Therapeutic touch, dialogue, and women’s experiences in breast cancer surgery. Holist Nurs Pract. 1997;12:62–70. 38. Ramnarine-Singh S. The surgical significance of therapeutic touch. AORN J. 1999;69:358–369. 39. Le Blanc-Louvry I, Costaglioli B, Boulon C, Leroi AM, Ducrotte P. Does mechanical massage of the abdominal wall after colectomy reduce postoperative pain and shorten the duration of ileus? results of a randomized study. J Gastrointest Surg. 2002;6:43–49. 40. Taylor AG, Galper DI, Taylor P, et al. Effects of adjunctive Swedish massage and vibration therapy on short-term postoperative outcomes: A randomized, controlled trial. J Altern Complement Med. 2003;9:77–89. 41. Goldstein FJ, Jeck S, Nicholas AS, Berman MJ, Lerario M. Preoperative intravenous morphine sulfate with postoperative osteopathic manipulative treatment reduces patient analgesic use after total abdominal hysterectomy. J Am Osteopath Assoc. 2005;105:273– 279. 42. Nicholas AS, Oleski SL. Osteopathic manipulative treatment for postoperative pain. J Am Osteopath Assoc. 2002;102:5–8. 43. Hirayama F, Kageyama Y, Urabe N, Senjyu H. The effect of postoperative ataralgesia by manual therapy after pulmonary resection. Man Ther. 2003;8:42–45.

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44. Faymonville ME, Laureys S, Degueldre C, et al. Neural mechanisms of antinociceptive effects of hypnosis. Anesthesiology. 2000;92:1257–1267. 45. Lawlis GF, Selby D, Hinnant D, McCoy CE. Reduction of postoperative pain parameters by presurgical relaxation instructions for spinal pain patients. Spine. 1985;10:649–651. 46. Gavin M, Litt M, Khan A, Onyiuke H, Kozol R. A prospective, randomized trial of cognitive intervention for postoperative pain. Am Surg. 2006;72:414–418. 47. Faymonville ME, Fissette J, Mambourg PH, Roediger L, Joris J, Lamy M. Hypnosis as adjunct therapy in conscious sedation for plastic surgery. Reg Anesth. 1995;20:145–151. 48. Lang EV, Benotsch EG, Fick LJ, et al. Adjunctive nonpharmacological analgesia for invasive medical procedures: A randomised trial. Lancet. 2000;355:1486–1490. 49. Mauer MH, Burnett KF, Ouellette EA, Ironson GH, Dandes HM. Medical hypnosis and orthopedic hand surgery: Pain perception, postoperative recovery, and therapeutic comfort. Int J Clin Exp Hypn. 1999;47:144–161. 50. Lambert SA. The effects of hypnosis/guided imagery on the postoperative course of children. J Dev Behav Pediatr. 1996;17:307– 310. 51. Dawson P, Van Hamel C, Wilkinson D, Warwick P, O’Connor M. Patient-controlled analgesia and intra-operative suggestion. Anaesthesia. 2001;56:65–69. 52. Lebovits AH, Twersky R, McEwan B. Intraoperative therapeutic suggestions in day-case surgery: Are there benefits for postoperative outcome? Br J Anaesth. 1999;82:861–866. 53. Van Der Laan WH, van Leeuwen BL, Sebel PS, Winograd E, Baumann P, Bonke B. Therapeutic suggestion has not effect on postoperative morphine requirements. Anesth Analg. 1996;82:148– 152. 54. Good M, Anderson GC, Stanton-Hicks M, Grass JA, Makii M. Relaxation and music reduce pain after gynecologic surgery. Pain Manag Nurs. 2002;3:61–70. 55. Nilsson U, Rawal N, Enqvist B, Unosson M. Analgesia following music and therapeutic suggestions in the PACU in ambulatory surgery; a randomized controlled trial. Acta Anaesthesiol Scand. 2003;47:278–283. 56. Hatem TP, Lira PI, Mattos SS. The therapeutic effects of music in children following cardiac surgery. J Pediatr (Rio J). 2006;82:186– 192. 57. Kliempt P, Ruta D, Ogston S, Landeck A, Martay K. Hemisphericsynchronisation during anaesthesia: A double-blind randomised trial using audiotapes for intra-operative nociception control. Anaesthesia. 1999;54:769–773. 58. McCaffrey RG, Good M. The lived experience of listening to music while recovering from surgery. J Holist Nurs. 2000;18:378–390. 59. Koch ME, Kain ZN, Ayoub C, Rosenbaum SH. The sedative and analgesic sparing effect of music. Anesthesiology. 1998;89:300–306. 60. Nilsson U, Rawal N, Unestahl LE, Zetterberg C, Unosson M. Improved recovery after music and therapeutic suggestions during general anaesthesia: A double-blind randomised controlled trial. Acta Anaesthesiol Scand. 2001;45:812–817. 61. Tracy S, Dufault M, Kogut S, Martin V, Rossi S, Willey-Temkin C. Translating best practices in nondrug postoperative pain management. Nurs Res. 2006;55:S57–S67. 62. Zollman C, Vickers A. ABC of complementary medicine: users and practitioners of complementary medicine. BMJ. 1999;319:836– 838.

25 Opioid-Related Adverse Effects and Treatment Options Kok-Yuen Ho and Tong J. Gan

Acute pain is common and occurs most often in the immediate postoperative period. Acute nonsurgical pain related to burns injury, trauma, sickle cell crisis, ureteric colic, and acute pancreatitis are also commonly encountered in the hospital. The role of opioids in acute pain management is well established. The high efficacy profile and selectivity of potent opioids provides effective management of severe postsurgical pain, particularly in settings where nonopioid pain relievers are inadequate (refer to Chapter 15, Clinical Application of Epidural Analgesia). In general, opioids share a collection of annoying to serious adverse effects and potentially life-threatening complications (Table 25.1). In general, the higher the dose of opioid administered, the greater the incidence and severity of adverse effects. However, there are interindividual variations and some patients may be exquisitely sensitive to the class in general, whereas others develop more side effects with one particular opioid compared to another. Opioid pharmacotherapy therefore requires careful drug selection and dose titration to achieve a satisfactory balance between analgesia and adverse effects. With greater understanding of their pharmacokinetics and pharmacodynamics, opioids have been administered via different routes to achieve greater efficacy in treating pain (Table 25.2). Consequently, there is also a difference in the type and incidence of adverse effects associated with the various routes of administration.

Morphine causes myocardial depression by producing bradycardia, probably by stimulation of the vagal nuclei in the medulla. It also acts directly on the sinoatrial node and atrioventricular node to slow conduction of cardiac impulses. Morphine indirectly produces hypotension through the release of histamine.2 The severity and incidence of morphineinduced histamine release is variable among individuals. Avoiding rapid administration of morphine, maintaining patient in a supine position, and optimizing intravascular volume can attenuate the reduction in blood pressure secondary to histamine release. Pretreatment with H1 and H2 histamine receptor antagonists is also protective against the hemodynamic changes seen with morphine administration, even though histamine release is unaffected.3 The administration of fentanyl or sufentanil is not associated with histamine release. With opioid doses commonly used for pain management, hypotension is uncommon. Hypotension after opioid administration is more likely in patients with high sympathetic tone, for example, patients in pain or with poor cardiac function. It is also seen in patients with hypovolemia. R E S P I R ATO RY A DV E R S E E F F E C T S

Opioids affect the respiratory system in a dose-dependent manner. Direct action on ␮-receptors in the brainstem produces depression of ventilation.4 Decrease in respiratory rate and tidal volume are common with standard therapeutic doses. Opioids are also known to depress the ventilatory response to hypercapnia, leading to a raised resting end tidal carbon dioxide level.5,6 Opioid-mediated respiratory depression has been linked to central nervous system (CNS) penetration of drug, binding to ␮1 -receptors in the brainstem, and inhibition of cells in the pneumotaxic and apneustic centers. Lipophilic opioids rapidly penetrate CNS and inhibit respiratory drive within seconds to minutes following administration. In general, peak CNS levels of lipophilic opioids and respiratory depressant effects correlate with peak plasma concentrations. In contrast, morphine has difficulty traversing the blood-brain barrier, and its entrance

C A R D I OVA S C U L A R A DV E R S E E F F E C T S

In general, opioids, particularly rapid-acting lipophilic agents, exhibit vagomimetic effects that tend to slow heart rate. The major exception to this rule is meperidine, which, because of intrinsic antimuscarinic properties, can increase resting heart rate. Administration of large doses of morphine induces a reduction in sympathetic nervous system tone.1 This results in venous pooling with a consequent decrease in venous return, cardiac output, and blood pressure. Patients are generally asymptomatic when lying supine in bed, but present with postural hypotension and/or syncope when asked to stand. 406

Opioid-Related Adverse Effects and Treatment Options

Table 25.1: Classification of Opioid-Related Adverse Effects

407

Table 25.2: Routes of Opioid Administration Oral (cost-effective, least dose efficient)

Cardiovascular

Respiratory

Bradycardia Hypotension Myocardial depression

Sublingual and buccal (rapid onset)

Decrease respiratory rate and tidal volume Respiratory depression/arrest

Subcutaneous (more rapid onset than oral, less painful)

Neurological

Excessive sedation Delirium/euphoria

Gastrointestinal

Delayed gastric emptying Nausea and vomiting Constipation/ileus

Genitourinary Dermatological

Urinary retention Pruritus and anaphylaxis

into, and exit from, the brain are delayed. As a result of this prolonged CNS transfer half-life, morphine’s respiratory depressant effects may persist for many minutes to hours, despite significant declines in plasma concentrations.5,6 Risk factors for opioidmediated respiratory depression, including patient, caregiver, and drug-related variables, are outlined in Table 25.3. Neuraxial administration of opioids has the same, or possibly, greater risk of respiratory depression. A multicenter trial involving 14 000 patients showed that the incidence of respiratory depression was between 0.25% and 0.40% after epidural morphine, with all occurrences within 12 hours of administration.7 Intrathecal morphine administration was shown to produce a diminished ventilatory response to hypoxia of the same magnitude as an equianalgesic dose of intravenous morphine, but the duration of respiratory depressant risk is longer lasting (more than 8 hours).8 Risk factors for neuraxial opioidinduced respiratory depression are similar to that outlined for parenteral and oral dosing. Additional risk factors with neuraxial doses of morphine include prolonged Trendelenberg positioning following intrathecal dosing and epidural administration via high thoracic catheters.7 Opioid-induced respiratory depression can be blunted with amphetamines and mixed agonist antagonists such as nalbuphine and reversed with opioid antagonists, including naloxone or naltrexone. The dose of naloxone should be titrated according to the patient’s response. Initially, intravenous naloxone in increments of 0.1–0.2 mg can be administered every 3–5 minutes, as needed, until return of adequate alertness or respiratory rate. Repeat doses of naloxone or naloxone infusions may be required as the duration of action of the opioid outlasts that of the antagonist. Prophylactic infusion of naloxone 40–100 ␮g/h may also be employed to prevent the worst aspects of respiratory depression in high-risk patients. Excessive doses of naloxone (ie, greater than 800 ␮g) may reverse opioidmediated analgesia. High doses and rapid reversal may also precipitate rebound hypertension, tachycardia, pulmonary edema, nausea, and vomiting. If naloxone does not improve the level of consciousness, the caregiver should assume that the patient is markedly hypercarbic and acidotic and initiate ventilatory resuscitation. A continuous intravenous infusion of naloxone

Rectal (greater dose efficiency than oral) Transdermal (delayed onset, not for acute pain) Intramuscular (can be painful) Intravenous Bolus dosing Continuous infusion Patient-controlled analgesia (PCA) Inhalational Nasal (in development) Pulmonary (in development) Neuraxial Epidural Intrathecal

can then be used. Additional discussion regarding the respiratory adverse effects of opioids may be found in Chapter 15. G A S T RO I N T E S T I NA L A DV E R S E E F F E C T S

Opioid-induced bowel dysfunction is a term used to describe a constellation of symptoms including delayed gastric emptying, increased gastroesophageal reflux, bloating, nausea, vomiting, and constipation.9 Bowel dysfunction can occur after surgery, especially when surgery involves manipulation or resection of the gut. This is further worsened with the use of opioids for analgesia. In patients taking opioids for chronic nonmalignant pain, the incidence of bowel dysfunction is as high as 40%.10 ␮-receptors are found in the central and peripheral nervous system. The effect of opioids on the gastrointestinal (GI) tract is mediated centrally as well as peripherally because both parenteral and epidural morphine influence GI motility.11 Opioids decrease the peristaltic contractions of the small and large intestines thereby allowing greater absorption of water from the intestinal contents and inhibiting GI motility.12 Opioids also play a direct role in decreasing GI secretions.13 With a longer intestinal transit time, there is formation of hard dry stools as well as constipation. There is evidence that ␮-receptors are found in the myenteric and submucosal plexi of the small and large intestines and that opioid-induced bowel dysfunction is peripherally mediated.14 Peripherally acting opioids, such as loperamide, that do not cross the blood-brain barrier have been demonstrated to increase GI transit time.15 Gastric emptying is similarly delayed and this is mediated through the vagus nerve.16 The tone of the pyloric sphincter, ileocecal valve, and anal sphincter are also increased. With a delay in gastric emptying, the risk of aspiration is greater. Intravenous metoclopramide has been shown to be an effective drug for improving gastric emptying in patients receiving opioid therapy.17

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Table 25.3: Risk Factors for Opioid-Mediated Respiratory Depression

Table 25.4: Medications for Treating Opioid-Induced Constipation

Excessive dose Extremes of age Pulmonary disease Morbid obesity Sleep apnea Renal failure (accumulation of active metabolites) Hepatic failure (accumulation of free drug) Coadministration of other central acting agents (benzodiazepines, antihistamines, anticholinergics) Alterations in the blood-brain barrier (tumor, infection, pharmacological agents) Coadministration of parenteral and neuraxial opioids Improper use of patient-controlled analgesia (“proxy dosing,” dose misprogramming, and use of basal infusions) Genetic sensitivity (polymorphisms of ␮-receptors, CSF transporter molecules, catechol-O-methyltransferase, and metabolic enzymes)

Fiber bulking agents Methylcellulose PO 1–3 times per day Psyllium PO 15–60 g/d Stool softeners Docusate sodium PO 100–400 mg 1–2 times per day Laxatives Bisacodyl PO 10 mg 1–3 times per day Senna PO 2–4 tablets 1–2 times per day Osmotics Magnesium citrate PO 10–15 g per day Lactulose PO 10–15 mL 2–3 times per day Peripheral opioid antagonists Methylnaltrexone Alvimopan Abbreviation: PO = per oral.

Patients usually do not develop tolerance to constipation and, therefore, constipation should be managed actively. Therapeutic goals should include maximizing stool volume, keeping stools softer and enhancing intestinal peristaltic movement.10 Fiber bulking agents, stool softeners, laxatives, and osmotic agents can be prescribed to treat constipation (Table 25.4). The efficacy of bulk-forming agents such as methylcellulose and psyllium in treating constipation has been well established.18,19 These agents work by retaining water in the stools so it is important that patients receive adequate oral hydration. Stool softeners, such as docusate sodium, work by lowering the surface tension of hard, dry stools to allow greater penetration of water. It has also been shown to directly stimulate contraction of the colon and rectum. Bisacodyl and senna are laxatives that stimulate peristalsis and improve GI motility. Osmotic agents such as magnesium citrate, sorbitol, and lactulose draw water into the stools by osmosis and improve laxation. In certain situations, an enema may be useful when defecation has not occurred for more than 5 days. Since the early 2000s, there has been growing interest in the role of peripheral opioid ␮-receptor antagonists in treating postoperative ileus and chronic constipation. Peripherally acting opioid antagonists (eg, methylnaltrexone and alvimopan) do not cross the blood-brain barrier, but can attenuate the delay in gastric emptying or intestinal transit.16 They are also effective in reversing opioid-induced bowel dysfunction.20 Methylnaltrexone, a quaternary derivative of naltrexone, blocks peripheral effects of opioids.21 Central analgesic effects are spared because methylnaltrexone has low lipid solubility and does not cross the blood-brain barrier.22 Intravenous (IV) methylnaltrexone (0.3 mg/kg) was able to reverse morphineinduced delay in gastric emptying in volunteers.23 Yuan et al24 demonstrated in a randomized, double-blind placebo-controlled trial that IV methylnaltrexone reduced orocecal transit time in patients on chronic methadone therapy. This group of patients also had an immediate laxation response after methylnaltrexone administration with no evidence of opioid withdrawal symptoms. Methylnaltrexone given as an oral dose of up to 3.0 mg/kg similarly improved GI motility and alleviated

opioid-induced constipation.25 A recent phase II trial examining intravenous methylnaltrexone for accelerating recovery of GI function in patients undergoing segmental colectomy via laparotomy demonstrated an improvement of 27 hours in mean time to GI recovery, measured by first toleration of solid food or first bowel movement, whichever occurred first. This was accompanied by a shorter time to eligibility for hospital discharge in the methylnaltrexone group compared with the placebo group.26 To date, two large-scale phase III trials involving more than 100 patients each showed that subcutaneous methylnaltrexone could be successfully administered to treat opioid-induced constipation.27,28 Alvimopan is a peripherally restricted specific ␮-opioid receptor antagonist.29,30 In a human volunteer study, it effectively prevented morphine-induced increase in GI transit time.31 Alvimopan also shortened the time to laxation after treatment and increased stool weight and number of bowel movements in patients on chronic methadone therapy.32,33 In the postoperative setting, alvimopan was effective in accelerating the return of bowel function after abdominal surgery.34,35 Webster and colleagues36 conducted one of the largest randomized, double-blind, placebo-controlled trials involving 522 subjects taking opioids for noncancer pain. A dose of alvimopan (0.5 mg twice a day) was well tolerated, with increased weekly spontaneous bowel movements and reduced straining and incomplete evacuation. There was also no evidence of reversal of opioid analgesia.36 However, further clinical studies of alvimopan have been suspending because of a possible increase in cardiovascular morbidity in exposed subjects.31,37 O P I O I D - I N D U C E D NAU S E A A N D VO M I T I N G

The development of nausea and vomiting is mediated through opioid receptors in the chemoreceptor trigger zone (CTZ) and the emetic center in the brainstem (Figure 25.1). The CTZ is located on the floor of the fourth ventricle and has unique attributes. This neural region lies outside the blood-brain barrier

Opioid-Related Adverse Effects and Treatment Options

409

Cerebellum

Oral. Parenteral and Neuraxial Opioids Chemoreceptor Trigger Zone

Brain Stem

(NK-1, PGE)

Vagal Motor Nucleus

Vomiting Reflex

Vomiting Center (D2)

Hollow Viscus & Peritoneum

(5HT3, D2, NK-1, H1)

Nucleus Tractus Solitarius (H1, M, ENK)

(M)

(D2)

Vestibular Nuclei

Stomach & Small Intestine

ENT Surgery Motion, N20

Surgical manipulation, Opioids acting in the myenteric plexus

Figure 25.1: Nausea and vomiting pathways: sites of opioid and visceral stimulation.

lowest possible dose of opioid is given to achieve adequate analgesia as opioids cause PONV. PONV remains an important cause for poor patient satisfaction (Table 25.5). PONV also results in increased costs of personnel, drug acquisition, materials, prolonged recovery room stay, and unanticipated hospital admission.47 It is therefore imperative to prevent or treat nausea and vomiting effectively. Receptors such as the 5-hydroxytryptamine type 3 (5-HT3 ), dopamine type 2 (D2 ), and neurokinin-1 (NK-1) are found in the CTZ. The nucleus tractus solitarius has high concentrations of enkephalin, histaminergic (H1 ), and muscarinic (M) receptors 80 70

Incidence of PONV

Percentage

60 50 40 30 20 10

Fa isk 4R

3R

isk

Fa

cto

cto

rs

rs

rs cto 2R

isk

Fa

Fa isk 1R

isk

Fa

cto

cto

r

r

0

No R

and is exposed to and responds to opioids in the systemic circulation. Opioids also sensitize the vestibular system such that patient movement may trigger nausea and vomiting. Nausea and vomiting is further aggravated by delayed gastric emptying as well as constipation caused by opioid therapy. The incidence of nausea and vomiting appear to be similar among the opioids, including morphine, meperidine, fentanyl, sufentanil, and alfentanil.38 Nausea and vomiting may be seen in one-fourth of patients receiving opioids.39 In the postoperative setting, the incidence of postoperative nausea and vomiting (PONV) for all surgeries and patient populations ranges between 25% and 30%. Severe, intractable PONV is estimated to occur in 0.18% of all patients.40 The use of opioids may increase the risk of PONV by more than 4-fold.41 In addition, there are many other factors that can increase the risk of PONV (Table 25.5).42 The greater the number of drug, patient, and surgical-related risk factors, the higher the percentage incidence of PONV (Figure 25.2).42,43 Administration of a regional anesthetic technique has advantages over a general anesthetic as nitrous oxide, volatile anesthetic gases, and opioids are avoided. If opioids are administered with local anesthetic agents into the epidural or intrathecal space, PONV can still occur. The high incidence of nausea and vomiting seen with neuraxial morphine is related to cephalad cerebral spinal fluid (CSF) flow with transport of morphine molecules to the CTZ. Seventeen percent of patients who had received epidural morphine reported nausea and vomiting after surgery.45 Therefore, using highly lipophilic opioids such as fentanyl or sufentanil can reduce cephalad spread and lower the risk of emesis.46 Postoperative pain prolongs gastric emptying time and contributes to emesis after surgery. A multimodal approach using a combination of systemic opioids, nonsteroidal antiinflammatory drugs (NSAIDs), neuraxial blocks, regional nerve blocks, and local infiltration of the surgical wound can reduce postoperative pain. Such an approach also will ensure that the

Figure 25.2: Impact of multiple risk factors on PONV. Primary risk factors for PONV: (1) postoperative opioids, (2) history of motion sickness or PONV, (3) female sex, and (4) nonsmoker. Modified from Gan TJ et al (2003).42

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Table 25.5: Risk Factors for Postoperative Nausea and Vomiting (PONV)40,43,44 Patient factors Female History of motion sickness or PONV Nonsmoker Anxiety Concurrent therapy (chemotherapy, radiation therapy) Pregnancy Surgical factors Type of surgery (laparoscopy, gynecologic, ENT, strabismus, and breast surgery) Long duration of surgery Anesthetic factors Inhalational anesthetic agents (nitrous oxide, volatile anesthetics) Opioids High dose neuromuscular reversal agents (>5 mg neostigmine) Poorly controlled pain

(Figure 25.1). These receptors transmit messages to the emetic center when stimulated. NK-1 receptors were also recently discovered in the emetic center.48,49 These receptors are therefore the targets for antiemetic therapy. Traditional antiemetic drugs used for treating nausea and vomiting include the anticholinergics (scopolamine),

antihistamines (diphenhydramine, dimenhydrinate), and antidopaminergics (droperidol, prochlorperazine, and metoclopramide) (Table 25.6). However, many of these are associated with undesirable side effects, including restlessness, dry mouth, sedation, hypotension, dystonia and extrapyramidal symptoms, and even QT prolongation. Serotonin (5-HT3 ) antagonists belong to a separate class of antiemetics that can effectively treat opioid-induced nausea and vomiting.50 Dexamethasone also is an effective antiemetic.51 Its mechanism of action may be related to the inhibition of prostaglandin synthesis and the stimulation of endorphin release, resulting in mood elevation and a sense of well-being. In PONV studies, dexamethasone (5–10 mg IV) has been demonstrated to have antiemetic efficacy.52,53 Aprepitant is an NK-1 receptor antagonist that has been used effectively for the prevention of postoperative nausea and vomiting.54 NK-1 receptor antagonists have also been shown to be efficacious in the treatment of established PONV after gynecologic surgery.55 Metoclopramide (10 mg IV) can be used for increasing gastric transit, but it is not an effective antiemetic at this dose, although higher doses of 20 mg IV may be more effective. Combination therapy has been shown to be superior to monotherapy for treatment of nausea and vomiting. The presence of multiple emetic receptors in the emetic center, CTZ, and their association supports the practice of using more than one antiemetic drug. The combination of a 5HT3 -receptor antagonist with either droperidol or dexamethasone is superior to using only a 5HT3 -receptor antagonist, droperidol, or dexamethasone as the sole agent.57–59 It also appeared that droperidol has greater efficacy against nausea, whereas ondansetron has better antiemetic properties.60 Patients with or who will be exposed to multiple risk factors for PONV should receive combination

Table 25.6: Antiemetic Drug Dosing and Timinga Class

Drugs

Dosage

Timing

Anticholinergic

Scopolamineb

Antihistamine

Transdermal patch

4 hours prior to surgery

Dimenhydrinate

IV 1–2 mg/kg (up to 12.5 mg) or PO 50–100 mg IV 6.25–12.5 mg

As required At end of surgery

Promethazine c

Antidopaminergic

Droperidol Prochlorperazine Metoclopramided

IV 0.625–1.25 mg IV 5–10 mg or PO 10 mg 10–20 mg

At end of surgery At end of surgery During/after surgery

Antiserotoninergic

Ondansetron Dolasetron Granisetron

IV 4 mg IV 12.5 mg IV 0.35–1 mg

At end of surgery At end of surgery At end of surgery

Steroids NK-1 antagonist

Dexamethasonee Aprepitant f

IV 4–5 mg PO 40 mg

Prior to induction 4 hours prior to surgery

a b

c d e f

Modified from Gan et al (2007).56 Useful for treating neuraxial opioid induced vertigo and nausea, not recommended in elderly and cognitively impaired. Not recommended in patients with Parkinson’s disease. Avoid in patients with surgical anastomosis. Clear with surgical staff; may affect immune function and wound healing. As effective as ondansetron, prolonged duration of effect permits preoperative dosing.

Opioid-Related Adverse Effects and Treatment Options

Evaluate risk of PONV in patients presenting for surgery

Low

Medium

High

Consider Regional Anesthesia

No prophylaxis unless there is risk of medical sequelae from vomiting

Not Indicated

If general anesthesia is used, reduce baseline risk factors and consider using non-pharmacological therapies

Patients at moderate risk

Consider antiemetic prophylaxis with monotherapy (older adults) or combination therapy (children and young adults)

Patients at high risk

Initiate combination therapy with 2-3 prophylactic agents from different classes

Figure 25.3: Algorithm for the management of postoperative nausea and vomiting. Modified from Gan TJ et al (2003)42 and Apfel CC et al (1999).43

therapy from at least two different classes for antiemetic prophylaxis. Patients at low risk of PONV may not require prophylactic antiemetics and can be treated postoperatively if they have nausea and vomiting. A treatment algorithm for limiting PONV is described in Figure 25.3. Opioid antagonists (eg, naloxone and nalmefene) in small doses have also been demonstrated to reduce opioid-related nausea and vomiting. In one study involving patients undergoing total abdominal hysterectomy, a low-dose IV infusion of naloxone at 0.25 ␮g/kg/h effectively reduce postoperative nausea and vomiting.61 A separate study showed that a single IV dose of nalmefene of 15–25 ␮g administered at the end of surgery reduced the need for antiemetic therapy in patients receiving IV PCA morphine after lower abdominal surgery.62 G E N I TO U R I NA RY A DV E R S E E F F E C T S

Bladder detrusor muscle relaxation occurs with either intravenous or neuraxial administration of opioids.63–65 As a consequence of the decrease in bladder tone, an increase in maximal bladder capacity occurs with urinary retention. At the

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same time, an increase in vesicle sphincter tone because of opioids also contributes to voiding difficulty.66 Urinary retention was reversible with a single dose of naloxone (0.01 mg/kg IV).67 Methylnaltrexone (0.3 mg/kg IV) was able to reverse opioidinduced bladder dysfunction as well. The efficacy of methylnaltrexone also proved that opioid-induced bladder dysfunction was peripherally mediated.67 When severe or distressing urinary retention remains, catheterization or discontinuation of opioid therapy may be required. N E U RO LO G I C A L A DV E R S E E F F E C T S

Opioids produce a variety of CNS effects, including sedation, cognitive impairment, and neuroexcitation. Sedation is a common side effect of opioid therapy. It is also a useful early indicator of the development of respiratory depression. Regular monitoring of sedation scores is therefore mandatory in all patients receiving opioids for acute pain management. In the presence of concomitant usage of CNS depressant drugs, such as benzodiazepines, antidepressants, anticonvulsants, or skeletal muscle relaxants, the incidence of sedation is markedly increased. Neuroexcitatory features may range from delirium to grand mal seizurelike activity. 68–70 Delirium is characterized by a global disorder of cognition and consciousness. Meperidine was particularly associated with delirium because of its anticholinergic activity. Normeperidine, the breakdown product of meperidine, has also been reported to produce seizures at high concentrations.71 Accumulation of breakdown metabolites of morphine in patients with renal impairment may also lead to postoperative delirium. Sleep disturbances, including reduction in rapid eye movement (REM) and slow wave sleep, as well as vivid dreams, can occur with postoperative opioid therapy.38 Doctors managing acute pain with opioids should be aware of the risk factors that may predispose a patient to delirium. These include patient age, comorbidities, and drug interactions (Table 25.7). D E R M ATO LO G I C A L A DV E R S E E F F E C T S

Cutaneous changes, such as erythema and urticaria, can result from opioid-induced histamine release. Pruritis, in the absence of urticaria, can occur with both systemic and neuraxial administration of opioids. The incidence of pruritis is higher with epidural or intrathecal morphine administration and, notably, it is most commonly seen in obstetric patients. It usually affects the face, neck, and chest in this population. The incidence has been reported to be as high as 80%.72 Pruritis is in fact the most common side effect associated with intrathecal opioid administration.73 The incidence among the different intrathecal opioids (morphine, fentanyl, and sufentanil) appears to be similar.74,75 The pathogenesis of pruritis remains unclear and therefore anti-itch therapies have lagged behind treatments for other opioid-related adverse effects. Previously, it was believed that opioid-induced histamine release or spinal modulation of nociceptive afferent input led to spinal and trigeminal interpretation of such information as pruritis.76 Animal studies published later showed that ␮-receptors at the level of the medullary dorsal horn

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Table 25.7: Risk Factors for Development of Delirium Patient Factors

Drug interactions

Advanced Age Preexisting cognitive dysfunction Renal impairment Hypercalcemia Sepsis Dehydration Hypoxia Poorly controlled pain Bladder distention Benzodiazepines Opioids (particularly ␬ agonists) Anticholinergics Residual volatile anesthetics

were responsible for pruritis and that its manifestation was not histamine mediated.77,78 It now appears that a distinct spinothalamic pathway exists for itch – one that is separate from the pain and temperature spinothalamic tracts.79 Opioid agonists reduce tonic inhibition of these itch-specific pathways, allowing spontaneous activity of central itch neurons.80 The reversibility of pruritis with naloxone also supports a mechanism that is mediated through opioid receptors. Various drugs have been used to treat pruritis, but none abolishes it completely. Traditionally, antihistamines have been used to treat this side effect but their poor efficacy can be explained by the absence of histamine-mediated pruritis. The continued use of antihistamines and the purported effectiveness may be related to the sedative effects of this class of drugs. The only effective treatment of pruritis appears to be naloxone. Other drugs that have been used to treat pruritis include serotonin antagonists, propofol, and NSAIDs. True allergy or anaphylactic reactions to opioids are rare. In general, opioids cause histamine release and patients may manifest signs and symptoms, including urticaria, pruritis, sneezing, and exacerbation of asthma. These are not considered allergic reactions. Such reactions can usually be prevented or treated with antihistamine agents such as diphenhydramine (25–50 mg orally). F U T U R E D E V E LO P M E N T S

Allyl-2,5-dimethyl-1-piperazines have been of interest as analgesic agents for the management of moderate to severe pain. One of these agents, DPI-3290, has been examined in animal studies.81,82 It is a combined ␦- and ␮-receptor opioid receptor agonist. When compared with strong opioids such as morphine and fentanyl, DPI-3290 had equivalent antinociceptive efficacy, but produced less respiratory depression.81 DPI-125 is another novel mixed ␦- and ␮-opioid receptor agonist that has successfully completed a phase 1 clinical trial for its IV formulation. Preclinically, DPI-125 has shown similar efficacy to morphine and fentanyl, with the potential for reduced respiratory depression, emesis, and addiction over those agents. A final analgesic in late stage development that has a lower incidence of adverse events is tapentadol. This combination ␮-receptor agonist/catecholamine reuptake inhibitor provides

Table 25.8: Approaches to Managing Opioid-Related Adverse Effects Reducing opioid dose (IV PCA and epidural PCA bolus dose) Addition of a nonopioid analgesics (multimodal analgesia) Prophylatic administration of antiemetics in at risk populations Assess and aggressively manage adverse effects symptomatically Consider opioid rotation Switch route of administration Further development and use of peripheral acting opioid antagonists (alvimopan, methylnaltrexone) Further development and use of opioid analgesics with low adverse event profiles such as tapentadol, (combined ␮ agonist/ norepinephrine reuptake inhibitor) and DPI-3290 (combined ␦-/␮-agonists)

analgesic efficacy similar to oxycodone, but with a lower incidence of nausea and vomiting in acute pain trials and a reduced risk of constipation following chronic exposure. The continued development of these drugs in human trials in the future shows great promise. An opioid analgesic that is as potent as the currently available strong opioids, such as morphine and fentanyl, whereas devoid of adverse effects like nausea, vomiting, and respiratory depression, will have an important role in acute pain management. C O N C LU S I O N

The side-effect profiles of equianalgesic doses of opioids are similar, but there are interpatient variations in the occurrence and severity of these adverse effects. A generalized approach that may be recommended to minimize morbidity and improve patient satisfaction includes reduction in opioid exposure and aggressive treatment of adverse events (Table 25.8). The use of nonopioid analgesics, including acetamino- phen (paracetamol), NSAIDs, and cyclooxygenase type 2 inhibitors, in postoperative pain management is well established.83 These drugs exert either an additive or synergistic effect when given in combination with opioids. At the same time, they reduce total opioid requirement (opioid-sparing effect), along with its associated adverse effects. There is also evidence to suggest that coxib-/NSAID-mediated inhibition of prostaglandin E synthesis in the brainstem and medulla may directly reduce nausea and vomiting responses. A multimodal approach to acute pain management, therefore, allows lower doses of different analgesics to be used while reducing the side effects associated with each of them.84 Opioid rotation, or switching from one opioid to another, may be helpful if the side effects experienced with one particular opioid are too distressing. Patients may tolerate one opioid better than another. Opioid-related adverse effects are commonly seen during acute pain management. With greater understanding and knowledge of the etiology of unwanted side effects of opioids, and with the ability to administer opioids via various routes into the body, it may be possible to reduce the incidence and severity of side effects, whereas maintaining or enhancing the efficacy of opioids. Currently, however, a potent ␮-opioid receptor agonist will

Opioid-Related Adverse Effects and Treatment Options

be associated with adverse effects as discussed in this chapter – with respiratory depression being the most feared and lethal complication. Developments in finding drugs that potentiate opioid analgesia without increasing the risk of opioid-induced respiratory depression are already ongoing85 and opioids that work on other receptor subtypes (eg, ␦ and ␬) may also reduce some of the ␮ related opioid side effects.

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20. Becker G, Galandi D, Blum HE. Peripherally acting opioid antagonists in the treatment of opiate-related constipation: a systematic review. J Pain Symptom Manage. 2007;34:547–565. 21. Yuan CS, Israel RJ. Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects. Expert Opin Investig Drugs. 2006;15:541–552. 22. Yuan CS. Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother. 2007;41:984–993. 23. Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology. 1997;87:765–770. 24. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA. 2000;283:367–372. 25. Yuan CS, Foss JF. Oral methylnaltrexone for opioid-induced constipation. JAMA. 2000;284:1383–1384. 26. Viscusi ER, Rathmell J, Fichera A, et al. A double-blind, randomized, placebo-controlled trial of methylnaltrexone (MNTX) for post-operative bowel dysfunction in segmental colectomy patients. Anesthesiology. 2005;103:A893. 27. Slatkin N, Karver S, Thomas J. A Phase III double-blind, placebocontrolled trial of methylnaltrexone for opioid-induced constipation in advanced illness (MNTX 302). Digest Dis Week. 2006: 686e. 28. Thomas J, Lipman A, Slatkin N, et al. A phase III double-blind placebo-controlled trial of methylnaltrexone (MNTX) for opioidinduced constipation (OIC) in advanced medical illness (AMI). Proc Am Soc Clin Oncol. 2005;23:8003. 29. Camilleri M. Alvimopan, a selective peripherally acting muopioid antagonist. Neurogastroenterol Motil. 2005;17:157–165. 30. Neary P, Delaney CP. Alvimopan. Expert Opin Investig Drugs. 2005;14:479–488. 31. Liu SS, Hodgson PS, Carpenter RL, Fricke JR, Jr. ADL 8–2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther. 2001;69:66–71. 32. Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction – a 21-day treatment-randomized clinical trial. J Pain. 2005;6:184–192. 33. Schmidt WK. Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg. 2001;182:27S–38S. 34. Delaney CP, Wolff BG, Viscusi ER, et al. Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies. Ann Surg. 2007;245:355–363. 35. Herzog TJ, Coleman RL, Guerrieri JP, Jr, et al. A double-blind, randomized, placebo-controlled phase III study of the safety of alvimopan in patients who undergo simple total abdominal hysterectomy. Am J Obstet Gynecol. 2006;195:445–453. 36. Webster L, Jansen JP, Peppin J, et al. Alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: Results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. Pain 2008;137:428– 440. 37. Gonenne J, Camilleri M, Ferber I, et al. Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study. Clin Gastroenterol Hepatol. 2005;3:784–791. 38. Coda BA. Opioids. In: Barash PG, Cullen BF, Stoelting RK, eds. Clinical Anesthesia. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001; 345–375. 39. Cepeda MS, Farrar JT, Baumgarten M, et al. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther. 2003;74:102–112.

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40. Watcha MF, White PF. Postoperative nausea and vomiting. Its etiology, treatment, and prevention. Anesthesiology. 1992;77:162– 184. 41. Junger A, Hartmann B, Benson M, et al. The use of an anesthesia information management system for prediction of antiemetic rescue treatment at the postanesthesia care unit. Anesth Analg. 2001;92:1203–1209. 42. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg. 2003;97:62– 71. 43. Apfel CC, Laara E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology. 1999;91:693–700. 44. Cheng CR, Sessler DI, Apfel CC. Does neostigmine administration produce a clinically important increase in postoperative nausea and vomiting? Anesth Analg. 2005;101:1349–1355. 45. Reiz S, Westberg M. Side-effects of epidural morphine. Lancet. 1980;2:203–204. 46. Borgeat A, Ekatodramis G, Schenker CA. Postoperative nausea and vomiting in regional anesthesia: a review. Anesthesiology. 2003;98:530–547. 47. Hill RP, Lubarsky DA, Phillips-Bute B, et al. Cost-effectiveness of prophylactic antiemetic therapy with ondansetron, droperidol, or placebo. Anesthesiology. 2000;92:958–967. 48. Rigby M, O’Donnell R, Rupniak NM. Species differences in tachykinin receptor distribution: further evidence that the substance P (NK1) receptor predominates in human brain. J Comp Neurol. 2005;490:335–353. 49. Saito R, Takano Y, Kamiya HO. Roles of substance P and NK(1) receptor in the brainstem in the development of emesis. J Pharmacol Sci. 2003;91:87–94. 50. Gan TJ. Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same? CNS Drugs. 2005;19:225–238. 51. Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg. 2000;90:186–194. 52. Wang JJ, Ho ST, Lee SC, et al. The use of dexamethasone for preventing postoperative nausea and vomiting in females undergoing thyroidectomy: a dose-ranging study. Anesth Analg. 2000;91: 1404–1407. 53. Wang JJ, Ho ST, Liu YH, et al. Dexamethasone reduces nausea and vomiting after laparoscopic cholecystectomy. Br J Anaesth. 1999;83:772–775. 54. Gan TJ, Apfel CC, Kovac A, et al. A randomized, doubleblind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting. Anesth Analg. 2007;104:1082–1089. 55. Diemunsch P, Schoeffler P, Bryssine B, et al. Antiemetic activity of the NK1 receptor antagonist GR205171 in the treatment of established postoperative nausea and vomiting after major gynaecological surgery. Br J Anaesth. 1999;82:274– 276. 56. Gan TJ, Meyer TA, Apfel CC, et al. Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2007;105:1615–1628. 57. Habib AS, El-Moalem HE, Gan TJ. The efficacy of the 5-HT3 receptor antagonists combined with droperidol for PONV prophylaxis is similar to their combination with dexamethasone. A meta-analysis of randomized controlled trials. Can J Anaesth. 2004;51:311–319. 58. Lopez-Olaondo L, Carrascosa F, Pueyo FJ, et al. Combination of ondansetron and dexamethasone in the prophylaxis of

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postoperative nausea and vomiting. Br J Anaesth. 1996;76:835– 840. Wu O, Belo SE, Koutsoukos G. Additive anti-emetic efficacy of prophylactic ondansetron with droperidol in out-patient gynecological laparoscopy. Can J Anaesth. 2000;47:529–536. Henzi I, Sonderegger J, Tramer MR. Efficacy, dose-response, and adverse effects of droperidol for prevention of postoperative nausea and vomiting. Can J Anaesth. 2000;47:537–551. Gan TJ, Ginsberg B, Glass PS, et al. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology. 1997;87:1075–1081. Joshi GP, Duffy L, Chehade J, et al. Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patient-controlled analgesia. Anesthesiology. 1999;90:1007–1011. Drenger B, Magora F. Urodynamic studies after intrathecal fentanyl and buprenorphine in the dog. Anesth Analg. 1989;69:348– 353. Malinovsky JM, Le Normand L, Lepage JY, et al. The urodynamic effects of intravenous opioids and ketoprofen in humans. Anesth Analg. 1998;87:456–461. Rawal N, Mollefors K, Axelsson K, et al. An experimental study of urodynamic effects of epidural morphine and of naloxone reversal. Anesth Analg. 1983;62:641–647. Dray A. Epidural opiates and urinary retention: new models provide new insights. Anesthesiology. 1988;68:323–324. Rosow CE, Gomery P, Chen TY, et al. Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone. Clin Pharmacol Ther. 2007;82:48–53. Haber GW, Litman RS. Generalized tonic-clonic activity after remifentanil administration. Anesth Analg. 2001;93:1532–1533. Mets B. Acute dystonia after alfentanil in untreated Parkinson’s disease. Anesth Analg. 1991;72:557–558. Parkinson SK, Bailey SL, Little WL, Mueller JB. Myoclonic seizure activity with chronic high-dose spinal opioid administration. Anesthesiology. 1990;72:743–745. Armstrong PJ, Bersten A. Normeperidine toxicity. Anesth Analg. 1986;65:536–538. Harrison DM, Sinatra R, Morgese L, Chung JH. Epidural narcotic and patient-controlled analgesia for post-cesarean section pain relief. Anesthesiology. 1988;68:454–457. Ko MC, Naughton NN. An experimental itch model in monkeys: characterization of intrathecal morphine-induced scratching and antinociception. Anesthesiology. 2000;92:795–805. Dahl JB, Jeppesen IS, Jorgensen H, et al. Intraoperative and postoperative analgesic efficacy and adverse effects of intrathecal opioids in patients undergoing cesarean section with spinal anesthesia: a qualitative and quantitative systematic review of randomized controlled trials. Anesthesiology. 1999;91:1919–1927. Nelson KE, Rauch T, Terebuh V, D’Angelo R. A comparison of intrathecal fentanyl and sufentanil for labor analgesia. Anesthesiology. 2002;96:1070–1073. Scott PV, Fischer HB. Intraspinal opiates and itching: a new reflex? Br Med J (Clin Res Ed). 1982;284:1015–1016. Thomas DA, Williams GM, Iwata K, et al. The medullary dorsal horn: a site of action of morphine in producing facial scratching in monkeys. Anesthesiology. 1993;79:548–554. Thomas DA, Williams GM, Iwata K, et al. Multiple effects of morphine on facial scratching in monkeys. Anesth Analg. 1993;77:933– 935. Andrew D, Craig AD. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci. 2001;4:72–77. Schmelz M. A neural pathway for itch. Nat Neurosci. 2001;4:9–10.

Opioid-Related Adverse Effects and Treatment Options 81. Gengo PJ, Pettit HO, O’Neill SJ, et al. DPI-3290 [(+)-3-((alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hyd roxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. II. A mixed opioid agonist with potent antinociceptive activity and limited effects on respiratory function. J Pharmacol Exp Ther. 2003;307:1227–1233. 82. Gengo PJ, Pettit HO, O’Neill SJ, et al. DPI-3290 [(+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hyd roxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A

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mixed opioid agonist with potent antinociceptive activity. J Pharmacol Exp Ther. 2003;307:1221–1226. 83. Dahl V, Raeder JC. Non-opioid postoperative analgesia. Acta Anaesthesiol Scand. 2000;44:1191–1203. 84. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77:1048– 1056. 85. Dahan A, Kest B. Recent advances in opioid pharmacology. Curr Opin Anaesthesiol. 2001;14:405–410.

26 Respiratory Depression: Incidence, Diagnosis, and Treatment Dermot R. Fitzgibbon

The overall effectiveness of any analgesic technique depends on the adequacy of pain relief that can be provided and the incidence of side effects or complications. Opioids represent the major class of analgesics for treating severe and unremitting pain and are widely used in the treatment of pain associated with surgery or chronic conditions. Most modern postoperative analgesic techniques incorporate the administration of neuraxial opioids (with or without local anesthetic) or systemic (usually by patient-controlled analgesia [PCA]) routes. Although opioid administration is generally considered safe on surgical wards,1,2 respiratory depression associated with opioids occur and have the potential for major morbidity and even mortality. Serious complications or deaths from opioid-induced respiratory depression are rare, but the risk is not zero, and a death or neurologic injury for a patient with an otherwise treatable illness is tragic. In July 2000, the Joint Commission on Accreditation of Health Care Organizations (JCAHO) developed new standards to create higher expectations for the assessment and management of pain in hospitals and other health care settings in the United States.3 In response, many institutions implemented treatments guided by patient reports of pain intensity indexed with a numerical scale. Vila et al4 reported that the incidence of opioid oversedation per 100,000 inpatient hospital days increased from 11.0 pre–numeric pain treatment algorithm (NPTA) to 24.5 post–NPTA (P 65 years) occur, as well as a decrease in taste sensitivity. The aging ANS has reduced autonomic abilities that influence a patients’ response to physiologic changes, stresses, surgery, and anesthesia. Increases in sympathetic nervous system activity are organ specific with the gastrointestinal (GI) system and skeletal muscle as targets. Neuronal noradrenergic reuptake is reduced in the elderly resulting in an increased sympathetic tone of the heart and an increase in basal adrenal secretions along

with attenuation of adrenal adrenergic secretion in response to stress.9 There is a loss of beat-to-beat heart rate variability during respiration in the elderly because of reduced respiratory vagal modulation of the resting heart. Findings of decreased baroreflex sensitivity are because of a function of increased arterial stiffness versus aging associated alterations of the ANS. The ANS and its effectors play an important role in responses to hemodynamic challenges. Advancing age could result in an imbalance of homeostatic mechanisms as evidenced by orthostatic hypotension, exercise intolerance, increased upper body sweating, and temperature intolerance that may be evident. Finally, older patients often have cognitive impairments that may not be recognized by some health care providers.10 Predictive stroke risk indices use advancing age as an important mediating factor of the 5-year stroke rate. Advancing age is an independent predictor of postoperative stroke, especially subsequent to coronary artery bypass grafting. Increasing age as a risk factor for stroke may be the result of an increased incidence of atherosclerosis or increased susceptibility to ischemia from the aging process. However, how age actually increases the risk of stroke is currently unclear, but the surgical procedure plays an important role in defining the perioperative risk of stroke in the elderly. Cardiac, vascular, orthopedic, and neurosurgical procedures have an increased incidence of perioperative (and microembolic) stroke compared to an incidence of 0.08%–0.2% following general surgery and this risk increases to 2.9% with a prior history of a stroke. P O S TO P E R AT I V E C O G N I T I V E DY S F U N C T I O N

Postoperative cognitive disorders include a broad spectrum of impairments in cognitive function and memory or of consciousness along with deficits in cognition and memory. Cognitive impairment includes acute confusion states and delirium as well as worsening progression of baseline dementia. Abnormal cognitive states in older patients may adversely affect the consistency of obtaining a medical history, negatively affect disposition planning, and complicate the perioperative course and rehabilitation. Acute cognitive impairment can also be an important underlying symptom of sepsis, congestive heart failure, metabolic abnormality, adverse drug effects, or subdural hematoma development. Studies on POCD have identified that patients 60 years and older are at increased risk of suffering cognitive impairment subsequent to major noncardiac surgery.11,12 Localized areas of the brain are responsible for cognitive function. For example, the frontal lobe and subcortical network portions control executive function (concentration, self-monitoring, and information processing) and the medial temporal lobe is for memory (learning and remembering). Brain regions associated with cognitive functions differentially change with aberrant brain processes (stoke, dementia) and with the aging process. Therefore, to better understand POCD, determining the type of cognitive change may provide information as to which brain system(s) are vulnerable to adverse events during the perioperative period. This will also have implications toward postsurgical convalescence and rehabilitation. Cognitive disorders can occur after surgery in which mental function reaches a nadir in the early postoperative period and returns to preoperative levels within 1 week following surgery

Elderly High-Risk and Cognitively Impaired Patients

in the majority of patients. Cognitive dysfunction is common in elderly postoperative patients, but stroke occurs relatively infrequently.13 A more common occurrence in the postoperative period is the incidence of POCD and postoperative delirium (POD); the most often observed psychiatric conditions of older hospitalized patients. The incidence of POD and POCD may exceed 50% in certain surgical settings such as cardiac and orthopedic (femoral neck fracture repairs) surgeries.14,15 POD and POCD are the two most common complications in elderly surgical patients and the incidence is higher than other postoperative comorbidities such as respiratory failure and myocardial infarction.12,16 Definitions of the various cognitive changes and dysfunctions that may be experienced by the elderly surgical patient are presented in Table 31.2. POD is further characterized by alterations in orientation, consciousness, memory, thought processes, and behavior.17 Elderly patients generally experience the onset of POD and acute confusion states in the postanesthesia care unit (PACU) or immediately following transport to a postsurgical care unit or intensive care unit (ICU). Although the onset of delirium may be abrupt, delirium can also develops over several hours to days and its course tends to fluctuate.18 Initial symptoms can often progress and extend into a variety of clinically significant complications, including patient agitation and the subsequent need for sedation, an increased risk of falls, wound seromas, pulled nasogastric tubes and IV catheters, aspiration pneumonia, and increased need for urinary catheters. When the onset of delirium is gradual, patients may experience fatigue, inability to concentrate, irritability, anxiety, and/or depression. Older patients may also have hallucinations, experience vivid and disturbing dreams, or have trouble distinguishing dreams from reality. Although patients may seem lucid at times, their symptoms of delirium are typically worse at night, leading to the colloquial term sun-downing. The perioperative etiology of cognitive dysfunction is multifactorial and may include drug effects, reactions to poorly controlled pain, underlying dementia, hypothermia, and metabolic disturbances. Elderly patients are extremely sensitive to centrally acting anticholinergic agents, opioids, and antihistamines, such as scopolamine, atropine, morphine, vistaril, and diphenhydramine. It is known that antinausea medications such as droperidol, phenergan, and a scopolamine patch can also precipitate acute confusion states, particularly when coadministered with opioid analgesics in the elderly. Specific pain management strategies that rely solely on opioids and other central-acting analgesics may be associated with a higher incidence of POD and POCD. Poorly controlled postoperative pain has also been implicated in development of POD and POCD in the elderly. High pain scores at rest are associated with an increased risk of delirium over the first 3 postoperative days and more effective pain management has been shown to reduce the incidence of POD in the elderly patient.5,19 Some geriatric patients suffer prolonged or permanent POCD after surgery and anesthesia. There are studies to suggest that POCD can be detected in 10%–15% of elderly patients >60 years of age for up to 3 months following major surgery.11,12 The most commonly affected cognitive dysfunction was attention to detail and cognitive speed. In certain settings, such as cardiac and major orthopedic procedures, intraoperative arterial emboli may also be contributory. Elderly patients admitted to the hospital following their surgical procedure appear to have a significantly higher risk for POCD than elderly outpatients.

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Although the etiology still remains unclear, both anesthetic and nonanesthetic factors are likely responsible for the development of POCD. Complications of POD and POCD are significant because adverse outcomes may result in increased length of hospital stay and medical complications, including death and could require discharge to skilled care facilities.20,21 The economic impact of delirium is considerable as it adds costs to hospitalization and is responsible for billions in additional Medicare charges along with significant health care implications. Becuase POD and POCD occurs more frequently in the elderly than in younger patients, and given the fact that the elderly surgical population is increasing in number, it is necessary to gain knowledge of these conditions and apply that understanding to the care of these surgical patients. Geriatric patients undergoing certain high-risk types of surgery or those with certain coexisting medical disease(s), patients with preoperative cognitive dysfunction, and patients with advanced age are at higher risk for the development of postoperative cognitive disorders and long-term cognitive dysfunction. Therefore, functional status of the elderly surgical patient may be more relevant than medical morbidity outcomes. Cognitive functioning relates directly to the patient’s functional status, which is a determining factor as to whether a patient is discharged to home or will require a skilled care facility for rehabilitation. In addition, functional status serves as a strong predictor of mortality as a result of hospitalization.22 Especially significant is the understanding that cognitive disorders are independent predictors of short- and long-term outcomes. This adverse event is also associated with an increased incidence of postoperative complications, increased mortality, higher rates of discharge to rehabilitation facilities, and longer lengths of hospital stay, even with adjustments accounting for functional status, age, and comorbidities.23 Decreased cognitive function diminishes health-related quality of life and is associated with adverse financial and social penalties for patients and their care providers.24 Investigations on normal aging show a relationship between abrupt declines in cognitive function with early death in older adults.24 POCD has also often been associated with cardiac surgery.25 Another study evaluated cognitive decline in elderly patients (1218 patients 60 years and older) who had major noncardiac surgery and found that 26% of older patients had cognitive dysfunction 1 week postsurgery and 10% had dysfunction 3 months after surgery.11 Therefore, one risk factor for POCD after major surgery is advancing age, and POCD can affect mortality during the time period following surgery.11,12 Older patients with POCD may be at increased risk of death within the first year following surgery. Therefore, efforts should be made to reduce the negative impact on independent factors and predictors of cognitive dysfunction after major surgery. Studies have shown and confirmed that advancing age and lower educational levels are risk factors for development of cognitive decline.11,12,26 In addition, a history of cerebral vascular injury (with or without impairment) and POCD at hospital discharge had a higher incidence of POCD at 3 months following surgery.12 These predictors of cognitive dysfunction correlate with an increased risk of early mortality in older patients because (1) patients with POCD at hospital discharge had a higher death rate in the first 3 months after surgery and (2) patients with POCD at discharge with persistence 3 months following surgery were also more likely to die within the year subsequent to surgery.12

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Table 31.2: Definitions of Cognitive Impairment Dementia Alzheimer’s disease (most common form), vascular dementias, frontal lobe, reversible, senile, Lewy body, and Parkinson-associated

Apathy and personality changes occur early Behavioral changes appear as the condition progresses Psychotic symptoms are late signs (typically difficult to control) Multiple cognitive deficits memory impairment∗ executive decision making aphasia inability to think abstractly apraxia inability to organize and sequence agnosia inability to plan (∗ memory impairment [most prominent] plus at least one of the above must be present) Clinical findings are associated with problems with social activities decline from a previous status problems of occupational activities Up to 75% of dementia cases are not diagnosed Gradual and progressive loss of mental abilities thought disturbances disorientation sensory impairment personality changes (symptoms may be treated, but not cured) Dementia often results in postoperative delirium

Mild cognitive impairment (MCI) (4 subtypes associated with causes of dementia)

Concept to describe transitional level of neurocognitive impairment normal aging process mild cognitive impairment early dementia MCI is a predictor of future dementia MCI diagnosis results in development of dementia at 12% per year Diagnosis by neuropsychological testing and clinical observation Divided into 4 subtypes (based on presence of memory impairment plus number of other cognitive domains affected) Preoperative MCI may result in postoperative delirium

Postoperative cognitive dysfunction (POCD)

Condition in which patients have difficulty in performing cognitive tasks after surgery that they could perform prior to surgery. Tasks/domains of perceiving recognizing sensing judging conceiving reasoning imagining quality of knowing Occurs frequently in and following carotid endarterectomy hip fracture repair surgery cardiac surgery patients (most frequent) Patients are generally alert and oriented POCD not yet defined as an objective condition True deterioration versus random variation International Study of Postoperative Cognitive Dysfunction (ISPOCD) developed criteria of POCD from range of above cognitive domains based on pre- and postoperative neuropsychological testing scores Controversy as to time point when POCD may exist (1 day/1 week/1 year) Predictors of POCD 1 week postoperatively include: duration of anesthesia age (predictor of POCD at 3 mo.) postoperative infection low level of patient education pulmonary complications need for a second operation Up to 2% of cases of POCD persists >1 year

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Delirium

Fluctuating consciousness that develops over hour to days Psychiatric diagnosis (inattention is a key feature) Altered perception and cognition (not associated with dementia) Condition is a result of a general medical condition102 Predictive models (such as impaired vision, dehydration, and severe illness) and interventional strategies exist for delirium in medical patients In-hospital predictors of delirium include bladder catheters functional status male sex malnutrition infection depression 3 or more medications H2 antagonists age iatrogenic events benzodiazepines opioids alcohol + drug abuse

Postoperative delirium (POD)

Not present in immediate postoperative period Develops on postoperative days 1–3 and can be sustained >1 week Predictors and preoperative factors of POD anticholinergic drugs polypharmacy benzodiazepines cognitive impairment advanced age sleep deprivation functional impairment impaired vision immobility low serum albumin impaired hearing dehydration glucose abnormalities ETOH abuse comorbidities hip fracture repair cardiac surgery eye surgery aortic aneurysm repair thoracic surgery other ortho intraperitoneal surgery massive blood loss hypoxia electrolyte abnormalities hypotension meperidine postoperative pain at rest ? age associated central cholinergic deficiency as a positive predictor Two types of postoperative delirium hypoactive form (more common and more commonly overlooked) hyperactive type Confusion Assessment Method tool for clinical diagnosis by assessing fluctuating course of an acute change in mental status inattention altered level of consciousness disorganized thinking (diagnosis of POD when a and b are present with either c or d) Perioperative use of benzodiazepines are associated with POD Ill-defined effects of POD on long-term cognitive outcomes ? perioperative haloperidol to decrease duration and severity of POD Postoperative in-dwelling perineural catheters reduce incidence of POD POD may indicate symptoms of other complications sepsis urinary tract infection myocardial infarction stroke pneumonia

Emergence delirium

Present on regaining consciousness following general anesthesia Common in the pediatric surgical population No agreed-on diagnostic criteria (? usefulness of traditional tools) Predicts postoperative delirium

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Thomas M. Halaszynski, Nousheh Saidi, and Javier Lopez

P H A R M AC O K I N E T I C A LT E R AT I O N S I N T H E E L D E R LY PAT I E N T

The aging process can produce pharmacokinetic (the relationship between drug dose and plasma concentration) and pharmacodynamic (the relationship between plasma concentration and clinical effect) alterations. Alterations of clinical response to anesthetic medications in the elderly may be the result of altered pharmacokinetics as well as increases in target organ sensitivity. Physiological changes that accompany aging affect key pharmacologic processes, including drug absorption, distribution, metabolism, and excretion. Some pharmacokinetic alterations are related exclusively to the aging process, whereas other alterations are likely the result of combined effects of age, disease, and environmental influences. Although increasing age is often accompanied by reductions in the physiologic reserve of several organ systems independent of the effects of any disease, these changes are not typically uniform. Consideration of the patients’ physiologic status (ie, hydration, nutrition, hepatorenal function, and cardiac output) and its impact on analgesic pharmacokinetics are as important as physiologic age-related changes. Changes in the body composition associated with aging include an increase in body fat, decrease in the content of totalbody water and lean body mass, and a progressive loss of muscle mass (sarcopenia).27 Muscle mass is reduced by approximately one-third between the ages of 50 and 80 years as a routine component of the aging process.28 Progressive decreases in totalbody water content result in a smaller body central compartment while increases in body fat lead to a greater volume of drug distribution.29 Increases in body fat and diminished muscle mass are generally more pronounced in older women. The relative increase in body fat and decrease in lean body mass of older patients alters drug distribution such that fat-soluble drugs are more widely distributed.30 In contrast, the volume of distribution of water-soluble compounds is reduced such that the dose required to reach a target plasma concentration is decreased. Age-related alterations in renal function lead to clinically significant reductions in the excretion rate of water-soluble drugs and their active metabolites.31 Renal blood flow and kidney mass, including glomerular number and glomerular tubular length, decrease with age.32 There is a progressive loss of GFR during the aging process. Renal blood flow (RBF) is maintained up until the fourth decade of life, but is reduced by approximately 10% per decade thereafter. The decline in RBF is associated with a 50% reduction in GFR between the ages of 20 and 90.33 Blood urea nitrogen (BUN) gradually increases by 0.2 mg/dL per year with aging, but the serum creatinine level is typically unchanged because of a decrease in body muscle mass and reduced creatinine production. Ultimately, reductions of drug clearance results in prolonged duration of action of several opioids and morphine-6-glucoronide. Therefore, elderly patients receiving opioid analgesics should have them administered judiciously, and BUN and creatinine clearance should be monitored throughout the perioperative period. Plasma binding proteins for the acidic class of drug is albumin and plasma binding proteins for basic type drugs are ␣1 acid glycoproteins. Circulating levels of albumin will typically decrease with age, whereas ␣1 -acid glycoprotein levels usually increase with age. For drugs that bind to serum proteins, equilibrium exists between the bound or ineffective portion and the unbound (free) or effective portion. In addition, reductions in albumin observed during illness further elevate levels of free

acidic drugs and may increase risks of toxicity. Basic drugs, such as lidocaine and propanolol, that bind primarily to ␣1 -acid glycoprotein are less affected by illness. Overall, plasma concentration of free drug correlates well with pharmacologic action. Because of an increase in hepatic reserve, loss of hepatic function in the elderly is less likely despite decreases in hepatic blood flow and liver cell mass with age.34 However, the rate of drug biotransformation decreases with age. The liver metabolizes drugs through two different mechanisms, phase I and phase II hepatic metabolism. Phase I metabolism involves drug oxidation and reduction, catalyzed primarily by the cytochrome P450 system within the smooth endoplasmic reticulum of hepatocytes. Phase II hepatic metabolism involves the conjugation of drugs and/or their metabolites into other organic substrates. Drugs that are metabolized through phase I enzymatic activity have prolonged half-lives, because this metabolic activity decreases with age. Opioid analgesics are primarily metabolized in the liver by enzymatic activity (microsomal CYP450-2D6, deaminases, and glucoronidases). Drugs that undergo phase II metabolism are less affected by the aging process and show no evidence of prolonged half-life in older patients. Therefore, because activity of hepatic cytochrome P450-dependent reactions and glucoronidases decrease with age, this may lead to increased risk of toxicity with opioid analgesics.35 P H A R M AC O DY NA M I C A LT E R AT I O N S I N T H E E L D E R LY

Pharmacodynamics will define the biochemical and physiological effects of drugs along with their mechanism of action. Age-related alterations in the number of drug receptors and sensitivity of receptors to specific drugs could influence pharmacodynamics. Elderly patients are generally more sensitive to anesthetics and analgesics. These patients usually require less medication to achieve the desired clinical response and often experience a prolonged duration of effect. Therefore, undesirable hemodynamic consequences may occur more frequently in older patients. For example, a hemodynamic response to intravenous anesthetics may be exaggerated in the elderly as a consequence of decreased myocardial reserve and reduced vasculature compliance. Expected compensatory or reflex responses are often slowed, blunted, or absent because of the physiologic changes associated with normal aging and age-related disease. A reduced or downward adjustment in drug dosage is often required in older patients secondary to the multifaceted causes of altered and often variable pharmacologic effect. However, many of these pharmacodynamic parameters are not well understood, so all drugs administered to older patients should be used with caution because reactions may be variable, different, and with unforeseen consequences and side effects. In the elderly, anesthetic dosage requirements for local anesthetic minimum concentration (Cm ) and GA minimum alveolar concentration (MAC) are reduced, and a longer duration of action may be expected from spinal and epidural anesthetics.36 A given volume of an epidural local anesthetic tends to result in more cephalad spread and a prolonged duration of motor block in older patients. Recovery time following GA is often prolonged in elderly patients along with evidence of a longer time to recover from its CNS depressive effects. Therefore, prolonged recovery times, potential for mental status changes and negative cognitive effects from GA may be exaggerated in older patients, especially those with underlying cognitive dysfunction.

Elderly High-Risk and Cognitively Impaired Patients

Elderly patients show lower postoperative pain relief requirements.37 Opioids are used during anesthesia and for postoperative pain management but may also have a high potential to be problematic for older patients. Enhanced sensitivity to fentanyl, alfentanil, and sufentanil seems to be pharmacodynamic in nature for elderly patients.29 Opioids have a larger volume of distribution in older patients, yet opioid pharmacokinetics do not appear significantly affected by age. In addition, dose requirements of fentanyl and alfentanil to achieve end-point reductions in the electroencephalogram (EEG) are lower in elderly patients.29 In a comprehensive review, activity of sufentanil, alfentanil, and fentanyl were found to be about twice as potent in elderly patients.29 Such findings are related to increased brain sensitivity with advancing age rather than alterations in opioid pharmacokinetics. Morphine and, to a lesser extent, meperidine are employed for postoperative analgesia. The clearance of morphine is decreased in the elderly and the clearance of morphine-6glucuronide is critically dependent on renal excretion.38,39 Patients with renal insufficiency have impaired elimination of morphine-6-glucoronide that may account for enhanced analgesia along with potential for increased adverse events.40 Meperidine should be avoided in the elderly, because it has a relatively long half-life and its metabolite, normeperidine, has anticholinergic activity that may lead to seizures and predispose patients to cognitive dysfunction.41,42 Because meperidine is metabolized in the kidneys and dependant on renal function, this may predispose older patients with decreased glomerular filtration rates to the deleterious effects of normeperidine. Opioid analgesic common complications include nausea and vomiting, sedation, delirium, and respiratory depression. Constipation is also a common side effect of opioids with elderly patients being very susceptible. Sedation and delirium are CNS side effects produced by opiates in older patients and when these symptoms develop, decreasing the opioid dosage or switching to a different opioid may minimize or alleviate these side effects. Another common effect of opioid use is respiratory depression that may be exacerbated in the opiate-na¨ıve and patients with chronic obstructive pulmonary disease (COPD) and sleep apnea. The volume of distribution for benzodiazepines increase with age and advancing age prolongs its elimination half-life. There is an enhanced pharmacodynamic sensitivity to benzodiazepines in older patients. For example, the elimination half-life of diazepam can be as long as 36–72 hours and elimination halflife of midazolam (requirements are 50% less in elderly patients) can be prolonged from 2.5 to 4 hours.43 Local anesthetic (LA) metabolism varies considerably in older patients and is a major factor in selecting a particular agent for use. LA toxicity is related to the free concentration of drug in the plasma and binding of LA to proteins in the serum and to tissue receptor sites reduces the concentration of free drug in the systemic circulation.44 Amide-linked local anesthetics are degraded by hepatic cytochrome P450 enzymes with the initial reactions involving N-dealkylation and then hydrolysis, so caution should be exercised with amide local anesthetics in elderly patients with hepatic disease. Amide local anesthetics are extensively (55% to 95%) bound to plasma proteins, particularly ␣1 -acid glycoprotein, and there are factors that may increase (eg, cancer, surgery, trauma, myocardial infarction, smoking, and uremia) or decrease (eg, oral contraceptives) plasma levels of ␣1 -acid glycoprotein and local anesthetic delivery to the liver. In addition to the age-related changes of protein binding abilities

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to local anesthetics, elderly patients with reduced cardiac output could result in slow delivery of amide compounds to the liver, thus prolonging their plasma half-lives.

A LT E R AT I O N S I N PA I N P E RC E P T I O N A N D D I F F I C U LT I E S A S S E S S I N G PA I N I N T H E E L D E R LY PAT I E N T

Clinical studies and experimental evidence provide support that pain perception and reaction to noxious stimulation are reduced in elderly patients.45,46 However, it is not clear if alterations in pain perception are because of aging processes or age-associated comorbid disease such as diabetes and neuropathy.47 Controversy exists regarding pain perception in cognitively impaired patients. Pain intensity measurements in patients with moderate to severe cognitive impairment is difficult for pain specialists and geriatricians alike.48 Nevertheless, basic principles for evaluating pain intensity and relief should remain similar to that employed for other patients.49 In mildly confused patients, continual pain assessment using descriptor or “faces” scales rather than difficult to comprehend numerical scales should be considered. There are several general principles that should be practiced when managing perioperative analgesic needs of elderly patients. It is important to reduce the burden of opioids, benzodiazepins, and other CNS depressants by incorporating alternative modalities of analgesia such as central-neuraxial blockade, peripheral nerve and nerve plexus blockade, nonopioid analgesics, and adjuvants. Intravenous patient-controlled analgesia (IV PCA) may be poorly understood and not optimized by elderly patients, and if cognitive dysfunction is evident, then discontinuation of such therapy should be considered. Peripheral nerve blockade (PNB), neuraxial analgesia, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and intermittent small doses of IV opioids will enhance analgesia, reduce opioid requirements, and minimize risk of narcotic toxicity. Use of multimodal regimens that include neural blockade is especially important in elderly patients with significant comorbid disease and decreased physiological reserve.50

N E U R A X I A L R E G I O NA L A NA LG E S I A A N D P E R I P H E R A L N E RV E B LO C K A D E V E R S U S O P I O I D - B A S E D A NA LG E S I A

A general approach to optimize perioperative pain management in geriatric patients is to consider postoperative complications commonly associated with routine surgical procedures to assess any potential benefits associated with PNB and neuraxial regional anesthesia/analgesia (NRA). Neurologic, pulmonary, and cardiovascular complications are among the most common observed in the elderly and occur most frequently in orthopedic and general surgical settings. There are both established and theoretical indications supporting the concept that NRA provides a more effective and safer analgesic option for elderly and cognitively impaired patients, and these are listed in Table 31.3. Nevertheless, it is the lack of consistency within NRA studies that has prevented firm recommendations, indications, and guidelines, about which techniques offer the greatest advantage for elderly and cognitively impaired patients undergoing particular surgical procedures.

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Table 31.3: Perioperative Outcomes of Regional Anesthesia and Analgesia Organ System

Theoretical and Established Benefits of Regional Anesthesia

Central nervous system

Questionable influence on postoperative cognitive function Preoperative placement of RA (with or without GA) may provide preemptive analgesia Improved functional outcome and less need for psychological rehabilitation

Cardiovascular system

May influence or reduce incidence of myocardial infarction Provide more stable perioperative hemodynamics

Respiratory system

When used as primary anesthetic technique, RA can avoid endotracheal intubation and mechanical ventilation RA may lead to less respiratory complications (especially if able to avoid GA) Preserved respiratory responses to hypercapnia and hypoxia Reduced incidence of pneumonia Reduced length of intubation time Maintenance of functional residual capacity Preservation of pulmonary gas exchange

Gastrointestinal system

Reduced risk of postoperative nausea and vomiting (especially when opioid use is reduced or not used perioperatively) Reduced incidence of gastrointestinal dysfunction

Endocrine and immune system

May preserve patient immune response Maintain glucose homeostasis and tolerance Reduce catabolic activity and responses (improve protein economy) May suppress stress response of surgery and GA Decreased incidence of postoperative infection

Hematologic system

Lowered incidence of venous thromboembolism Reduced occurrence (lowers risk) of deep vein thrombosis Lowered risk/incidence of pulmonary embolism Reduced intraoperative blood loss Reduced need for perioperative blood transfusion Reduced incidence of graft thrombosis

Other

Possibly improved postoperative recovery profile (especially early) Reduced dependence on opioids and opioid-related complications (pulmonary function, GI system, CNS, etc) Superior perioperative pain relief (RA anesthesia and analgesia) May result in shortening or bypassing the PACU May shorten hospital stay (shorter home readiness time), along with reductions in hospital readmissions Superior pain management/pain relief may lead to reduced costs and reduction of intensity of medical ancillary provider care Improved economics and cost-effectiveness Better satisfaction from the patient and patient family Overall improved surgical outcomes

Abbreviations: CNS = central nervous system; GA = general anesthesia; GI = gastrointestinal; PACU = postanesthesia care unit; RA = regional anesthesia.

Definitions and descriptions of RA are variable as are definitions of the various techniques of analgesia and anesthesia (Table 31.4). Most clinical investigations use neuraxial anesthesia (with or without analgesia) to mean RA, yet some studies will include peripheral nerve plexus blockade and PNB, LA infiltration, and LA injection to depict RA. In this chap-

ter, NRA will refer to neuraxial regional anesthesia and analgesia (spinal and/or epidural anesthesia and analgesia), PNB will be considered separately, and RA will be used to encompass all non-GA techniques. Perioperative outcomes and clinical outcomes associated with NRA effectiveness, morbidity (traditional and nontraditional complications51 ), and mortality to be

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Table 31.4: Techniques of Analgesia and Anesthesia Regional Anesthesia and Analgesia Neuraxial

With or without other intravenous perioperative medications (analgesics, sedation) Spinal (subarachnoid) and/or epidural anesthesia and/or analgesia single injection, with or without catheters local anesthetic (type, concentration) with or without opioids and other adjuncts vertebral level of block placement/initiation level of blockade achieved length or duration of postoperative anesthesia and analgesia

Peripheral nerve/nerve plexus blockade

Peripheral nerve block local anesthetic with or without additives single injection or continuous catheter technique

Infiltration/field block

Local anesthetic infiltration/injection (diffusion blockade) with or without indwelling catheters

General anesthesia and analgesia

With or without perioperative medications

Anesthesia

Inhalation agents, intravenous agents, and/or total intravenous anesthesia (TIVA)

Analgesia

Systemically administered analgesia with opioids, nonopioids, and other adjuncts intramuscular injections intravenous boluses patient-controlled analgesia (PCA) transdermal, mucous membrane and oral routes

Local monitored anesthesia care (LMAC)

LMAC with and/or without intravenous and oral sedatives, hypnotics, analgesics (opioid and nonopioid)

discussed include pain management, functional and economical outcomes, functional health status, quality of life measurements, morbidity (cognitive, CNS, cardiovascular, pulmonary, GI, immune, endocrine, and coagulation), and mortality. With either NRA or PNB, it is important to consider and take into account patient age, anticipated surgical procedure, patient comorbidity(ies), and potential postoperative pain management requirements when deciding on an appropriate choice of anesthetic technique in the elderly. C H O I C E O F A N E S T H E S I A A N D A NA LG E S I A : I M PAC T O N P O S TO P E R AT I V E C O G N I T I V E F U N C T I O N I N E L D E R LY PAT I E N T S

Drugs administered to the elderly during the perioperative period may have significant variability, profound influence, and many potential adverse effects on the nervous system. Prior to surgery, a comprehensive perioperative evaluation of the elderly patient should be performed as a multidisciplinary team approach. In addition to assessing vital organ function, the preoperative evaluation should always assess for evidence of any cognitive impairment. Elderly patients often present with agerelated changes of the nervous system, and whether these changes are normal or pathologic, they are to be considered in the anesthetic plan and during the selection of appropriate postoperative pain management. Hypothesis and theory abound that NRA and PNB followed by continuous neural infusion may reduce the incidence of POCD in the elderly.52 Preliminary outcome studies have noted

such reductions in morbidity when RA was provided to elderly patients undergoing certain surgical procedures (Table 31.5). For example, (1) the incidence of acute postoperative confusion in elderly patients recovering from hip fracture surgery was reduced with RA53 and (2) elderly patients recovering from high delirium risk surgery (femoral neck fracture repair) performed under spinal anesthesia did not experience clinically significant delirium.54 It is important to note that these individuals did not receive perioperative premedication or excessive sedation. As discussed, poorly controlled postoperative pain is associated with an increased incidence of cognitive dysfunction.19 Thus, it would seem prudent to provide optimal pain management and use agents that have fewer adverse events along with medications and medication concentrations yielding minimal influence on cognitive function. This implication is important when considering RA techniques because LA infusions have been shown to provide superior pain control compared to systemic opioids55 along with reductions in side effects, such as POCD, that have been associated with use of systemic narcotics.56 In addition, epidural analgesia can reduce the incidence of postoperative pulmonary complications that have shown to be connected with an increased occurrence of POCD.11,57,58 Numerous trials examining intraoperative neuraxial anesthesia versus GA have not observed improved preservation of postoperative cognitive function and neuraxial anesthesia has yet been shown to reduce the overall incidence of POCD. There is inconclusive evidence that PNB and continuous regional analgesia are associated with a lower incidence of POCD. Some of the problems evaluating studies that address the issue of cognitive preservation in elderly patients are related to multiple

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Table 31.5: Comparing Effects of Regional Anesthesia on Morbidity and Mortality Positive Conclusions with Regional

Negative Conclusions with Regional

Reference

Reductions of intraoperative blood loss and postoperative thromboemblic events after prostatectomy and hip surgery

No definitive results confirming reductions in CNS, cardiac, respiratory, and GI morbidity

Kehlet (1984)105

Diminished incidence of postoperative morbidity Decreased incidence of postoperative mortality Atanassoff (1996)62

30% reduction in early mortality Some benefit on short-term survival Epidural opioid vs. systemic opioid: decreased occurrence of atelectasis decreased incidence of pulmonary infections increased PaO2 decreased overall rate of pulmonary complications

Epidural opioid vs. systemic opioid: no significant differences in other pulmonary function factors

Ballantyne et al (1998)57

Reduced morbidity in patients with neuraxial block: decreased incidence of MI (30%) decreased incidence of DVT (40%) decreased incidence of PE (55%) decreased incidence of respiratory depression (59%) decreased incidence of pneumonia (39%) decreased incidence of blood transfusion (50%)

Most of the study subjects (N = 9559) received single-shot epidural anesthesia

Rodgers et al (2000)58

The study subjects (N = 9559) were predominantly orthopedic patients and no significant effects were found in other surgical procedures

Overall mortality reduced (33%) Group 1 – GA + PCA, Group 2 – epidural + GA Group 2 – epidural + GA: reduced ICU stay in abdominal surgical pts reduced incidence of major complications in abdominal surgical pts shorter intubation time for abdominal surgical pts improved pain relief despite reduced analgesic drugs reduced mortality in abdominal surgical pts improved overall outcome in abdominal surgical pts

No difference in mortality when all types of abdominal surgeries (4 types) were combined from all subjects (N = 1021)

Park et al (2001)64

Patients in the epidural group:

Results of this meta-analysis did not show statistical significance in mortality of study subjects (N = 1173)

Beattie et al (2001)66

Epidural (+ GA) group of patients for AAA had reduced time to extubation compared to the GA only group

Study patients (N = 168) had similar postoperative outcomes related to: morbidity (renal failure, MI, medical costs, reoperation, length of hospital stay, pneumonia) and mortality

Norris et al (2001)104

Reduced pulmonary morbidity from epidural opioid analgesia in thoracic surgery patients

No difference in length of hospital stay No change in cardiac morbidity No effects toward POCD

Kehlet and Holte (2001)79

better analgesia reduced incidence of postoperative MI significantly reduced postoperative MI in the patients with thoracic epidural analgesia

Reduced pulmonary morbidity from epidural (with or without opioid) in abdominal surgical patients Reductions of surgical stress response from epidural Reductions of thromboembolic problems from epidural Reductions of ileus from epidural (without opioids) Improved transition to rehabilitation

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Positive Conclusions with Regional

Negative Conclusions with Regional

Reference

Improved oxygen saturation on first postoperative day with RA Reduced incidence of DVT Reduced incidence of mortality at 1 month

No differences for study subjects (N = 2262) in: length of surgery, PE incidence, or length of hospital stay

Sharrock (1995)112

When RA combined with GA in major abdominal surgery: reduced pulmonary failure and improved pain control

Other morbidity events were not reduced in patients (N = 915) undergoing abdominal surgery with the addition of RA to GA

Rigg et al (2002)76

Epidural anesthesia and analgesia had reduced pulmonary failure

No differences in other morbidity events or mortality

Peyton et al (2003)106

Reduced mortality but not significant statistically

Matot et al (2003)65

Preoperative epidural reduced preoperative cardiac events in elderly hip fracture patients (N = 68) Epidural compared to parenteral opioids: improved analgesia for thoracic surgery improved rest and movement pain scores improved analgesia for abdominal surgery reduced PONV (without epidural opioid)

Of the 100 study trials, thoracic epidural was similar to the parenteral opioids

Block et al (2003)55

Beattie et al (2003)67

Reductions in postoperative MI with thoracic epidural analgesia (meta-analysis, N = 2427) Unadjusted 7- and 30-day mortality reduced in RA (+ GA) compared to GA alone group

No difference in multivariate regression analysis in morbidity and mortality at 7 and 30 days

Wu et al (2003)107

Reduced risk of DVT Reduced rate of acute postoperative confusion Reduced mortality at 1 month in 8 of 22 trials (N = 2567)

No difference in mortality in 6 of 22 trials (N = 2567)

Parker et al (2004)53

Reduced mortality at 7 and 30 days with postoperative epidural analgesia (N = 12,780)

Incidence of pneumonia increased at 30 days in epidural analgesia group (N = 12,780)

Wu et al (2004)68

Overall, morbidity unchanged (N = 68,723) Thoracic epidural + GA in CABG: reduced pain and pain scores (also intrathecal group) reduced opioid use and requirements reduced time to extubation reduced risk of respiratory complications decreased incidence of dysrhythmias

No difference in morbidity and mortality of intrathecal RA

Improved cognitive function in first few hours postoperatively

No difference in mental status beyond first few hours postoperatively

Handley et al (1994)109 ; Williams-Russo et al (1995)59

Permits increased activity and improved mobility (short- and long-term postoperatively)

Time to first ambulation is not effected

Gottsahalk et al (1998)110 ; Gilbert et al (2000)111

Liu et al (2004)108

No difference in mortality with thoracic epidural

Abbreviations: AAA = abdominal aortic aneurysm; CABG = coronary artery bypass grafting; CNS = central nervous system; DVT = deep vein thrombosis; GA = general anesthesia; GI = gastrointestinal; ICU = intensive care unit; MI = myocardial infarction; PCA = patient controlled analgesia; PE = pulmonary embolism; POCD = postoperative cognitive dysfunction; PONV = postoperative nausea and vomiting; RA = regional anesthesia.

design flaws and the methodological variability of clinical trials (Table 31.6). Attempts at interpreting past and current evidence provides conflicting results and even in the hierarchy of evidence, such as meta-analysis of randomly controlled trials and large randomized trials as best evidence, there is lack of data to demonstrate preservation of cognition beyond the first few hours after surgery when selecting NRA and PNB rather than GA.59,60

Meta-analysis results may demonstrate significant improvement in mortality when neuraxial blockade is used without GA,55,58,61 but until POCD predictors and consequences are determined, it will remain difficult to make recommendations for appropriate treatment and prevention of POCD. When POCD has been identified or suspected in a surgical patient, work-up for additional causes of cognitive impairment (ie, Alzheimers’,

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Table 31.6: Study Design Flaws and Complexity of Conflicting Results Design Flaws

Conflicting Results and Methodological Difficulties

Indiscriminant use and lack of accounting for use of sedative/hypnotic drugs. No controls for preoperative sedation/analgesia in RA patients

Mortality rates are decreasing, necessitating the need for studies that have large numberss of patients (underpowered studies)112

Duration of postoperative analgesia must be identified and remains important factor for pain & stress responses, morbidity and mortality

Diverse surgical procedures and heterogeneous patient populations

Diversity of assessment of POCD No uniformity of neuropsychological testing

Lack of control of sedation depth may disregard differences between GA & RA63

Studies not being double-blinded30

Timing of placement of RA (uncontrolled factor)

Diversity on modes of POCD analysis

Lack of routine consideration of different anesthetic techniques: upper vs lower body, anesthesia vs analgesia, RA + GA vs RA, LA alone vs LA + adjuncts

Parenteral use of postoperative sedatives and opioids uncontrolled and indiscriminately used

Diversity of definitions of POCD and POD

Vertebral location of RA (thoracic, lumbar, etc) Abbreviations: GA = general anesthesia; LA = local anesthesia; POCD = postoperative cognitive dysfunction; POD = postoperative delirium; RA = regional anesthesia.

stroke, cerebral hematoma) should be initiated. These patients should be followed closely with subspecialty consultation if necessary and then reassured because POCD does not typically persist (>1 year in 1%–2% of cases). Additional consequences warranting further examination are that symptoms from pain and untoward effects of postoperative medications may result in poor performance in the varied forms of neuropsychological testing. These factors may prove to lead to declines in cognition in the days following major surgery when use of such postoperative medications and pain levels are at there greatest. C H O I C E O F A N E S T H E S I A A N D A NA LG E S I A : I M PAC T O N P O S TO P E R AT I V E C A R D I OVA S C U L A R F U N C T I O N I N T H E E L D E R LY

With aging, there are a variety of morphological and functional changes in the cardiovascular system. These changes include reduction in left ventricular compliance, generalized hypertrophy of the left ventricular wall, fibrotic changes in the heart, and decreased myocardial compliance. These changes result in increased stoke volume and elevated diastolic and systolic blood pressure (Table 31.7). Many elderly patients present with cardiac pathology, including moderate to severe coronary artery disease, valvular heart disease, and conduction defects that increases risk of postsurgical morbidity and death. Aging effects on cardiac output have minimal influence in the resting individual, but functional changes become evident with stress. Similar effort dependent stress is observed with negative influences on pulmonary function. Aging influences on the heart and vascular system have important clinical implications for the treatment of elderly surgical patients and for considerations of postoperative pain management, especially those patients receiving RA. Currently, there is little statistical evidence to suggest differences in cardiovascular outcome and effects on mortality between RA versus GA in the elderly,62,63 although there have been studies showing a significant benefit for use of RA and its influence on cardiac morbidity and short-term survival (Table 31.5). Even though there is little suggestion and data to indicate a statistically signif-

icant difference in anesthetic technique (RA versus GA) toward the overall incidence of death or major complications; analysis of RA has detected a positive influence on pain management and better outcomes when considering the type of surgery being performed. For example, when epidural anesthesia and analgesia are combined with GA for elective abdominal aortic aneurysm repair, the duration of postoperative tracheal intubation, mechanical ventilation, total ICU stay, and use of resources are reduced. In addition, the quality of postoperative analgesia is improved, whereas the incidence of major complications and death are reduced.64 Early placement of continuous epidural analgesia in elderly patients for hip fracture surgery versus a regimen of systemic opioids has been associated with a reduced incidence of adverse cardiac events.65 Therefore, when studies are tailored with consideration for planned surgery, patient comorbid disease(s), and perioperative patient management needs, evidence may then be available to better provide guidelines followed by anesthesia protocols that could affect surgical patient cardiovascular outcomes. Currently, there remains conflicting results and altering consensus between analgesic technique and cardiac morbidity. However, recent meta-analysis of randomly controlled trials (N = 9559) showed that patients undergoing various orthopedic procedures and receiving neuraxial blockade had a onethird reduction in overall mortality.58 An additional metaanalysis (N = 2427) found that patients who received epidural anesthesia and analgesia (with or without GA) had a reduced incidence of perioperative myocardial infarction and, in those instances when a thoracic epidural was maintained for analgesia longer than 24 hours, results showed significantly fewer postoperative myocardial infarctions.66,67 Yet another meta-analysis (N = 68 723) on Medicare patients found the association of a significantly lower odds ratio of death at 7 and 30 days when postoperative epidural analgesia was used.68 Perioperative stresses of acute lifestyle disruption, anesthesia, surgery, postoperative pain, and convalescence will activate (to a varying degree) the sympathetic nervous system of the elderly surgical patient. These stresses result in mixed and potentially negative imbalances between myocardial oxygen supply and demand and possibly lead to myocardial ischemia and infarction. Perioperative myocardial infarction and other

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Table 31.7: Influence of Age on the Cardiovascular System Morphological Cardiovascular Changes of Aging

Functional Cardiovascular Effects of Aging

Progressive loss of elasticity of large arteries Generalized hypertrophy of the left ventricular wall

Increased systolic blood pressure Increased afterload for the left ventricle Increased left ventricular end-diastolic volume Cardiovascular system is volume sensitive and volume intolerant

Fibrotic changes and diminished elasticity of heart muscle (reduced myocardial compliance) Reduced compliance of left ventricular ejection fraction (LVEF)

Unable to optimally respond to stress (cannot significantly increase LVEF) Cardiac output is maintained by increasing end diastolic volume Overall results are an increased stroke volume Elderly patients may not maintain blood pressure when challenged with minor hypovolemia or added cardiovascular stresses Sympathetic blockade from neuraxial anesthesia may lead to hypotension in a setting of hypovolemia

deleterious cardiovascular events such as congestive heart failure (CHF), sudden death, and cardiac arrhythmias typically occur with increased frequency within the first few days following a surgical intervention69,70 and patients with a reduced cardiovascular reserve or patients at risk of perioperative myocardial events have a higher incidence of perioperative myocardial ischemia and infarction.71 Therefore, goals for anesthesia and surgery during the perioperative period would be to reduce or eliminate the many physiologic imbalances and stresses associated with operative interventions to minimize negative cardiovascular effects. Thoracic epidural analgesia may attenuate adverse cardiovascular pathophysiologic events because neural blockade decreases sympathetic outflow yielding a more favorable balance between myocardial oxygen supply and demand. Reductions in sympathetic activity result in decreased cardiac inotropy and decreased heart rate and blood pressure instability, whereas at the same time increasing coronary blood flow to subendocardial regions at risk for ischemia. There currently remains uncertainty to the statistically proven beneficial influence of postoperative epidural analgesia on the incidence of myocardial ischemia, myocardial infarction, or myocardial malignant arrhythmias (Table 31.5). However, use of thoracic epidural analgesia (not lumbar) has revealed statically significant reductions in ventricular malignant arrhythmias and decreased incidence of postoperative myocardial infarction.66 Therefore, in the appropriate surgical setting, physiologic benefits of thoracic epidural analgesia can decrease adverse cardiovascular pathophysiologic events such as myocardial infarction in the older surgical candidate. There is relatively little information or outcome data regarding the benefits of PNB with or without continuous LA infusion on perioperative cardiac morbidity and mortality in the older surgical patient. However, it is likely that adequately controlled postoperative pain could have beneficial cardiovascular effects with regard to development of myocardial dysfunction if catecholamine levels associated with stress and pain of the perioperative period are minimized. Also apparent are benefits of superior analgesia with PNB compared to systemic opioids that may result in reductions or preventions of myocardial sensitization and minimizing the pain induced stressful component associated with surgery. PNB are used in older surgical patients to provide preemptive analgesia, reduce or avoid the need for GA and its many deleterious effects, and reduce untoward sympathetic stimulations and stress responses associated with surgical interventions. PNB that

complement multimodal therapies have been demonstrated to have ameliorative effects on acute pain72 with resulting potential indirect influence of improvement in anesthesia and surgical management that may lead to a reduction in cardiac morbidity and mortality. An additional important factor to consider is the method used to achieve the necessary duration of postoperative analgesia. Postoperative analgesia is important because pain from surgery, surgical stress responses, and effects from surgery on the cardiovascular system do not subside until a few days following surgery. Therefore, timing and duration of a PNB, achieved with a continuous catheter technique, may provide cardiovascular benefits by reducing surgical pain and associated sympathetic and neuroendocrine stress responses during the postoperative period. C H O I C E O F A N E S T H E S I A A N D A NA LG E S I A : E F F E C T O N P O S TO P E R AT I V E P U L M O NA RY F U N C T I O N I N T H E E L D E R LY

Significant perioperative risk among elderly patients is attributable to respiratory compromise and complications. A substantial portion of the risk is explained by both functional and structural changes within the pulmonary system commonly associated with aging (Table 31.8). Reductions in functional residual capacity (FRC) are created by assuming the supine position and under the influence of GA. GA can reduce FRC by 15%– 20% and can last 7–10 days following surgery.73 Older patients undergoing GA are predisposed to atelectasis from the combination of reduced FRC and age-associated increases in closing volume. Vital capacity can be reduced after upper abdominal incisions (25%–50%) and postoperative pain along with systemic opioid analgesics can contribute to a reduction in tidal volume and impair clearing of secretions (altered cough mechanics). Hypoxic pulmonary vasoconstriction (HPV) is adversely affected and maybe abolished during inhalation anesthesia. Blunting of HPV in the elderly during GA causes a greater incidence of intraoperative ventilation perfusion (V/Q) mismatch, and an increased alveolar-to-arterial oxygen gradient. Inhalation anesthesia depresses respiratory responses to hypoxia and hypercarbia and patients receiving inhalation agents commonly require tracheal intubation because of a high incidence of airway obstruction. These negative influences can compromise the usual protective responses of the pulmonary system during the perioperative period and are to be considered in the

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Table 31.8: Influence of Aging on the Pulmonary System Structures

Functional Changes

Results

Conducting airways (nose to respiratory bronchioles)

Changes (minor) of muscle and cartilaginous support Slow loss of elastin, collagen, water content, along with muscle atrophy

May result in dry mouth, snoring, bleeding, and mucosal injury Predisposes to upper airway obstruction

Diameter of trachea and central airways

Increase in size of cartilaginous airways (trachea and bronchi) by 10% Calcification of central airway cartilage Bronchial mucous gland hypertrpophy ? increased compliance of small and large airways

Functional increase in anatomical dead space Airways more prone to compression with forced exhalation Decreased maximum expiratory flow rate Increased residual volume

Upper airway reflexes

Depression of protective airway reflexes (sneezing, coughing, etc) Decreased upper laryngoesophageal sphincter contractile reflex Decreased number and activity of respiratory cilia Coughing reflex impairment

Increased chance of pulmonary aspiration Greater stimulation required to trigger sensory and motor components of airway reflexes

Lung parenchyma, alveolar surface area and elastic recoil

Enlargement of bronchioles and alveolar ducts and shortened alveolar septa Alveolar air decreases as air volume in alveolar ducts increases Reduced surfactant production Lung parenchyma loses elastic recoil Chest wall becomes stiffer

Alveolar surface area decreases (15% by age 70 years) Aging lung: airspace enlargement Flattening of the volume-pressure curve of the lung and less lung compliance

Function of lung defenses

Local defenses (cough, mucocilia) are decreased Humoral defenses (cellular, immune) reduced by decreased T-cell function and regeneration

Failure of T-cell homeostasis

Pulmonary mechanics, chest wall compliance

Calcification of rib cage, vertebral joints, and costal cartilage Osteoporosis and vertebral compromise Altered diaphragm affecting force-generating ability

Chest wall stiffens and decreased chest wall compliance Increase in respiratory work requirements

Respiratory muscles

Decreased strength and speed of skeletal muscle contraction Loss of motor neurons Reduced diaphragm strength Shortened rest-length of inspiratory muscles

Increased oxygen cost of ventilation (especially with stress and physical activity)

Pulmonary vasculature

Reduced volume of pulmonary capillary bed

Increased pulmonary arterial pressure and vascular resistance

Lung volumes and capacities

Increased residual volume because of chest wall stiffness, loss of lung recoil, and decreased muscle strength. Decreased FEV1

Decreased vital capacity Mild increase of functional residual capacity

Expiratory flow

Decreased elastic recoil pressure

Reduced maximum expiratory flow rate

Gas exchange diffusing capacity

Loss of functional alveolar surface area

Decreased oxygen diffusing capacity Increased arterial-alveolar oxygen gradient

Ventilation/perfusion matching

Premature lung airway closure (occurs in tidal volume range) Inspired air is distributed at apexes rather than lung bases Site where small airways close is shifted distally so airways close at smaller exhaled tidal volume

Reduced capillary oxygen tension of basilar lungs Decreased arterial oxygen tension Increased closing volumes Ventilation-perfusion mismatch

Control of respiration ventilatory responses

Decrement of central and peripheral chemoreceptors

Decreased ventilatory response to hypercapnia and hypoxia Increased sensitivity to narcotic induced respiratory depression Increased disruption of sleep ventilation

Elderly High-Risk and Cognitively Impaired Patients

elderly surgical candidate during the postoperative period. Negative effects on pulmonary function predispose older patients to atelectasis, increased risk of hypoxemia and pneumonia, V/Q mismatch, and other postoperative pulmonary complications.74 Therefore, clinicians should titrate analgesic medications carefully and assess patients frequently for evidence of adverse side effects and adequate pain control throughout the perioperative period. Although NRA is commonly used for older patients, many studies have shown that the anesthetic choice has no significant effect on respiratory perioperative morbidity and mortality within any age group. Intuitively it seems reasonable to believe that elderly patients may benefit from NRA because they can remain minimally sedated while breathing spontaneously, airway manipulation is avoided, postoperative pain control is provided, and recovery from any adverse respiratory influences of inhalation anesthetics/GA is minimized or eliminated (Table 31.5). A multitude of factors influence perioperative outcome and make it difficult to decide which form of anesthesia is most appropriate for a given patient and surgical setting. Therefore, the decision to perform RA must be determined on a case-by-case basis, and consideration of the patient’s cardiopulmonary reserve, baseline cognitive function, anesthesiologist expertise, type of surgery, and surgical duration must all be assessed. For example, epidural analgesic techniques may benefit elderly patients undergoing thoracic and upper abdominal surgery because these techniques allow a more rapid restoration of respiratory function with added benefits of decreasing morbidity and hospital stay.75 With NRA, airway manipulation is avoided and respiratory parameters of lung volumes, tidal volume, respiration rate, respiratory drive (effort), and end-tidal carbon dioxide concentration are preserved. Unchanged FRC, from baseline, has been observed during spinal and lumbar epidural anesthesia. However, intercostal blocks and cervical or high thoracic epidural blockade can be associated with lung volume reductions secondary to intercostal muscle relaxation. Therefore, choice of anesthesia may affect the degree of pulmonary dysfunction (Table 31.5). Studies have shown that elderly patients undergoing lower extremity orthopedic procedures have fewer hypoxic events with epidural anesthesia (using LA) compared to systemic opioids; GA in older patients results in lower PaO2 levels (on postop day 1) compared to epidural anesthesia; and respiratory complications are less frequent when comparing GA with postoperative intravenous morphine analgesia versus combined epidural plus GA with postoperative epidural analgesia.76 NRA with dilute LA solutions for analgesia may provide a greater safety margin for elderly patients compared to administration of systemic and epidural opioids. Using NRA (without opioids) in the elderly population, especially for patients with severe pulmonary dysfunction, may be more appropriate for postoperative pain relief.62,77 Oxygen saturation in elderly patients with epidural anesthesia and analgesia without an opioid is typically higher and the use of systemic (and epidural) opioids results in a higher incidence of hypoxic events compared to epidural analgesia with a LA alone.78 However, overreliance on LA may be associated with a greater incidence and severity of hypotension. In addition, there is a reduced incidence of pulmonary infection, an increase in PaO2 , and an overall decrease in pulmonary complications with epidural LA compared to systemic opioids for postoperative analgesia.57 However, several meta-analysis have found that reduced atelectasis is observed

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with epidural opioids compared to systemic opioids (for postoperative analgesia) and that continuous epidural LA or local anesthetic-opioid mixtures resulted in reduced postoperative pulmonary morbidity after major abdominal and thoracic procedures when compared to parenteral opioids.79 Another meta-analysis has shown that RA may decrease pulmonary complications because patients receiving epidural analgesia were found to have shortened ICU stays and reduced tracheal intubation times versus patients receiving systemic postoperative opioids for analgesia.53 A meta-analysis of 141 clinical trials have discovered results showing a 39% reduction in pneumonia and 60% less pulmonary depression with thoracic epidural anesthesia and analgesia versus GA and postoperative patient-controlled analgesia.58 Therefore, much of the controversy as to why several randomized trials have not demonstrated a statistical advantage to RA in reducing respiratory complications in the elderly is lack of differentiation and uniformity of epidural mixtures, whether an opioid or how much opioid (systemic and/or epidural) was used, the site of surgery, timing and duration of neuraxial anesthesia and analgesia, and vertebral level of neuraxial blockade insertion. The benefits of PNB on postoperative pulmonary function have not been well studied. However, with utilization of PNB, manipulation of the airway can be avoided, patient lung volumes and function are preserved, and the respiratory drive is minimally (sedation for block placement) or not affected. Given that GA may have greater negative effects on the respiratory system compared to RA, the choice of anesthesia may affect the degree of postoperative pulmonary dysfunction in the elderly. Therefore, any surgery involving the extremities (orthopedic procedures), vascular procedures, skin grafting, and amputations should be considered for a PNB anesthetic. Because the reduction of FRC following GA may persist for up to 10 days following surgery with GA,74 possibly fewer hypoxic events with PNB using LA compared to systemic opioids after surgery may result. The lower PaO2 levels80 and other potential respiratory complications76 reported with GA may also be minimized or eliminated if the surgical intervention is amendable and a PNB with LA is used versus reliance on postoperative intravenous opioid analgesia. PNB differ from GA and neuraxial anesthesia/analgesia in terms of influence on the respiratory system. There are few investigations comparing pulmonary morbidity and mortality among GA, neuraxial anesthesia, and PNB, although there are several advantages of PNB to consider for elderly patients, especially in orthopedic procedures. PNB of the lower extremities and neuraxial anesthesia has a positive influence on vascular blood flow. Increased blood flow reduces the incidence of postoperative thromboembolic complications such as deep vein thrombosis (DVT) and pulmonary emboli. By avoiding airway manipulation and preserving respiratory drive, PNB are also associated with a lower incidence of hypercarbia, hypoxia, and pulmonary complications. By minimizing exposure to opioids, PNB and central neuraxial LA blockade may shorten tracheal intubation time and ICU stay when compared to systemic analgesia with opioids. C H O I C E O F A N E S T H E S I A A N D A NA LG E S I A : E F F E C T O N P O S TO P E R AT I V E E N D O C R I N E AND IMMUNE FUNCTION

With possible exception of large doses of opioids prior to surgical incision, GA alone cannot prevent stress responses of surgery

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from being initiated.81 Some of the metabolic effects of surgical stress are hyperglycemia and overall catabolism. RA may provide the most physiological anesthesia for surgery and theoretically prevent or reduce the surgical stress response (Table 31.5). For example, epidural anesthesia may minimize surgical stress by blocking sympathetic and somatic nervous systems from being activated. Epidural blockade reduces postoperative hyperglycemia and improves glucose tolerance despite plasma insulin concentrations being unchanged.79 More stable cardiovascular hemodynamics and attenuation of the stress response to surgery has been demonstrated with RA.82 The metabolic effects of surgical stress, hyperglycemia, and catabolism may predispose patients (especially critically ill patients) to increased morbidity (polyneuropathy, infection, multiorgan dysfunction/failure) and mortality. Plasma glucose normalization and improved glucose tolerance with epidural anesthesia and analgesia can improve perioperative management of optimal glucose control. Epidural anesthesia and analgesia can reduce the catabolic response to surgery and improve on gastrointestinal rehabilitation, economy of proteins, and nutritional status of surgical patients, especially in abdominal surgery.83 The communicating capability of circulating immune cells and cytokines of the immune system serve as major defense systems in the human body. However, there are reduced cellular and humoral responses seen throughout the entire immune system and there is a corresponding reduction and deterioration of immune system components with aging. The thymus gland and thymulin secretions undergo an involutionary process and decreased production, respectively, as we age. Hormones responsible for mature T-cell modulation and progenitor phenotypic cell maturation processes are reduced and T-lymphocyte number contribution into circulation is lessened with aging. Immunological changes of the aging process become evident when older patients become stressed and move away from the homeostatic state. Therefore, measures taken to ensure homeostasis and to reduce surgical stress will help preserve function of the immune system. It has been shown that epidural anesthesia and analgesia can preserve both humoral and cellular immune functions in surgical patients (especially for procedures below the umbilicus).84 GA may worsen the immunosuppression responses that can occur subsequent to surgery. Both GA and lumbar epidural anesthesia have minor influences on the human immune function in the absence of surgery, but it is with epidural anesthesia and analgesia (with LA) that may decrease the postoperative infectious complications of surgery.84 Whether PNB and continuous peripheral catheter infusion techniques blunt the effects of stress on the endocrine and immune system and improve surgical outcomes remains unclear. Many components of the pain pathway are sensitized by painful stimulation and there are a network of theories (immune deficiency, autoimmune, network, etc) to explain the complex interactions of pain and influence on the immune and endocrine systems of all patients. Therefore, attempts to achieve a balanced multimodal anesthetic (along with the theory of preemptive analgesia) may provide a significant role for PNB as an intervention that targets one of the key sites (peripheral nociceptors) along the pain pathway aiding in the prevention of nervous system sensitization and activation of the endocrine system. In many surgical settings (especially surgery performed on the extremities), superior pain relief provided by PNB may reduce the stress response that could have otherwise been

escalated by inadequately controlled pain. Reductions in pain intensity may lead to additional endocrine and immune response benefits, including improved postoperative mood and better sleep after surgery.85 PNB using LA can also provide preemptive analgesia and postoperative pain management that may reduce the incidence of chronic pain syndromes known to negatively influence the immune system. C H O I C E O F A N E S T H E S I A A N D A NA LG E S I A : E F F E C T O N P O S TO P E R AT I V E O U TC O M E S I N E L D E R LY PAT I E N T S

Patient age alone should no longer be considered a key variable in predicting the risks associated with anesthesia and surgery. More important factors and better predictors of outcome for the elderly are their overall physical status, medical history, and disease state or condition. In the absence of significant disease, anesthetic complication rates do not increase dramatically with advancing age. Instead, perioperative risk is directly related to the number of patient comorbidities and extent of existing diseases, evidence of cognitive dysfunction, and medical condition(s) discovered in the preoperative period. Adverse preoperative medical conditions most indicative of the need for concern and predictive of higher surgical risk of perioperative morbidity and mortality are diabetes mellitus, hypertension, and ischemic heart disease.86 In addition, the extensiveness of surgery, duration, and site of planned or emergency surgery also play important roles as major determinants of perioperative risk. Upper abdominal surgical procedures followed by thoracic and open-heart surgical procedures are associated with the highest morbidity and mortality and pose increased risk for the elderly surgical patient. Therefore, the geriatric patient may be at an increased risk of perioperative morbidity and mortality because of the higher incidence of coexisting disease (four-fifths of older patients have at least 1 complicating condition and one-third have 3 or more coexisting diseases), but additional issues of concern are type, urgency, and potential duration of surgery, which also serve as important predictors of elderly patient outcome. Postoperative pain management continues to be a problem in the elderly despite advanced understanding of pain management modalities, improved drug delivery systems, and known benefits of optimal analgesia. Studies and surveys of surgical patients have reported varying degrees and intensities of pain following surgery along with reports of inadequate postoperative pain management, sometimes necessitating hospital readmission.87,88 Part of the problem lies with the fact that caregivers worry about prescribing opioids to elderly patients because of fears of initiating or exacerbating cognitive dysfunction, ileus, addiction, and respiratory depression. These concerns may provide greater justification for employing RA and nonopioid analgesics in the elderly. Positioning elderly patients for neuraxial anesthetic techniques becomes more difficult with age, creating potential risks for failure or complications. Geriatric individuals often have dorsal kyphosis, resulting in anatomic changes of the thoracic and lumbar vertebral spine. Osteoarthritis changes and calcification of cartilage in elderly individuals often results in an increasing likelihood of the patient to flex at the hips and knees. Compression and distortion of the epidural space is common with advanced age because of degenerative disk and joint changes. The ligamentum flavum changes and may be calcified in which

Elderly High-Risk and Cognitively Impaired Patients

attempts to accomplish an epidural or dural puncture may not be successful. This may occur because needle placement and advancement encounters difficulty in passing through the calcification and may also present obstruction to the intended path or direction of needle insertion causing deviation from a straight path. Bony overgrowth (osteophytes) may limit access to the desired central neuraxial space because of decreased size and/or obstruction of the intervertebral foramina. An anatomical characteristic that may be of aid to gaining access to the epidural or subarachnoid space is the awareness that the largest intervertebral foramen in elderly individuals is the L5–S1 interspace. Therefore, to avoid the technical difficulties caused by ligament calcification and alterations in dorsal vertebrae, a lateral approach (“Taylor” approach) may be employed for subarachnoid or epidural needle/catheter placement in elderly patients. Continuous neuraxial and PNB techniques can provide targeted pain relief and minimize postsurgical opioid dose requirements. Although these pain management modalities are well tested and generally quite successful, they can be associated with patient safety issues that must be considered. These include patient tampering, need for patients to comprehend the system operation, and adequate patient cognition and psychological ability to play an active role in their own pain management. There are also mechanical issues to consider, including pump programming (failures, pump malfunctions, programming errors), catheter concerns (obstruction, kinks), effect on patient mobility, and concern for postoperative requirements of anticoagulation (increased risk epidural hematoma). These techniques also place a burden on the health care staff for preparation, implementation, and monitoring of the chosen pain management modality. There are staff-related system errors (syringe and drug mix-ups, programming errors) to consider, cost and time allocation of these pain treatment programs, and adverse event monitoring that should be constantly assessed. A major issue of concern is the portrayal of epidural analgesia as being viewed merely as an alternative to IV opioids or IV PCA, despite evidence to suggest that postoperative regional analgesia results in improved patient perioperative outcomes.56,57,66,76 This interpretation is unfortunate because various parameters, including choice of analgesic agent(s), vertebral level of catheter placement, duration of epidural analgesia, and so on, will affect both technique efficacy and influence patient outcome. Optimal epidural analgesic effects on postsurgical pain and outcome are gained when the epidural catheter is placed in close proximity to the corresponding dermatome distribution of the surgical incision.89 There are physiologic benefits in placing epidural catheters at dermatomes (T8–T12) involved with abdominal surgery. Such placement reduces sympathetic inhibition of gastrointestinal tone, increases intestinal blood flow, and facilitates return of gastrointestinal function.56 High-risk cardiovascular patients presenting for noncardiac thoracic and upper abdominal surgery show benefits from thoracic epidural analgesia. When the epidural catheter more closely corresponds to the surgical incision, the results are attenuation of sympathetic-mediated coronary vasoconstriction and increased coronary blood flow to subendocardial and potentially ischemic areas of the heart, both of which can be supportive of a decreased incidence of myocardial infarction.66,90 Therefore, the demonstrated benefit of postoperative catheter location, coinciding closely with the surgical area, may show physiologic and analgesic improvement in patient outcome that has not been consistently established with either (1) epidural catheter location

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incongruent with the surgical incision or (2) pain management with systemic opioids. Patients will not receive intended analgesic and physiologic benefit of epidural analgesia if the epidural catheter should become accidentally dislodged or removed prematurely. Postoperative epidural analgesia (not intraoperative epidural anesthesia) appears to minimize the negative influence and incidence of myocardial infarction that coincided with the peak occurrence of myocardial compromise between 24 and 48 hours following surgery.66,69 Surgical studies that have identified a facilitated return of gastrointestinal function were those in which surgical patients’ maintained epidural analgesia for >24 hours postoperatively versus those patients receiving epidural analgesia for less time.56,91 Therefore, the duration of epidural analgesia is an additional factor influencing patient outcome because the pathophysiologic responses that begin intraoperatively will frequently continue into the postoperative period. The choice of specific analgesic agents used with epidural analgesia (LA with or without opioids and other adjuncts) will influence patient outcome. Central-neuraxial opioids prove effective in controlling postoperative pain, but only epidural LA have the ability to attenuate and influence adverse pathophysiologic responses that can contribute to perioperative morbidity.92 Neuraxial LA are effective through prevention of spinal reflex inhibition of diaphragmatic and gastrointestinal function, suppression of responses to surgical stress, and blockade of efferent and afferent nerve signals to and from the spinal cord. In addition, epidural local analgesia used without neuraxial opioids may improve patient outcome as a result of a decreased incidence of respiratory complications and earlier recovery of gastrointestinal motility following abdominal surgery.57,93 PNB techniques and the many advantages they provide for the surgical candidate are reemerging into the practice of anesthesia and analgesia (Table 31.9). Success and effectiveness of PNB may be improved when single-shot techniques and catheters are placed using a nerve stimulator and/or under ultrasound guidance. Studies of PNB in the elderly patient are currently limited to small study series and case reports with yet inconclusive evidence of influence on morbidity and mortality. PNB are used as an attempt to reduce perioperative stress responses and in an effort to avoid the need or reduce the potential deleterious effects of GA. Studies have shown that LA used in PNB can ameliorate the negative influence on wound hyperalgesia for several days subsequent to surgery.94 Therefore, including PNB into the mainstream of multimodal anesthesia care of the elderly surgical patient will allow opioid sparing and permit the proved benefits of LA (regarding sensitization of the nervous system) to become a useful choice in anesthetic care of the elderly. Reviewing the many benefits associated with PNB is beyond the scope of this chapter; however, Evans et al have provided a review of supportive evidence for the various PNB techniques.95 The advantages of PNB may be further facilitated with the added benefits and safety profile provided by the use of nerve stimulator evidence and ultrasound guided/directed block placement. Ultrasound-guided PNB placement is also an emerging field and studies are being performed to assess the role it may play in the setting of perioperative pain management in the elderly patient. In addition, more studies are embarking on investigating the use of continuous PNB and nerve plexus catheter techniques to provide postoperative analgesia. The use of continuous catheter techniques may prove to be even more efficacious than

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Table 31.9: Comparing Effects of Peripheral Nerve Blocks Positive Conclusions

Negative Conclusions

Ref. #

Interscalene Nerve Block Ideal for analgesia for shoulder and upper arm surgery compared to opioid analgesia Delayed time to first PO analgesics Reduced total opioid requirements (reduced PONV) Improved sleep and postoperative mood Preservation of cognitive function

Potential complications local anesthetic toxicity total spinal anesthesia Horner’s syndrome diaphragm paralysis (phrenic nerve block, up to 90%)

Kinnard et al (1994)113

Potential complications: pneumothorax phrenic nerve block (up to 50%)

Kinnard et al (1994)113

Interpreting the response from a nerve stimulator

Desroaches (2003)114

Septae within the sheath may influence local anesthetic spread and extent of anesthesia Maintaining a clean, sterile site

Kinnard et al (1994)113

Inconsistent anesthesia of proximal n. (eg, ilioinguinal, iliohypogastric, genitofemoral) No long-lasting benefit with single shot (when compared to GA) Potential for LA toxicity Risk of epidural spread (up to 15%)

Parkinson et al (1989)115

Possible inadequate analgesia (because of unblocked sciatic or obturator n.) Low risk of complications (LA toxicity, vascular puncture, infection, difficult to keep catheter site clean, n. injury)

Hirst et al (1996)116

Catheter needed to prolong analgesia Moderate patient discomfort (needle passes through gluteus muscle)

Taboada et al (2004)117

Supraclavicular Nerve Block Consistent, rapid onset of anesthesia of long duration Broad upper extremity coverage

Infraclavicular Nerve Block Good analgesic efficacy Favorable safety profile (low chance of pneumothorax) Lower pain scores compared to GA with IV PCA Reduced opioid requirement and time to first opioid use Easy to maintain catheter insertion site compared to other locations in the brachial plexus Axillary Nerve Block Favorable safety profile with reduction in pain scores Broad applicability (hand, wrist, forearm) High patient acceptance with improved PACU profile Easy peripheral nerve block to master Prolonged analgesia and reduced opioid requirements with addition of adjuvants to solutions Sympathectomy from block enhances blood flow Lumbar Plexus Block Reliable anesthesia of 3 terminal n. of the lumbar plexus (eg, femoral, lateral femoral cutaneous, obturator) Safe and effective for hip and knee procedures Possible PACU bypass, lower pain scores, decreased PO analgesics (same-day surgery patients) compared to GA Lower opioid use and lower opioid-related side effects Combined with sciatic n. block, easier recovery, less opioid use compared to GA in TKA Femoral Nerve Block Simple technique, excellent analgesia post-knee surgery High patient acceptance, decreased length of hospital stay, lower pain scores compared to GA for knee surgery Prolong time to first PO analgesic and reduced opioid need Reduced incidence of opioid side effects Shorter hospital stay compared to GA and IV PCA Improved short-term rehabilitation and joint mobility Sciatic Nerve Block Safe and effective analgesia of foot and ankle surgery Reduced postoperative pain scores and opioid needs Excellent patient satisfaction Reduced incidence of phantom limb pain

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Positive Conclusions

Negative Conclusions

Ref. #

Popliteal Fossa Nerve Block Preserves hamstring muscle function (easier ambulation) High patient acceptance of both anesthesia and analgesia Lower pain scores, opioid sparing with fewer to no opioid side effects, longer analgesia than ankle/infiltration blocks Reduced sleep disturbances Reduced hospital stay and lowered readmission rates

Sensation to posterior thigh remains Possible difficult positioning of posterior approach Vascular injury/hematoma Catheter issues of continuous technique

Provenzano et al (2002)118

Total spinal Paravertebral muscle pain Puncture of the lung or abdominal contents

Richardson et al (1999)119

Paravertebral Nerve Block Dense sensory and sympathetic unilateral/segmental block for thoracic, abdominal, inguinal, and breast surgeries Analgesia similar or better than thoracic epidural with equal or better influence on pulmonary function Fewer side effects of continuous block versus epidural: reduction of hypotension decreased incidence of PONV reduced rate of urinary retention Lower pain scores and reduced opioid use compared to GA

Abbreviations: GA = general anesthesia; LA = local anesthetic; n. = nerves; PACU = postanesthesia care unit; PCA = patient controlled analgesia; PO = parenteral; PONV = postoperative nausea and vomiting; RA = regional anesthesia; TKA = total knee arthroplasty.

the historically used single injection technique and achieve prolonged analgesia without reliance on the mainstay of systemic opioids for both in- and outpatient surgical procedures in elderly patients. R E C O M M E N DAT I O N S

Perioperative RA and PNB techniques may positively influence surgical outcome by (1) reducing neuroendocrine stress responses, (2) improving effective pain control, (3) facilitating return of gastrointestinal function (earlier enteral feeding), and (4) encouraging patient mobilization, all of which will play an integral and important role in elderly patients recuperating from major surgery.96 Optimal pain relief and facilitated return to normal daily functioning of elderly patients is difficult to achieve with analgesic monotherapy because of the possible risks of side effects from reliance on a single agent. The inclusion of RA as part of a multimodal treatment paradigm may further enhance overall physiologic and analgesic benefits in elderly and cognitively impaired patients. Improvement in surgical outcome and convalescence has been reported in the following studies: (1) postoperative regional analgesia as part of a perioperative multimodal approach in patients undergoing abdominal-thoracic esophagectomy can result in a shorter time to patient extubation, earlier return of bowel function, superior analgesia, and earlier fulfillment of discharge criteria of an intensive care unit.97 (2) Patients participating in a perioperative multimodal pain pathway following major surgery benefited from a diminution in metabolic and hormonal stress, as well as a more rapid return to baseline functionality during convalescence,98 and (3) patients undergoing colon resection incorporating epidural analgesia and receiving a multimodal

approach to surgical rehabilitation showed a decreased length of hospitalization from 6–10 days to a median of 2 days.99 For surgery of the extremities, PNB provides highly effective and site-specific postoperative analgesia with few side effects, particularly when supplemental opioid use is reduced or eliminated. Following major joint surgery, single-injection techniques and continuous PNB offer benefits of enhanced mobilization and rehabilitation along with potential cost savings and outcome improvements. In elderly patients, symptoms of excessive sedation, concentration difficulties and negative cognitive influence commonly observed with opioids may be reduced with PNB techniques along with more rapid return to preoperative baseline functions of ambulation, sleeping, eating, and drinking. C O N C LU S I O N S

Elderly patients and those presenting with cognitive deficits for major surgery are at an increased risk for developing postoperative cognitive dysfunction and further reductions in baseline cognition. Anesthetic and analgesic techniques that provide optimal pain control with low side-effect profiles and minimizing opioid analgesic and benzodiazepine exposure should always be considered for elderly and cognitively impaired patients. Such therapy, including RA and PNB techniques, along with incorporation of a multimodal analgesic approach may help in reducing the risk and burden of postoperative delirium and cognitive dysfunction. Moreover, improvements in analgesic efficacy may help attenuate pathophysiologic surgical responses, reduce the length of hospitalization, facilitate patient benefit and satisfaction, and accelerate patient rehabilitation and recovery.100 Although the many beneficial effects of multimodal

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analgesia, NRA, and PNB techniques are evident and becoming progressively more recognized, additional research is needed to demonstrate clear evidence of improved outcomes and to further justify there expanded use in elderly surgical patients.

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Elderly High-Risk and Cognitively Impaired Patients 46. Washington LL, Gibson SJ, Helme RD. Age-related differences in the endogenous analgesic response to repeated cold water immersion in human volunteers. Pain. 2000;89:89–96. 47. Gibson SJ, Helme RD. Age-related differences in pain perception and reporting. Clin Geriatr Med. 2001;17:433–456. 48. Cohen-Mansfield J, Lipson S. Pain in cognitively impaired nursing home residents: How well are physicians diagnosing it? J Am Geriatr Soc. 2002;50:1039–1044. 49. Katz PR, Grossberg GT, Potter JF, Solomon DH. Geriatrics Syllabus for Specialists. New York, NY: American Geriatrics Society; 2002. 50. Egbert A. Postoperative pain management in the frail elderly. Clin Geriatr Med. 1996;12:583–599. 51. Wu CL, Fleisher LA. Outcomes research in regional anesthesia and analgesia. Anesth Analg. 2000;91:1232–1242. 52. Mackensen GB, Gelb AW. Postoperative cognitive deficits: more questions than answers. Eur J Anaesthesiol. 2004;21:85–88. 53. Parker MJ, Handol HH, et al. Anaesthesia for hip fracture surgery in adults. Cochrane Database Syst Rev. 2004;4:CD000521. 54. Inouye SK, Viscoli CM, et al. A predictive model for delirium in hospitalized elderly patients based on admission characteristics. Ann Intern Med. 1993;119:474–481. 55. Block BM, Liu SS, et al. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA. 2003;290:2455–2463. 56. Hodgson PS, Liu SS. Thoracic epidural anaesthesia and analgesia for abdominal surgery: effects on gastrointestinal function and perfusion. Clin Anaesthesiol. 1999;13:9–22. 57. Ballantyne JC, Carr DB, et al. The comparative effects of postoperative analgesic therapies on pulmonary outcomes: cumulative meta-analysis of randomized controlled trials. Anesth Analg. 1998;86:598–612. 58. Rodgers A, Walker N, et al. Reductions of postoperative mortality and morbidity with epidural or spinal anesthesia: results from overview of randomized trials. Br Med J. 2000;321:1493. 59. Williams-Russo P, Sharrock NE, et al. Cognitive effects after epidural vs general anesthesia in older adults: a randomized trial. JAMA. 1995;274:44–50. 60. Riis J, Lomholt B, et al. Immediate and long term mental recovery from general versus epidural anesthesia in elderly patients. Acta Anaesthesiol Scand. 1983;27;44–49. 61. Peters A. Structural changes in the normally aging cerebral cortex of primates. Prog Brain Res. 2002;136:455–465. 62. Atanassoff PG. Effects of regional anesthesia on perioperative outcome. J Clin Anesth. 1996;8:446–455. 63. Roy RC. Choosing general versus regional anesthesia for the elderly. Anesthesiol Clin North Am. 2000;18:91–1104. 64. Park WY, Thompson JS, et al. Effect of epidural anesthesia and analgesia on perioperative outcome: a randomized controlled Veterans Affairs cooperative study. Ann Surg. 2001;234:560–571. 65. Matot I, Oppenheim-Eden A, et al. Preoperative cardiac events in elderly patients with hip fracture randomized to epidural or conventional analgesia. Anesthesiology. 2003;98:156–163. 66. Beattie WS, Badner NH, et al. Epidural analgesia reduces postoperative myocardial infarction: a meta-analysis. Anesth Analg. 2001;93:853–858. 67. Beattie WS, Bander NH, et al. Meta-analysis demonstrates statistically significant reduction in postoperative myocardial infarction with the use of thoracic epidural analgesia. Anesth Analg. 2003;97:919–920. 68. Wu CL, Hurley RW, et al. Effect of postoperative analgesia on morbidity and mortality following surgery in Medicare patients. Reg Anesth Pain Med. 2004;29:525–533. 69. Mangano DT, Hollenberg M, et al. Perioperative myocardial ischemia in patients undergoing non-cardiac surgery-I: incidence

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91. Neudecker J, Schwenk W, et al. Randomized controlled trial to examine the influence of thoracic epidural analgesia on postoperative ileus after laparoscopic sigmoid resection. Br J Surg. 1999;86:1292–1295. 92. Kehlet H. Modification of responses to surgery by neural blockade: clinical implication. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd ed. Philadelphia, PA: Lippincott-Raven; 1998;129–175. 93. Liu SS, Carpenter RL, et al. Effects of perioperative analgesic technique on the rate of recovery after colon surgery. Anesthesiology. 1995;83:757–765. 94. Bugedo GJ, Carcamo CR, et al. Preoperative percutaneous ilioinguinal and iliohypogastric nerve block with 0.5% bupivacaine for post-herniorrhaphy pain management in adults. Reg Anesth. 1990;15:130–133. 95. Evans H, Steele SM, et al. Peripheral nerve block and continuous catheter techniques. Anesthesiol Clin North Am. 2005;23:141–162. 96. Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anaesth. 1997;78:606–617. 97. Brodner G, Pogatzki E, et al. A multimodal approach to control postoperative pathophysiology and rehabilitation in patients undergoing abdominalthoracic esophagectomy. Anesth Analg. 1998;86:228–234. 98. Brodner G, Van Aken H, et al. Multimodal perioperative management-combining thoracic epidural analgesia, forced mobilization, and oral nutrition-reduces hormonal and metabolic stress and improve convalescence after major urologic surgery. Anesth Analg. 2001;92:1954–1600. 99. Basse L, Jacobsen D, et al. A clinical pathway to accelerate recovery after colonic resection. Ann Surg. 2000;232:51–57. 100. Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. Am J Surg. 2002;183:630–641. 101. Peters A. Structural changes in the normally aging cerebral cortex of primates. Prog Brain Res. 2002;136:455–465. 102. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington DC: American Psychiatric Association; 2000. 103. Kehlet H. Influence of regional anesthesia on postoperative morbidity. Ann Chir Gynaecol. 1984;73:171–176. 104. Norris EJ, Beattie C, et al. Double-masked randomized trial comparing alternate combinations of intraoperative anesthesia and postoperative analgesia in abdominal aortic surgery. Anesthesiology. 2001;95:1054–1067. 105. Lien CA. Regional versus general anesthesia for hip surgery in older patients: does the choice effect outcome? J Am Geriatr Soc. 2002;50:191–194.

106. Peyton PJ, Myles PS, et al. Perioperative epidural analgesia and outcome after major abdominal surgery in high-risk patients. Anesth Analg. 2003;96:548–554. 107. Wu CL, Anderson GA, et al. Effect of postoperative analgesia on morbidity and mortality after total hip replacement surgery in Medicare patients. Reg Anesth Pain Med. 2003;28:271–278. 108. Liu SS, Block BM, et al. Effects of perioperative central neuraxial analgesia on outcome after coronary artey bypass surgery: a metaanalysis. Anesthesiology. 2004;101:153–161. 109. Handley GH, Silbert BS, et al. Combined general and epidural anesthesia versus general anesthesia for major abdominal surgery: postanesthesia recovery characteristics. Reg Anesth. 1997;22:435–441. 110. Gottschalk A, Smith DS, et al. Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial. JAMA. 1998;279:1076–1082. 111. Gilbert TB, Hawkes WG, et al. Spinal anesthesia versus general anesthesia for hip fracture repair: a longitudinal observation of 741 elderly patients during 2-year follow-up. Am J Orthop. 2000;29:25–35. 112. Sharrock NE, Cazan MG, et al. Changes in mortality after total hip and knee arthroplasty over a ten-year period. Anesth Analg. 1995;80:242–248. 113. Kinnard P, Truchon R, et al. Interscalene block for pain relief after shoulder surgery: a retrospective randomized study. Clin Orthop. 1994;304:22–24. 114. Desroches J. The infraclavicular brachial plexus block by the coracoid approach is clinically effective: an observational study of 150 patients. Can J Anaesth. 2003;50:253–257. 115. Parkinson SK, Mueller JB, et al. Extent of blockade with various approaches to the lumbar plexus. Anesth Analg. 1989;68:243– 248. 116. Hirst GC, Lang SA, et al. Femoral nerve block: single injection versus continous infusion for total knee arthroplasty. Reg Anesth. 1996;21:292–297. 117. Taboada M, Alverez J, et al. The effects of three different approaches on the onset time of sciatic nerve blocks with 0.75% ropivacaine. Anesth Analg. 2004;98:242–247. 118. Provenzano DA, Viscusi ER, et al. Safety an efficacy of the popliteal fossa nerve block when utilized for foot and ankle surgery. Foot Ankle Int. 2002;23:394–399. 119. Richardson J, Sabanathan S, et al. A prospective, randomized comparison of preoperative and continuous balanced epidural or paravertebral bupivacaine on post-thoracotomy apin, pulmonary function and stress responses. Br J Anaesth. 1999;83:387– 392.

32 Postcesarean Analgesia Kate Miller and Ferne Braveman

A commitment to postoperative analgesia has been mandated in the present health care environment. Pain assessment as the fifth vital sign provides the opportunity for us to identify and treat a symptom that has for years been undermanaged. Intrapartum analgesia has always been an important part of the practice of obstetrical anesthesiology. The cesarean delivery, at 38% of all deliveries, is now the most common surgical procedure in the United States, and thus we must address postpartum/postoperative analgesia as part of our obstetrical anesthesia practice. The goal of intrapartum analgesia has always been to provide safe and efficacious analgesia with minimal effects on the mother, fetus, or course of labor. Postcesarean analgesia must also be safe and efficacious, with minimal effect on the mother’s ability to bond with her newborn. The physiologic perturbations associated with pregnancy and the surgical stress and physiologic changes that occur with intra-abdominal surgery affect maternal well-being and postoperative outcome. Pain therapy must take into account all of these variables. Nikolajsen et al1 has suggested that patients with recall of severe postoperative pain are more likely to experience chronic pain following cesarean delivery. More effective analgesia would thus minimize the occurrence of chronic pain complaints. Women recovering from cesarean section desire to ambulate early and care for their infants. However, because of their wish to bond with their babies, many mothers avoid analgesics that may cause sedation and as a result have a level of pain that impairs mobility. Nursing mothers are concerned about the neonatal effects of medications, especially opioid analgesics that may cross into breast milk. Although not all postcesarean section mothers share such attitudes or anxieties, attention must be given to these issues to facilitate a positive experience for the mother. The goal is to provide effective pain relief that is safe for the mother as well as her baby. It should allow the mother to ambulate, care for her baby, and breastfeed without causing adverse consequences.2 Because most cesarean sections in the United States are performed under regional anesthesia, the use of epidural and intrathecal opioids has become a popular means of providing postoperative analgesia. Currently at Yale-New Haven Hospital and in many other teaching institutions, more than 95% of cesarean deliveries are performed with regional anesthesia. A

recent survey of type of anesthesia used for cesarean section in the United Kingdom from 1992 to 2002 showed that regional anesthesia was used in 94.9% of elective and in 86.7% of emergent cesarean sections.2 If present, an indwelling epidural catheter facilitates the administration of epidural opioids for augmentation of anesthesia during cesarean section and for effective control of postsurgical pain. A survey of anesthesiologists at the 1987 meeting of the Society of Obstetric Anesthesia and Perinatology (SOAP) revealed that greater than 77% utilized epidural opioids, predominantly morphine, fentanyl, or both, for pain relief after cesarean section.3 Twenty years later, almost all patients receiving regional anesthesia for cesarean delivery receive neuraxial opioids for intraoperative and postoperative analgesia. Spinally administered opioids bind and activate opioid receptors located in the substantial gelatinosa of spinal cord dorsal horn.4,5 After epidural administration, a small portion of the opioid dose crosses the dura to enter the cerebrospinal fluid (CSF) and then penetrates spinal tissues in amounts proportional to its lipid solubility. The remainder of the dose is absorbed systemically, producing plasma levels comparable to an intramuscular injection and adding to the analgesic effect as the drug is distributed to the central nervous system. There is no difference in the rate of cesarean section in women receiving neuraxial versus intravenous analgesia during labor.6 The misconception still exists, however, that neuraxial analgesia increases the risk for cesarean section. The American College of Obstetricians and Gynecologists currently recognizes that there are many techniques for pain relief of parturients, including neuraxial analgesia, and none of them are associated with an increased risk of cesarean delivery when compared to one another or unmedicated labor.7 The current trend in postcesarean analgesia is to use a multimodal approach. As noted above, most cesarean sections are performed with regional anesthesia and most patients received neuraxial opioids as part of that anesthetic. The addition of other medications with different mechanisms and/or sites of action will create additive or supraadditive effects with a lower incidence of dose-related side effects as the dosage of each drug is lower than if a single drug were used. 537

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The vast majority of patients receive opioid therapy for postcesarean analgesia – neuraxial and/or parenteral and/or oral. Obviously, those patients who have general anesthesia will not have neuraxial opioids but rather parenteral and/or oral opioid therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coadministered. Clonidine, metaclopramide, and ondansetron are also used as analgesic adjuvants. E P I D U R A L A NA LG E S I C S

Morphine Morphine was the first opioid to receive Food and Drug Administration (FDA) approval for epidural and/or intrathecal administration. Morphine is highly ionized and is the least lipid-soluble opioid currently employed in this setting. These qualities create a unique pharmacodynamic profile. Most notably, morphine has a slow onset, often taking 60 to 90 minutes to appreciate peak analgesic effect, and a prolonged duration of action. Epidurally administered morphine may be an excellent choice for the high-risk obstetric patient. Patients with severe preeclampsia, cardiac disease, and morbid obesity may benefit from the reduced stress and improved pulmonary function that excellent levels of postsurgical analgesia can provide. Rawal and coworkers8 compared the effects of intramuscular and epidural morphine in 50 “grossly obese” patients recovering from gastric stapling procedures. Patients in the epidural morphine group were more alert, able to walk unassisted sooner, recovered bowel function earlier, and “benefited more from vigorous physiotherapy routine, which resulted in fewer pulmonary complications.” No similar study has been performed in morbidly obese obstetric patients, but the use of epidural morphine in this group should provide significant benefits as well. Fuller and colleagues9 retrospectively reviewed the records of nearly 5000 patients who received epidural morphine at the conclusion of cesarean section. The average time to first request for additional analgesia was 23.5 hours, but patients differed greatly. The shortest time to supplemental analgesia was 30 minutes, but 8% of patients did not require additional analgesics for over 48 hours. Leicht and colleagues10 did a comparison of postcesarean section pain relief, side effects, and 24-hour narcotic requirements in two groups of patients receiving epidural morphine. One group was administered morphine as a single 5 mg bolus dose versus a regimen of reduced bolus (2.5 mg) plus continuous infusion (0.5 mg/hour). Patients receiving single 5 mg doses of morphine had a higher incidence of severe nausea and vomiting (17%). Only 50% of patients experienced excellent pain relief, two patients were extremely dissatisfied, and 100% requested supplemental postoperative analgesia. In comparison, the group receiving the 2.5 mg bolus plus continuous infusion noted superior pain relief, a lower requirement for additional analgesics, and no complaints of severe nausea or vomiting. In a randomized dose-response study by Palmer and colleagues,11 patients received epidural morphine following cesarean section in increments of 1.25, 2.5, 3.75, and 5 mg and were then given intravenous patient-controlled analgesia (IV PCA) for pain relief. As measured by IV PCA use, the quality of analgesia was dose dependent in patients who received up to 3.75 mg of epidural morphine, and there was no difference in the analgesic effect above that dose. The duration of analgesia was 18–26 hours. Although all patients experienced pruritis, this was not related to the dose of morphine received.

Depodur is a sustained-release epidural morphine release preparation. It has shown promise for postoperative analgesia but requires that no other medication be administered through the epidural catheter to protect the integrity of the sustained release preparation. Its role in obstetrics will thus be limited to those receiving CSE, in whom the epidural catheter does not need to be used for anesthesia.12–14 The choice of local anesthetic utilized for epidural anesthesia may affect the action of epidural morphine. Kotelko and coworkers15 studied 276 parturients treated with various local anesthetics plus 5 mg of epidural morphine during cesarean delivery. Of the patients who received 2-chloroprocaine as the primary local anesthetic, “an unexpectedly high proportion (13 of 23) had poor postoperative pain relief, usually lasting less than three hours.” The authors speculated that the low pH of the 2-chloroprocaine solution may have been the cause. However, the efficacy of epidural morphine is similar when either unbuffered 2-chloroprocaine (pH < 4.0) or bicarbonatebuffered 2-chloroprocaine (pH approximately 6.17) was used for cesarean section. Hess and colleagues found no effect from chloroprocaine on morphine analgesia.16 Meagher and coworkers17 compared the efficacy of 5 mg of epidural morphine for cesarean section when 2% lidocaine with epinephrine (1:200 000) or 0.5% bupivacaine was used. The analgesia obtained by the lidocaine and bupivacaine groups did not differ, and the median time to narcotic supplement was 25 hours. E P I D U R A L A NA LG E S I A

Lipophilic Opioids Fentanyl is much more lipid soluble and less ionized than morphine and rapidly penetrates the dura and spinal tissues to find and activate opioid receptors.4,5 The standard commercial preparation contains no preservative and is suitable for intravenous or epidural use. Epidurally administered fentanyl is frequently employed for intraoperative augmentation of epidural anesthesia and to provide effective but limited duration for postcesarean analgesia. Naulty and coworkers18 originally reported that fentanyl 50 to 100 ␮g produced 4 to 5 hours of postoperative analgesia in parturients receiving epidural anesthesia with 0.75% bupivacaine and significantly reduced 24-hour parenteral analgesic requirements. Follow-up studies have been unable to duplicate these results, however, and report postcesarean analgesia lasting up to a maximum of 1 to 2 hours.19 Several techniques have been employed to extend fentanyl’s relatively short duration of action. The degree to which epidurally administered fentanyl is diluted affects both its onset and duration of action. Both Naulty and coworkers18 and Robertson and coworkers20 used total fentanyl volumes of 10 mL. Birnbach and colleagues21 evaluated the analgesic efficacy of a standardized fentanyl dose (50 ␮g) that was diluted in 1 to 25 mL of saline solution; total volumes less than 10 mL were associated with a significantly longer onset time. Furthermore, patients who received a 1 to 2mL total volume frequently failed to develop complete analgesia. Volumes of 20 mL or greater were associated with the longest durations of analgesia, 200 minutes or more. The addition of epinephrine21 appears to increase the duration of epidural fentanyl analgesia. Youngstrom and coworkers22 proposed continuous epidural infusion of fentanyl and epinephrine for postcesarean analgesia. By using a dilute concentration of fentanyl and epinephrine, both

Postcesarean Analgesia

opiate and adrenergic-mediated spinal analgesia was effected. Postoperatively, an infusion of 4 ␮g of fentanyl with 1.6 ␮g of epinephrine per milliliter, was administered in doses of 10, 15, or 20 mL/h. Patients receiving 15mL/h continuous infusion obtained excellent pain relief and required minimal use of PCA for supplementation of analgesia. The high-dose requirements, that is, 60 to 80 ␮g/h, and 1500 to 2000 ␮g/d, underscore the relative inefficiency of fentanyl and other lipophilic opioids when continuously administered via lumbar epidural catheters. Such doses given parenterally provide similar intensities of postsurgical analgesia.23 One final attempt to extend analgesic duration has been to combine fentanyl with small doses of morphine. Naulty and Ross24 administered either 5 mg of epidural morphine or 50 ␮g of epidural fentanyl with 0, 1, 2, or 3 mg of epidural morphine to patients undergoing cesarean section delivery. They noted that the onset of analgesia was significantly more rapid in all patients who received fentanyl. Moreover, patients receiving 3 mg of morphine with fentanyl noted potentiation of analgesia in that duration, and the 24-hour supplemental narcotic dosage was similar to that observed in patients treated with higher doses (5 mg) of morphine alone. These researchers found no respiratory depression in any of the 104 patients evaluated. Sufentanil is another highly lipid-soluble opioid agonist that provides an extremely rapid onset, usually within 15 minutes of epidural administration. However, dose requirements are much higher than one might expect, given the drug’s high potency when compared with fentanyl or morphine. In cesarean section patients, doses of 25 ␮g of sufentanil produced less than 2 hours of complete analgesia, whereas 50 ␮g provided only 3 to 4 hours of complete analgesia.31 Rosen and coworkers30 compared the effects of 5 mg of epidural morphine and epidural sufentanil (30, 45, or 60 ␮g). Sufentanil analgesia lasted only 3.9, 4.5, and 5.6 hours, respectively. In contrast, most patients receiving morphine experienced 26 hours of pain relief. Although generalized pruritus and nausea with vomiting were more common in patients who received morphine, respiratory rates did not differ among any of the treatment groups. Rosen et al concluded that sufentanil “may be superior to morphine for epidural analgesia in clinical settings in which rapid onset is desired.” However, the authors cautioned that “if the relatively large doses of sufentanil evaluated in this study are accidentally injected intravenously, there is a high likelihood of adverse effects, particularly respiratory depression.” A more rational method of extending the duration of epidural sufentanil analgesia may be accomplished by the addition of small amounts of morphine.31 Other opioids that are less commonly employed epidurally include hydromorphone,32 meperidine,33 butorphanol, buprenorphine, and methadone.34,35 Hydromorphone is a hydroxylated derivative of morphine available in preservativefree solution that provides effective epidural analgesia in patients recovering from cesarean section. Chestnut and colleagues evaluated the use of 1.0 mg of hydromorphone in a total 10mL volume given during wound closure in patients who had received epidural anesthesia with either 2% lidocaine with epinephrine 1:200,000 or 0.5% bupivacaine.32 The mean time to first request for supplemental analgesia was 13.0 ± 12.4 hours, and 92% of patients reported good or excellent pain relief. In another study of patients receiving the same hydromorphone dose, analgesia lasted a median of 19.3 hours. Pruritus was the most common side effect, reported in approximately 50% of patients. Nausea

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was also reported frequently. No patient in either group had clinical signs of respiratory depression. Epidural meperidine provides about 2.5 hours of postoperative pain relief at doses up to 25 mg. Ngan and colleagues found that duration of analgesia is not extended with larger doses.33 The onset of methadone is faster compared to morphine, but the duration of analgesia is only 4 to 5 hours after a dose of 4 to 5 mg.34 Diamorphine, or heroin, provides an inconsistent duration of epidural analgesia and is not available in the United States.35,36 Epidurally administered mixed agonist-antagonist opioids, including butorphanol, provide intermediate durations of analgesia but are associated with significant sedation secondary to vascular uptake and activation of ␬-receptors in the central nervous system. Excessive maternal sedation detracts from the overall mission of epidural analgesia in this clinical setting and often leads to patient dissatisfaction. Nalbuphine, also a mixed agonist-antagonist, has also been found to cause significant sedation.25 See Tables 32.1 and 32.2 for epidural medications.

Epidural Adjuvant Therapy The addition of local anesthetics such as bupivicaine and ropivicaine in combination with neuraxial opioids produces an additive and possibly a synergistic effect, allowing for a decreased dose requirement of both classes of drugs, and therefore a decreased potential for side effects associated with each drug.2 The addition of clonidine, an ␣2 -adrenergic agonist, to epidural morphine has been shown to prolong the duration of analgesia after cesarean section as compared with morphine alone. This is attributed to the activation of ␣-adrenergic receptors in the descending inhibitory pathways of the spinal cord. Capogna and colleagues37 found that 2 mg of epidural morphine provided analgesia for 6.27 ± 1.6 hours, but adding 75 ␮g and 150 ␮g of clonidine increased the time of analgesia to 13.25 ± 3.8 hours and 21.55 ± 6.3 hours, respectively. However, its use is not currently recommended for postcesarean analgesia because of the increased risk for excessive sedation and hypotension.25 Epinephrine, an ␣- and ␤-adrenergic agonist, also prolongs the duration of analgesia, decreases systemic uptake, and decreases the incidence of side effects attributed to opioids. The mechanism for analgesia is likely its ␣2 agonist property. When given with lidocaine, it prolongs and enhances the quality of analgesia.38

Side Effects Administering epidural morphine for postcesarean section analgesia is easy and effective, and perhaps it would be universally popular were it not for troublesome side effects. The most common of these is pruritus. Pruritus occurs more often in obstetric patients than in any other group, ranging from 40% to 90%.9,15,17 Mild pruritus, usually of the face or chest, is probably even more frequent because patients may not mention it unless directly questioned. Why pruritus occurs is poorly understood, but its occurrence does not appear to be related to excessive histamine release, nor is it thought to be dose related for clinically appropriate doses.11 Nonetheless, antihistamines may provide some relief, and 12.5 to 25 mg of diphenhydramine is a recommended treatment. Nalbuphine (5 mg IV) will relieve pruritis without reversing analgesia or causing other side effects and is

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Table 32.1: Neuraxial Opioid Administration Opioid

Spinal Bolus (with Intraoperative LA)

Epidural Bolus

PCEA/CI

Morphine

01–0.2 mg (duration: 18–24 hours)

2–5 mg (duration: 18–24 hours)

Loading: 1–3 mg CI: 50 ␮g/mL @ 6–12 mL/h PCEA: 2–4 mL every 10–15 minutes, 50–60 mL 4-hour lockout

Depodur

Not recommended

10 mg (duration: 24–48 hours)

Not recommended

Meperidine

10 mg (duration: 4 hours)

50 mg (duration: 4 hours)

Not recommended

Hydromorphone

Not recommended

200–300 ␮g (duration: 8–12 hours)

Loading: 200–300 ␮g CI: 3–5 ␮g/mL @ 6–12 mL/h PCEA: 2–4 mL every 4–6 minutes, 50–60 mL, 4-hour lockout

Diamorphine

0.25–1 mg (duration: 6–8 hours)

2–5 mg (duration: 8–12 hours)

Not recommended

Sufentanil

15 ␮g (duration: 2 hours)

25 ␮g (duration: 2–3 hours)

Loading: 25 ␮g CI: 2 ␮g/mL @ 5–10 mL/h PCEA: 2–4 mL every 4–6 minutes, 40–50 mL, 4-hour lockout

Fentanyl

10 ␮g (duration: 2 hours)

50 ␮g (duration: 2–3 hours)

Loading: 50–100 ␮g CI: (5 ␮g/mL) @ 10–15 mL/h 40–50 mL, 4-hour lockout

Butorphanol

Not recommended

2–4 mg (duration: 4–6 hours)

Not recommended

Abbreviations: PCEA = patient-controlled epidural analgesia; CI = continuous infusion. Modified from: Braveman. The Requisites in Anesthesiology: Postcesarean Analgesia. 2006.

an excellent first-line choice.25 A small intravenous bolus, 0.04 to 0.08 mg, of naloxone usually will also improve patient comfort without reversing analgesia. Occasionally, the intensity of itching interferes with sleep. In our experience, severe pruritus is the most frequent cause of patient dissatisfaction with epidurally administered morphine. Nausea, another common side effect associated with epidural morphine, is attributed to rostral spread of the drug in spinal fluid to higher brainstem nuclei, including the vomiting center and chemoreceptor trigger zone. Nausea and vomiting occurs in 20% to 60% (or 11% to 30% according to others) of postcesarean patients, although the percentage of patients whose symptoms are severe enough to require treatment is lower. In the presence of intractable nausea, a small intravenous bolus of naloxone followed by continuous infusion may be useful. One may conveniently manage a continuous infusion by adding 1 or 2 ampules of naloxone, 0.4 to 0.8 mg, to each liter of the patient’s maintenance intravenous fluid. An infusion rate of 125 mL/hour will deliver 50 to 100 ␮g/hour of naloxone and will usually attenuate the symptoms without significant loss of analgesia. The use of a transdermal scopolamine patch has also been reported to reduce the incidence of nausea and vomiting, particularly during the first 10 hours after cesarean delivery. However, it must be applied a few hours prior to the exposure of epidural morphine to have its desired effect.27 Ondansetron (4 mg IV) and droperidol (0.625 mg IV) are other effective treatment options.25 Table 32.3 summarizes treatment for opioid-related side effects. Reactivation of herpes simplex virus labialis (HSVL) is a more unusual and worrisome side effect of epidural morphine. In a prospective study of 729 patients recovering from cesarean

section, Crone and coworkers26 reported recurrent oral herpes lesions in 13 of 140 (9.3%) patients treated with epidural morphine but in only 6 of 583 (1.0%) of those who did not receive morphine. The authors proposed that the mechanism responsible for facial pruritus might be involved in reactivating the HSVL, perhaps because of opioid activity within the spinal nucleus of the trigeminal nerve. These researchers found no incidence of primary neonatal HSV infection and did not determine the frequency of maternal asymptomatic oral viral shedding. Similar results were also found by Gieraerts et al28 in 1987. Of 44 postcesarean patients, 9 of 26 patients who received epidural morphine developed recurrent herpes simplex labialis lesions, as opposed to none of the patients who received intramuscular morphine.29 Davies and colleagues found an association between the use of parenteral and spinal morphine and reactivation of oral herpes. Spinal morphine was associated with a greater incidence of reactivation. The current opinion on reactivation of herpes is not yet conclusive. Although rare in comparison with other side effects, respiratory depression is the most feared complication associated with epidural morphine. Fortunately, only 0.2% to 0.3% of obstetric patients have been found to exhibit clinically significant respiratory depression after receiving 5 mg or less of epidural morphine.25 An early period of respiratory depression occurs 30 to 90 minutes after epidural administration, in association with peak serum morphine concentrations. However, “delayedonset” respiratory depression resulting from rostral spread of morphine in CSF occurs 6 to 10 hours later. On reaching the fourth ventricle, the drug rapidly equilibrates with intracranial CSF and acts on the medullary respiratory centers to reduce the

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541

Table 32.2: Intrathecal and Epidural Opioids Employed for Postcesarean Delivery Analgesia Drug Epidural analgesia

Intrathecal analgesia

Dose

Onset (Minutes)

Peak Effect (Minutes)

Duration (Hours) 16–24

Advantages

Disadvantages

Long duration

Delayed onset: significant side effects; delayed respiratory depression

Morphine

24–5 mg

45–60

90–120

Fentanyl

50–100 ␮g

10

20

2–3

Rapid onset; few side effects; may be combined with PCA

High dose requirement; short duration

Sufentanil

25–50 ␮g

10

15–20

2–4

Rapid onset; may be combined with PCA

High dose requirement; short duration

Hydromorphone

0.2–0.3 mg

30

45–60

10–18

Long duration; more rapid onset than morphine

Similar side-effect profile to morphine

Butorphanol

2–4 mg

15

40

2–4

Fairly rapid onset

Excessive sedation

Meperidine

50 mg

15

30

5–6

Rapid onset; intermediate duration; few side effects; reduces “shaking”

None

Morphine/ fentanyl

3 mg/50 ␮g

10

15

12–18

Rapid onset; long duration

Pruritus

Morphine/ sufentanil

3 mg/20 ␮g

10

15

12–18

Rapid onset; long duration

Pruritus

Continuous fentanyl

100 ␮g bolus 50–60 ␮g/h

10

20

Indefinite

Rapid onset; long duration; reduced side effects

Labor intensive; requires infusion device; must maintain epidural catheter Cumulative toxicity? High-dose requirement

Continuous sufentanil

25 ␮g bolus

10

15

Indefinite

Rapid onset; long duration; reduced side effects

Labor intensive; requires infusion device; must maintain epidural catheter Cumulative toxicity? High-dose requirement

Morphine

0.1–0.2 mg

30

60

18–24

Long duration

Significant side effects; delayed respiratory depression

Fentanyl

10–12.5 ␮g

5

10

2–3

Rapid onset; few side effects

Short duration

Sufentanil

5–15 ␮g

5

10

2–4

Rapid onset; few side effects

Short duration

Meperidine

10 mg

10

15

5–6

Rapid onset; potentiation of spinal anesthesia

Smooth transition from spinal anesthesia to IV opioid analgesia; may increase intraop nausea and vomiting

ventilatory response to carbon dioxide. This effect may persist for up to 24 hours. The risk is increased at doses of epidural morphine greater than 5 mg, with the concomitant administration of other narcotics, and in the obese population. The treatment of respiratory depression is 0.2 to 0.4 mg of naloxone IV with ventilatory support if necessary. A naloxone bolus followed by continuous infusion appears to reverse the most severe aspects of both early- and late-onset respiratory depression. Most patients presenting for cesarean section do not have severe underlying pulmonary disease or other risk factors that

increase the likelihood of respiratory depression after epidural morphine administration. However, life-threatening respiratory depression has been reported in this “low-risk” population. Fuller’s survey revealed a respiratory rate of less than 10 breaths per minute in 2.5 of 1000 patients.9 What is the most appropriate method of respiratory monitoring if epidural morphine is to be used routinely in the patient after cesarean section? This question is difficult, and no one solution appears applicable to every institution. In most published studies, hourly monitoring of respiratory rate has been

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Table 32.3: Treatment of Side Effects of Neuraxial Opioids Side Effect

Incidence

Therapy

Dose

Route

Pruritis

40%–60%

Naloxone

0.04–0.08 mg

IV

Nausea/vomiting

25%–30%

Naloxone

400 ␮g/L in maintainance IVF

IV

Nalbuphine

5 mg

IV

Propofol

10 mg

IV

Diphenhydramine

12.5 to 25 mg

IV

Cyclizine

50 mg

IV

Metoclopramide

10 mg

IV

Ondansetron

4 mg

IV

Acupressure

at P6 point

Dexamethasone

5 to 10 mg

IV

Droperidol

0.625 mg

IV

Naloxone

0.2–0.4 mg

IV

Promethazine Hydroxyzine Respiratory depression

Ventilatory support IVF = intravenous fluid.

the most commonly used method. However, respiratory depression caused by epidural morphine may develop rapidly once the drug reaches the intracranial CSF, and either hypercapnia or hypoxemia can develop with a respiratory rate of 10 or more. Furthermore, ensuring hourly checks on a busy ward may be difficult, especially during the night shift when many hospitals are short staffed. Apnea monitors may be prone to annoying false alarms, do not detect hypoventilation, and require cooperation from patients and nurses to turn them off during wakefulness or ambulation. Pulse oximetry has the drawback of frequent motion artifact alarms and cannot detect hypercapnia. Vigilant nursing attention to observe inadequate respiratory effort, slow respiratory rate, or unusual somnolence is probably the best form of monitoring, but the hospital that can guarantee such care 24 hours a day outside of the intensive care setting is rare. See Table 32.3 regarding summary of therapeutic interventions for side effects of neuraxial opioids. No matter which dose regimen is used, managing patients who have received morphine epidurally on a routine postpartum ward presents certain problems. As we have seen, significant percentages of patients require additional analgesia within 12 hours. Should standard doses of opioids be ordered if analgesia is needed within 12 hours of epidural morphine administration or should doses be reduced to avoid any additive risk of respiratory depression from residual epidural activity? No study has addressed this question or whether the onset of pain in an individual patient after cesarean section means that the respiratory depressant effect of the initial epidural dose has completely ceased. Ketorolac tromethamine may be the analgesic of choice in this setting because it augments epidural analgesia without increasing the risk of additive opioid-induced respiratory depression; otherwise, reduced doses of opioids should be available. After 12 hours, “standard” opioid dosing may be safely employed to augment epidural morphine analgesia. The side effects of nausea and pruritus may be severe enough to warrant low-dose naloxone infusions in some patients, but on

many routine care wards, the nursing staff may not wish to assume responsibility for administering such infusions. At the very least, a member of the anesthesia care team must be available at all times to respond if an urgent problem develops in a patient who has received epidural morphine. Side effects noted with epidural fentanyl include pruritus of the face, chest, or both, seen in up to one-third of patients, as well as occasional nausea.33,42 Both pruritus and nausea tend to be much milder than that occurring with epidural morphine, are generally self-limited and rarely require treatment. No large published series has addressed the question of whether epidurally administered fentanyl increases the rate of HSVL reactivation in patients after cesarean section. There has also been no evidence indicating that epidural fentanyl may cause “late” respiratory depression beyond the period of its clinical analgesic effect. Although many previously described studies focused on postoperative analgesia, all noted significant intraoperative benefits after epidural administration of fentanyl. In particular, there is a noticeable reduction in visceral discomfort during abdominal manipulation and peritoneal closure. In this regard, Ackerman and coworkers,29 observed a significant reduction in nausea and vomiting associated with extra-peritoneal uterine closure in patients receiving 50 ␮g of epidural fentanyl epidurally. Patients routinely stay in the postanesthesia recovery area for 1 to 2 hours after cesarean section for observation of bleeding and return of function after regional anesthesia. Thus staff members observe them closely for a minimum of 60 minutes after epidural administration of fentanyl. The literature indicates that 1.5 hours should be ample time for any untoward effect to manifest. Most patients do not need additional pain relief until 2 to 3 hours after the end of surgery. Opioid therapy on the postpartum ward may then be provided by intravenous PCA or oral medication combined with other adjuvants (see Multimodal Therapy). A final epidural analgesic that may be considered for patients following cesarean delivery is extended

Postcesarean Analgesia

duration morphine (DepoDur). A single epidural dose of DepoDur (10 mg or less) may provide up to 48 hrs of pain relief. The safety and effectiveness of this preparation are discussed in Chapter 20 (Novel analgesics and drug delivery systems).

Intrathecal Analgesia A large percentage of patients in the United States undergo cesarean section under spinal anesthesia. Thus, intrathecally administered morphine offers an attractive option for longlasting postoperative analgesia. The clinical use of intrathecal morphine is similar to that of epidural morphine, except that dose requirements are much smaller (0.1 to 0.5 mg). Onset of analgesia, though faster than that observed with epidural dosing, still requires up to 45 to 60 minutes to achieve peak effect, whereas the duration of postoperative pain relief averages 16 to 24 hours.2,4,39 Early-onset respiratory depression resulting from vascular uptake and delivery to the central nervous system is not seen with intrathecal morphine because of the small dose administered. However, late-onset respiratory depression similar to that observed with epidural dosing may develop 6 to 10 hours after administration, as drug migrates rostrally in the cerebrospinal fluid. Ventilatory response to CO2 and respiratory rate may require 8 to 12 hours to return to normal. Chadwick and Ready40 reviewed their experience with intrathecal and epidural morphine in cesarean section patients. A significantly greater proportion of patients (78%) receiving spinal anesthesia and intrathecal morphine (0.3 to 0.5 mg) experienced 20 or more hours of postoperative analgesia, compared with only 64% of patients who received epidural anesthesia and 3 to 5 mg of epidural morphine. The side effects of pruritus and nausea were similar in the spinal and epidural groups. A respiratory rate less than 11 breaths per minute was present in two patients in each group but did not require intervention. Other authors have used even smaller doses of intrathecally administered morphine with success. In a double-blinded study, Abouleish and coworkers41 administered 0.2 mg of morphine or an equal volume of saline solution to 34 patients with their dose of hyperbaric spinal bupivacaine for cesarean section. Patients who received intrathecal morphine required intraoperative opioid supplements less often and in smaller amounts, and their time to first request for additional analgesia after the operation averaged almost 27 hours, compared with only 3 hours for the saline solution group. Pulse oximetry of all patients for 24 hours after the operation showed that both oxygen saturation and respiratory rates were similar. Likewise, neonatal apgar scores, cord blood gases, and neurobehavioral scores in the two groups did not differ. Furthermore, a more recent metanalysis by Dahl and colleagues demonstrated excellent results with 0.1 to 0.2 mg of intrathecal morphine, and no additional pain relief at doses higher than 0.2 mg. The median time to requesting additional analgesia in this study was 27 hours.42 Abboud and colleagues39 studied the ventilatory responses to carbon dioxide in 33 cesarean section patients, who received, in double-blind fashion, either 0.25 mg of morphine, 0.1 mg of morphine, or saline with hyperbaric spinal bupivacaine. All patients in the saline group required 8 mg of subcutaneous morphine within 3 hours of spinal anesthesia. Analgesia lasted a mean of 27.7 hours for patients who received 0.25 mg of morphine and 18.6 hours for those who received 0.1 mg. The authors measured the ventilatory responses to progressive hypercapnia

543

in all 3 groups at intervals up to 24 hours. Neither the CO2 response curves, nor the minute ventilation at a PaCO2 of 50 changed significantly over 24 hours for patients in either of the 2 intrathecal morphine groups, but both values were significantly depressed for 3 hours after the administration of subcutaneous morphine to the saline solution group. On the basis of data verifying the safety and efficacy of lowdose intrathecal morphine for analgesia after cesarean section, this technique is very popular. It seems a dose of 0.2 mg of morphine is ideal for providing 18 to 20 hours of postcesarean analgesia without significant side effects.25 Respiratory monitoring other than the routine monitoring of vital signs appears to be unnecessary, making low-dose intrathecal administration convenient on postpartum wards. Appropriate education of the nursing staff is extremely important if long-acting intraspinal narcotics are to be used on any routine-care ward and 24hour in-house anesthesia coverage is a reasonable expectation. If an intrathecal morphine dose larger than 0.5 mg is administered, prudence recommends arranging overnight care in a more supervised setting such as “step-down” unit. Less information is available concerning the use of subarachnoid fentanyl for postoperative analgesia.43 Palmer and colleagues44 found that the duration of analgesia was even shorter as opposed to bupivacaine when fentanyl was added to lidocaine. In the usual clinical setting, the effects of intrathecally administered fentanyl wane soon after the patient is discharged from the postanesthesia recovery area. PCA may then be initiated as soon as the patient perceives mild-moderate discomfort. Although effective for intraoperative cesearean pain management, the short duration of postcesarean analgesia limits the usefulness of fentanyl as a postoperative analgesic.25 Intrathecal sufentanil (2.5 and 5 ␮g) may result in better analgesia in the first 6 hours postoperatively than fentanyl (10 ␮g).46,47 Nevertheless, its short duration limits the usefulness of sufentanil as a postoperative analgesic. Meperidine has commonly been used in the postcesarean section patient as a parenteral analgesic. Intrathecally administered meperidine is efficacious as a surgical anesthetic. Although meperidine is not approved by the FDA for spinal opioid analgesia, clinical experience indicates that 10 mg of preservative-free meperidine administered intrathecally provides effective postsurgical analgesia of intermediate duration (ie, 5 to 6 hours). Although significant complications have not been reported, potential side effects include pruritus, nausea, vomiting, and urinary retention. The use of intrathecal nalbuphine is limited by the lack of safety trials in humans, as well as the potential to elicit withdrawal in opioid-dependent patients because of its opioid agonistantagonist property.2 It has also been noted to increase nausea.25 Buprenorphine (0.045 mg) added to bupivacaine spinal results in 6 to 7 hours of effective postcesarean pain relief with a lower incidence of pruritis as compared to morphine.48 Continuous intrathecal analgesia has been achieved best with highly lipid-soluble opioids such as fentanyl and sufentanil because of their fast onset and short duration. For example, infusions of bupivacaine (1.5 mg/hour) and fentanyl (15 ␮g/hour) or sufentanil (2.5 to 5 ␮g/hour) have been used successfully.49 The disadvantage is the increased risk for respiratory depression, especially with sufentanil.50,51 This may require closer monitoring with continuous pulse oximetry, possibly in an intensive care setting. Tables 32.1 and 32.2 summarize intrathecal opioid dosing.

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Table 32.4: Maternal Goals after Cesarean Delivery Guide Selection of Opioid and Mode for PCA PCA Opioid and Mode

Table 32.5: IV PCA Opioids Drug

Bolus Dose (mg)

Interval (min)

CI (mg/hr)

4 hr Lockout (mg)

0.01–0.05

3–5

0.02

≤1

Postcesarean Maternal Goal

Optimal

Less Optimal

Fentanyl

Alertness

PCA meperidine

PCA morphine

Meperidine

5–10

6

5–10

300

Ambulation

PCA + BI morphine

PCA meperidine

Morphine

1–1.5

6

1–2

30

Rapid onset of analgesia

PCA oxymorphone

PCA morphine

Hydromorphone

0.1–0.2

6

0.1–0.5

5–10

Sleep

PCA + BI morphine

PCA + BI oxymorphine

Source: Braveman. Requisites in Anesthesiology: Postcesarean Analgesia. 2006.

Abbreviation: BI = basal infusion; PCA = patient-controlled analgesia.

Intrathecal Adjunct Therapy Just as clonidine prolongs the duration of analgesia when added to epidural morphine, the addition of 60 ␮g of clonidine to 100 mcg of morphine in a bupivacaine spinal52 will prolong the duration of spinal morphine analgesia. Although epinephrine may prolong the effects of intrathecal local anesthetics, it has not been shown to be helpful in postcesarean analgesia when added to 0.2 mg of intrathecal morphine.53

Intravenous Patient-Controlled Analgesia Intravenous patient-controlled analgesia (IV PCA) can be used as the sole method for postoperative pain management, or it can be added as supplemental analgesia to epidural or intrathecal opioid analgesia. Intravenous PCA allows the patient to selfadminister a preprogrammed dose of opioid IV at a determined lockout interval, and maximum doses that can be delivered in certain time periods are also preset as an added safety feature. The advantages of this method include improved pain relief, a more consistent blood concentration, and the convenience of bypassing the need for a nurse to administer each dose of pain medication. IV PCA therapy thus eliminates delays related to communication, nursing evaluations and drug preparation. Overall, this results in greater patient satisfaction and better pain relief when compared with intramuscular (IM) opioids.2,58 There are a wide variety of opioids that may be administered by intravenous PCA at equipotent dosages to provide equivalent analgesic responses (Table 32.3); however, differences in opioid-specific pharmacokinetics, pharmacodynamics and complications may result in different patient satisfactions. An investigation of PCA with morphine, meperidine, or oxymorphone after cesarean delivery showed that patient groups had similar opioid requirements and achieved equivalent pain relief at rest.54 However, PCA oxymorphone promoted the most rapid onset of analgesia, whereas patients receiving PCA morphine reported the lowest pain scores beyond 8 hours postoperatively. Meperidine was associated with the most pain during movement, morphine produced the most sedation, and oxymorphone induced the greatest degree of nausea and emesis (Table 32.4). Depending on individual patient risk factors, patient preferences, and efficacy of supplemental medications to prevent or treat complications, each PCA opioid has unique benefits and risks. Using PCA meperidine, parturients with morbid obesity may be reluctant to ambulate and thus increase their risk of deep vein thrombosis and pulmonary embolus; patients with renal insufficiency may accumulate normeperidine and risk develop-

ing neuromuscular tremors or seizures.55 PCA morphine-related sedation may adversely affect maternal-infant bonding. However, after prolonged course of labor followed by cesarean delivery, parturients may benefit from the sedating properties of PCA morphine postoperatively. Prophylaxis against nausea and emesis might be necessary for patients receiving PCA oxymorphone. Table 32.5 summarizes IV PCA opioid therapeutic options. Frequent, intermittent activation of the PCA device maintains plasma concentrations of opioids within a narrow therapeutic range to produce a consistent level of analgesia over time. However, during periods of sleep, this plasma opioid level declines because the PCA pump is not activated. As a result, patients may awaken at night because of waning analgesia or may arise early in the morning with normal movement evoking unexpected pain. These problems can be avoided by programming the PCA pump to infuse opioid continuously, in addition to delivering bolus doses in response to patient activation (patient-controlled analgesia + basal infusion, PCA + BI). The use of PCA alone versus PCA + BI has been studied among parturients after cesarean delivery who received either morphine or oxymorphone.56 Among patients receiving oxymorphone, the addition of a basal infusion to PCA decreased pain scores at rest and with movement, increased the incidence of nausea and emesis, did not increase sedation or produce respiratory depression, and, had no significant effect on patient satisfaction. For patients receiving morphine, the addition of a basal infusion to PCA decreased pain scores with movement, did not significantly increase the incidence of sedation or produce respiratory depression, had no effect on the severity of sedation, and had no effect on satisfaction scores. These results emphasize that although analgesia may be enhanced by adding a basal infusion of opioid, patient satisfaction varies independent of the level of analgesia. Specifically, overall satisfaction remained unchanged because the incidence of adverse side effects was unchanged (sedation) or exacerbated (nausea, emesis). Among postcesarean patients, there are some (as after cesarean hysterectomy) who might benefit by the addition of a basal infusion of opioid, particularly if they experience inadequate analgesia with PCA alone. In those instances, however, close attention must be given toward adequate prophylaxis and treatment of side effects to optimize patient satisfaction. See Table 32.5 to choose the most appropriate opioid to optimize patient satisfaction. It is evident that many factors contribute to the development of a logical plan for maintaining analgesia by PCA after cesarean delivery, including patient evaluation, opioid drug choice, programming infusion pump modalities, and the prevention and treatment of side effects. In addition, one must recognize that intraoperative anesthetic management also plays a significant role, especially as parturients begin to use the PCA pump.

Postcesarean Analgesia

Intravenous opioidsmust be present in plasma at or above their minimum effective concentrations to produce analgesia. Usual PCA dosing regimens are designed to maintain this plasma level, thus effective analgesic with PCA must be preceeded by an intravenous loading dose of opioid to achieve an initial therapeutic level. Most parturients after cesarean delivery use PCA to achieve adequate but not exquisite analgesia. In fact, when compared to neuraxial morphine administration, pain relief is less, but satisfaction is greater because of decreased side effects.58 Limiting self-administered doses tends to reduce the incidence and severity of opioid-related side effects, thus enhancing patient satisfaction. IV PCA may also be initiated as neuraxial opioid effects wane postoperatively, allowing for a smoother transition to postoperative analgesia. On occasion, however, a postcesarean patient may complain of moderate to severe pain despite a loading dose and appropriate use of PCA. Parturients with a recent history of drug abuse (that is, opioids or cocaine) may present in this manner. Among patients with a remote history of drug abuse, inadequate postoperative analgesia may also occur, especially if their usual daily methadone maintenance dose is omitted. Management of such patients should include maintaining a daily methadone dose (oral or parenteral) preadmission and throughout their hospitalization. This will allow normal utilization of PCA opioids after cesarean delivery. The use of opioid antagonists or mixed agonist antagonists must be avoided in these patients so as not to precipitate opioid withdrawal symptoms.59 One must anticipate increased opioid dose requirements to maintain adequate postoperative analgesia in selected patients.

Multimodal Therapy Typically, following cesarean delivery oral intake is begun within 12 hours of surgery. Sips of fluids are often tolerated and requested by the patient in the postanesthesia care unit (PACU). Thus, the use of oral analgesics can be an effective, inexpensive, and labor-saving method of achieving postoperative analgesia. Oral therapy with opioid, nonopioid, or opioid/nonopioid combinations has been shown effective for analgesia when administered around the clock (RTC) with additional PRN dosing for breakthrough pain. Therapy is especially efficacious when combined with a single-dose neuraxial opioid. In fact, Davis and colleagues suggest that oral therapy may be associated with better analgesia and fewer side effects than IV PCA therapy.57 Table 32.6 lists commonly used oral opioid medications. Because the intensity of postcesarean pain diminishes progressively, IV PCA may also be initiated as neuraxial opioid effects wane, with less risk of a “transitional hiatus” with inadequate analgesia.58 Ideally, neuraxial opioids should decrease overall opioid requirement during the postoperative period. However, epidural fentanyl does not, as its effects do not last beyond the intraoperative period. Neuraxial opioids with long durations (24 hours) should best promote a smooth transition to postoperative analgesia; however, the duration of analgesia averages only 4 to 6 hours after epidural meperidine, methadone, butorphanol, or buprenorphine. Only intrathecal morphine and epidural hydromorphone or morphine produce 20 to 24 hours of analgesia, and the latter is associated with a 73% incidence of pruritus and 20% incidence of nausea despite prophylaxis. Clearly, reductions in cumulative opioid dose achieved by neuraxial opioids may not reduce the incidence of opioid-related side effects. Despite much larger cumulative amounts of opioid

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Table 32.6: Oral Opioid Therapy Opioid

Dose

Interval (Hour)

Morphine

10–30 mg

3–4

Oxycodone

5–10 mg

3–4

5/325–15/1000

3–4

Hydromorphone

2–6 mg

3–4

Hydrocodone

5–15 mg

4–6

(Lortab) (hydrocodone/ acetaminophen)

5/500–15/1000

4–6

Vicoprofen (hydrocodone/ ibuprofen)

7.5/200–15/400

4–6

Percocet (oxycodone/ acetaminophen)

Source: Braveman. Requisites in Anesthesiology: Postcesarean Analgesia. 2006.

accrued using PCA, compared to neuraxial administration, side effects with PCA are proportionally fewer and seem to be better tolerated. The use of intramuscular and subcutaneous opioids do not provide the consistent levels of analgesia obtained with the therapies discussed above and are thus not recommended for postcesarean analgesia in 2007. NSAIDs and COX-2 inhibitors, such as celecoxib, have been helpful in treating visceral pain, such as menstrual cramping, and are useful in a multimodal approach to pain relief in terms of enhancing analgesia and reducing opioid-related side effects. The site of action of these agents is not the opioid receptor. NSAIDs decrease inflammation and prostaglandin release centrally and peripherally. Intramuscular diclofenac (75 mg) or IV ketorolac (15 mg), for example, can be beneficial in women postcesarean, regardless if they had general anesthesia or neuraxial blockade (Table 32.7).2 Subcutaneous local wound infiltration with local anesthetics with or without NSAIDs has been used to decrease opioid requirements by blocking pain transmitters.60 Clonidine administered both neuraxially and orally has also been a useful agent to opioid therapy.37 N E O NATA L C O N S I D E R AT I O N S

Maternal use of parenteral opioids after cesarean delivery carries the potential risk for central nervous system depression in the fetus or neonate, secondary to opioid distribution via the placental circulation or breast milk, respectively. The incidence and severity of opioid-related depression is difficult to assess. Evaluation of the fetus in utero is usually limited to fetal heart rate pattern, fetal movements (including breathing patterns), and scalp capillary blood gas analysis. These measurements may reveal fetal distress but are not diagnostic for or predictive of opioid-related depression. After cesarean delivery, PCA, in addition to its maternal effects, may also produce neonatal manifestations if the mother is breastfeeding. Thus, the maternal option to nurse should be a routine part of the evaluation of parturients who are scheduled for cesarean delivery and who elect to receive PCA for postoperative pain relief. After clamping of the umbilical cord, any opioids administered intravenously to the mother must take a circuitous

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Table 32.7: Nonopioid Therapy Drug

Dose

Route

Interval (Hours)

Ketorolac

15 mg

IV/IM

Diclofenac

75 mg

IM

12

PR PO PO Spinal

8 3–4 12 Single dose

First dose 3 hours postoperative Does not affect platelet function Multimodal therapy with spinal opioid provides 6 hrs of analgesia.

Single dose

Higher doses (alone or with opioid) have unacceptable incidences of side effects. Continuous infusion necessary for sustained analgesia.

Single dose –

In combination with opioids, clonidine will prolong the duration of analgesia. Give 1 hour preoperatively Can be administered via a SQ infusion pump (On-Q)

Ibuprofen Celecoxib Clonidine

100 mg 400 mg 200 mg 60–150 ␮g

150–300 ␮g

Bupivacaine

4 ␮g/kg Varies

Epidural

PO Skin infiltration

4–6

Comments Avoid NSAIDs in patients with hepato-renal disease, severe preeclampsia, and those with coagulation disorders and/or postsurgical bleeding. Avoid NSAIDs in patients with hepato-renal disease, severe preeclampsia, and those with coagulation disorders and/or postsurgical bleeding.

Abbreviations: IV = intravenous; IM = intramuscular; PR = per rectum; PO = per os. Source: Requisites in Anesthesiology: Postcesarean Analgesia, Ferne Braveman, M.D., 2006.

pathway through maternal breast milk and neonatal gastrointestinal tract to the neonatal circulation. Regulatory mechanisms in this pathway are complex. First, maternal uptake of opioid during PCA utilization depends on the degree of postcesarean pain, its duration, and the level of maternal tolerance to pain. As a result, opioid concentrations in maternal plasma reflect the need for postoperative analgesia over time. Second, plasma opioids will distribute into and out of the breast milk tissue compartment. Influx and efflux depend on many factors, including regional blood flow, lipid solubility, milk solubility, and maternal metabolic and excretory pathways. Third, neonatal ingestion relies on the adequacy of both maternal lactation and infant sucking. Fourth, to enter the neonatal circulation, opioids must undergo gastrointestinal absorption (which is enhanced by greater lipid solubility) and venous drainage through the liver (exposing opioids to possible first-pass metabolism). Fifth, the degree to which opioids persist in the neonatal circulation (and may depress central nervous system functions) depends on their biodegradation and elimination pathways (notably in hepatic and renal systems). Because this pathway is so complex, it is difficult to predict opioid-specific effects on neonatal neurobehavioral. However, applied opioid biochemistry may forma basis for a few common principles. Given the same requirement for postcesarean analgesia and sufficient time to achieve equilibrium between maternal plasma and breast milk, parturients using different PCA opioids will accumulate opioids in breast milk with equivalent potencies.61,62 Neonatal gastrointestinal absorption of ingested opioids will be greater with more lipid-soluble opioids and opioid metabolites. Finally, if neonates cannot adequately detoxify or secrete certain opioids (notably those that require renal excretion), neonatal CNS depression is more likely to occur. To detect neonatal CNS depression in this setting is not difficult. In a study of intravenous fentanyl for postcesarean analgesia, it was noted that among a group of 9 infants, 1 (who was nursing) developed recurrent apnea and cyanosis requiring cardiopulmonary resuscitation and naloxone.63 Intensive followup observation revealed no intrinsic imbalance in respiratory control, but quantitation of fentanyl in maternal breast milk or

neonatal serum were not performed. It is not surprising that a serum concentration of fentanyl producing maternal analgesia may (through that circuitous pathway through breast milk) also produce neonatal apnea, especially since fentanyl is very highly lipid soluble. However, fentanyl (like butorphanol), in small doses via epidural catheter (for analgesia during cesarean delivery), elicits no decrement in neonatal respiratory function. Detecting more subtle neurologic depression among nursing neonates requires one or more neurobehavioral exams as performed by trained and certified personnel. Furthermore, to determine why this depression occurs requires quantitation of opioid concentrations in relevant tissue compartments. One study utilized both these approaches to assess the incidence, severity, and cause of neonatal depression among infants of nursing parturients who used PCA meperidine or PCA morphine after cesarean delivery.62 Neonates in the morphine group were significantly more alert and significantly more responsive to human orientation cues than neonates in the meperidine group on their third day of life. Decrements in alertness and human orientation seen with meperidine not only reflect opioid-related neonatal depression, but may also inhibit normal maternal-infant bonding interactions. To approach an understanding of the cause of these opioidspecific effects, breast milk specimens were obtained at intervals throughout the 4-day hospitalizations and analyzed for meperidine, morphine, and their metabolites.61 Beyond 48 hours postpartum, normeperidine concentrations in breast milk exceeded meperidine concentrations by a 3:1 ratio, whereas morphine and morphine-3-glucuronide accrued in equal concentrations. Although both morphine and meperidine patient groups were similar in opioid potency of milk, the gastrointestinal absorption, metabolism, and excretion patterns of the 2 drugs are dramatically different. Meperidine, being far more lipid soluble than morphine, is much more rapidly and fully absorbed from the neonatal gastrointestinal tract. In the neonate, meperidine, undergoes first-pass hepatic N-demethylation to form normeperidine, an active metabolite that persists with a prolonged half-life of 63 hours.62 In contrast, morphine also undergoes hepatic first-pass metabolism, but forms an inactive glucuronide

Postcesarean Analgesia

Local anesthetic infiltration IV PCA Morphine Oral opioid/combination therapy

Day of Surgery

POD #1

547 POD #2

POD #3

Figure 32.1: Multimodal therapy: pain management following general anesthesia. Modified with permission from: The Requisites in Anesthesiology: Postcesarean Analgesia, Ferne Braveman, M.D., 2006.

Clonidine (25–50 µg) + Morphine (0.2 mg intrathetcal) Ketorolac (15 mg every 6 hours IV RTC) Oral opiod/combination therapy

Day of Surgery

POD #1

POD #2

POD #3

Figure 32.2. Multimodal therapy: pain management following spinal anesthesia. Abbreviation: RTC = around the clock. Modified with permission from: The Requisites in Anesthesiology: Postcesarean Analgesia, Ferne Braveman, M.D., 2006.

DepoDur Ketorolac (15 mg IV every 6 hours PRN) Oral opioid/combination therapy

Day of Surgery

POD #1

POD #2

POD #3

Figure 32.3. Multimodal therapy: pain management following DepoDur. Abbreviation: PRN = as needed. Modified with permission from: The Requisites in Anesthesiology: Postcesarean Analgesia, Ferne Braveman, M.D., 2006.

Morphine (0.2 mg Intrathecal) PCEA Ketorolac (15 mg IV every 6 hours PRN) Oral opioid/combination therapy

Day of Surgery POD #1

POD #2

POD #3

Figure 32.4. Multimodal therapy: CSE-PCEA. Abbreviation: PRN = as needed. Modified with permission from: The Requisites in Anesthesiology: Postcesarean Analgesia, Ferne Braveman, M.D., 2006.

PCEA Ketorolac (15 mg every 6 hours PRN Oral opioid/combination therapy

Day of Surgery POD #1

POD #2

POD #3

Figure 32.5. Multimodal therapy: PCEA. Abbreviation: PRN = as needed. Modified with permission from: The Requisites in Anesthesiology: Postcesarean Analgesia, Ferne Braveman, M.D., 2006.

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metabolite. As a result, neonates are more capable of detoxifying morphine, by glucuronidation, than of detoxifying meperidine, which ultimately depends on renal excretion. Because PCA with meperidine results in accumulation (in breast milk) of normeperidine and associated neonatal neurobehavioral depression, PCA with morphine may be a better choice for postcesarean analgesia in the parturient who nurses. Especially with a low-birth-weight infant ( 4 mg → commence methadone 40 mg/d or morphine 80 mg/d. Acute or emergency admissions Liaise with HADS Maximize nonopioid analgesic treatments If pain control not adequate, admit to HDU for titration of high dose IV opioids and close observation to monitor for opioid toxicity as partial agonist effects decline. It may be prudent to use a shorter acting opioid such as fentanyl in this context. If the duration of convalescence is expected to be short, buprenorphine may be continued at the usual dose during this period. Otherwise, conversion to a full opioid agonist may be prudent. Discharge from hospital The patient should be stabilized on their preoperative buprenorphine dose ± simple analgesics at the time of discharge. They may be transferred to their standard buprenorphine regimen when postoperative analgesic requirements are minimal. Buprenorphine should be administered either 8 hours after the last opioid dose, or when early signs of opioid withdrawal are noted Adapted from Alfred et al,31 Peng et al,64 and Roberts and Meyer-Witting.65 573

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opinion, clinical experience, and extrapolation from pharmacological principles rather than rigorous scientific data that are urgently needed. P E R I O P E R AT I V E M A NAG E M E N T

Preoperative Period Perioperative management of opioid-dependent patients begins with preoperative administration of their daily maintenance or baseline opioid dose prior to induction of general, spinal, or regional anesthesia. Patients may be instructed to take their usual dose of oral opioid on the morning of surgery. Because most sustained-release opioids provide 12 hours or more of analgesic effect, baseline requirements will generally be maintained during preoperative and intraoperative periods. Thereafter baseline requirements may be provided orally, particularly following ambulatory surgery, or parenterally for those recovering in hospital from more invasive procedures.4,67 Unless contraindicated, patients may also be instructed to take their morning dose of COX-2 inhibitor to reduce inflammatory responses to surgery and to augment opioid-mediated analgesia.13 Patients who are instructed not to take, or those who forget to take, baseline opioids may be treated with an equivalent loading dose of morphine or hydromorphone, administered preoperatively as an oral elixir (if time permits), or intravenously, either at anesthetic induction or during the operative procedure. Patients may also be instructed to maintain their transdermal fentanyl patch into the operating room. If the preparation was removed, an intravenous fentanyl infusion may be initiated to maintain baseline plasma concentrations. A new patch may then be applied intraoperatively; however, it may take 6–12 hours to reestablish baseline analgesic effects.68,69 During that time interval, the fentanyl infusion may be gradually decreased in rate and eventually discontinued. Baseline intravenous opioid infusions may also be maintained preoperatively and then converted to IV PCA following recovery from anesthesia. Epidural and intrathecal opioid infusions delivered by internally implanted devices are generally maintained throughout the perioperative period and are used to maintain baseline pain control. The only exception to this rule applies to patients receiving intrathecal infusions of the nonopioid relaxant lioresal (Baclofen). It may be prudent to discontinue or reduce the intrathecal infusion rate of lioresal during the immediate perioperative period as central effects and peripheral skeletal muscle-relaxing effects of this agent may enhance neuromuscular blockade and increase the incidence of hypotension and excessive sedation.70

Intraoperative Period If the surgical or anesthetic technique permits, it is preferable to continue with oral opioids such as oral transmucosal fentanyl (Actiq), rapidly disintegrating oral fentanyl (Fentora), or “swish and swallow” doses of methadone, during the intraoperative and immediate postoperative period.71 Patients recovering from ambulatory surgery may initially be treated with intravenous boluses of fentanyl or sufentanil. Following stabilization in the postanesthesia care unit (PACU), they may be restarted on oral opioids in doses higher than baseline requirements depending on the invasiveness of the procedure.71

Differences in oral to intravenous dose equivalence must be appreciated to estimate perioperative baseline and supplemental opioid dose requirements. Because parenteral administration bypasses gastrointestinal absorption variables and first-pass hepatic clearance and metabolism, most IV or intramuscular (IM) doses of opioids can be adjusted downward from doses taken orally.72,73 This is particularly the case with IV morphine and hydromorphone, which have 3 and 2–4 times, respectively, greater bioavailability and systemic potency than equivalent oral doses.73–75 In contrast, oxycodone and sustained-release oxycontin have high oral bioavailability that approaches 83% of an IV dose, therefore baseline oral dose can be approximated by nearly similar doses of IV morphine (1–1.5 mg oral oxycodone = 1 mg IV morphine).76,77 Patients treated with transdermal fentanyl (Duragesic) or receiving IV PCA morphine/hydromorphone at home or hospice are more straightforward as their baseline requirement may be supplied with an equivalent IV dose of opioid.73 Because there may be significant interpatient variability in opioid dose requirements, intraoperative vital signs, particularly heart rate, respiratory rate, and degree of pupil dilation, need to be closely monitored. The optimal intraoperative dose should avoid both under- and overmedication, both associated with negative perioperative outcomes.5–7,71 One technique that may help gauge the adequacy of intraoperative opioid dosing is to reverse neuromuscular blockade and allow patients to breathe spontaneously at later stages of the general anesthetic. Patients with respiratory rates greater than 20 breaths per minute and exhibiting slight to markedly dilated pupils generally require additional opioid dosing. Intravenous boluses of morphine, fentanyl, or hydromorphone are titrated as needed to maintain a rate of 12–14 breaths per minute and a slightly miotic pupil.7

Postoperative Period To provide effective postsurgical analgesia, a continuous parenteral opioid infusion or IV PCA provide useful options.78,79 IV PCA may be started in the PACU as soon as patient becomes oriented and capable of utilizing the device. Initiation in the PACU minimizes the risk of undermedication and breakthrough pain that may occur during patient transport to the surgical care unit. To compensate for opioid tolerance and receptor downregulation, higher than normal doses of morphine or hydromorphone might be considered. A basal infusion equivalent either to the patient’s hourly oral dose requirement or 1 to 2 PCA boluses per hour may be added to maintain baseline opioid requirements. Basal infusions may not be required in patients receiving baseline analgesia via transdermal fentanyl patch. Oral methadone has been advocated for use in patients who experience ineffective post surgical analgesia despite administration of relatively high doses of morphine or synthetic derivatives of morphine.56 The improved analgesic efficacy may be related to (1) methadone’s ability to activate a different spectra of ␮-receptor subtypes to which morphine tolerance has not developed; (2) methadone’s activity at ␣-adrenergic receptors may provide useful analgesic effects that are not influenced by high-grade opioid tolerance; and, finally, (3) d-methadone has been shown to block morphine tolerance and opioid-induced hyperalgesia by virtue of its NMDA-receptor antagonistic and ␣-adrenergic agonistic properties.80,81 For these reasons, some

Patients with Opioid Dependence and Substance Abuse

have even advocated methadone as the IV PCA opioid of choice in opioid-dependent patients.82,83 Nonopioid analgesic adjuvants may also be employed to reduce opioid dose requirements and provide multimodal analgesia in the postoperative period, although relatively few evaluations have been performed in opioid-dependent patients. Nonopioid analgesics, including NSAIDs and selective COX-2 inhibitors,13,84 low-dose ketamine, and clonidine by various routes, have all been studied (see General Patient Management). A recent review on the topic has encouraged the use of multimodal pain management therapy in the perioperative management of chronic pain patients with opioid dependency by using a round-the-clock regimen of NSAIDs, COX-2 inhibitors, acetaminophen, and regional blockade.75 Finally, it may be worthwhile to consider the contribution of fear and anxiety to the overall pain syndrome. This is especially true for opioid-tolerant patients and polydrug abusers. Anxiety and fear need to be discussed and treated with appropriate medication as required. Anxiolytic agents, benzodiazepines, and tricyclic antidepressants may be administered to treat symptoms as they arise. Liaison with appropriate agencies (addiction medicine, psychiatry) may become necessary.

Neuraxial Analgesia for Postoperative Pain Neuraxial administration of opioids offers a more efficient method of providing postsurgical analgesia than parenteral or oral opioids.85–88 Intrathecal and epidural doses of morphine are roughly 100 times and 10 times more potent than for the same dose of morphine given parenterally.86 Thus, significantly greater levels of analgesia can be delivered to those patients recovering from more extensive procedures where postsurgical parenteral opioid doses would be expected to be very high. Despite this, there have been few evaluations of neuraxial analgesia in opioid-dependent patients.89 In contrast to local anesthetic blockade, neuraxial opioid analgesia is influenced by downreglation of spinal opiate receptors and epidural and intrathecal dose requirements are increased proportionally.86–88 With intrathecal administration, opioid dose is generally a small fraction of the patient’s baseline oral requirement. Despite the fact that patients experience effective pain relief, plasma concentrations and supraspinal receptor binding may decline to the point that acute withdrawal is precipitated, unless supplementary opioids are given.86 For this reason it is important to maintain baseline opioid requirements either orally or by intravenous PCA in patients who remain nil per os (NPO). Monitoring for complications in particular excessive sedation and respiratory depression is mandatory when administering opioid drugs in higher than normal concentrations and via different routes of administration. Increasing the concentration of epidurally administered opioids may compensate for spinal receptor downregulation. For patients treated with epidural infusions, an opioid loading dose greater than that used in na¨ıve patients, followed by a more concentrated infusion may improve pain control in highly tolerant patients. Patient-controlled epidural boluses (PCEA) may be added to complement the basal epidural infusion. Local anesthetics such as bupivacaine (0.1%), levobupivacaine (0.1%), or ropivacaine (0.2%) may be added to the epidural infusate to provide selective neural blockade and augment opioid-mediated analgesia.86 Rescue doses of parenteral and possibly oral opioids might be administered to gain supraspinal analgesic effects

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and to prevent withdrawal symptoms. In patients ordered to take nothing by mouth, epidural analgesia is employed for postsurgical pain while baseline requirements are maintained with IV PCA, IV boluses of opioids, or “sip and swallow” doses of methadone. In addition to increasing the epidural opioid infusion concentration, some advocate switching to an opioid that has high intrinsic potency such as sufentanil.89

Regional Analgesia for Postoperative Pain Expert opinion suggests that, whenever possible, opioid-tolerant patients should be offered regional analgesia particularly on procedures performed on the extremities.7,71 Techniques that may be considered include tissue infiltration and nerve and plexus blockade. Advantages of a regional analgesic approach include reduction in parenteral/oral opioid requirements and improvement in distal perfusion as a result of sympathetic blockade. Regional blockade may offer a useful alternative for most peripheral vascular and reimplantation surgeries and for other procedures requiring graft revision or replacement. For upper extremity procedures, brachial plexus blockade can be performed using interscalene and supraclavicular approaches. Similarly, for lower extremities, sciatic block, lumbar plexus block, continuous femoral block, and ankle block may be performed. Neural blockade may be initiated with bupivacaine or levbupivacaine in standard doses. A continuous infusion of bupivacaine or levobupivacaine may be continued postoperatively. With appropriate protocols and safety guidelines, patients may be discharged home with indwelling brachial plexus catheters and local anesthetic infused for up to 48 hours via disposable pumps. Other interventions include injection of local anesthetics and opioids into knee and other articular joints and injections of local anesthetics into disk spaces or iliac crest for spinal surgery. The goal is to minimize pain perception and reduce, although not completely eliminate, the use of oral or parenteral opioids.6,71

Dose Tapering Following ambulatory surgery, baseline requirements for oral opioids generally need to be supplemented with additional doses, generally 20%–50% increase above baseline, to accommodate pain associated with surgical injury.71 Oral opioids may then be downtitrated daily over 3–7 days to presurgical amounts, as the intensity of acute pain diminishes. Although opioid analgesics should never be withheld from dependent patients, some caregivers cautiously underestimate theoretical IV dose equivalencies in patients requiring extremely high baseline doses of oral or transdermal opioids, especially in patients recovering from surgical procedures performed to reduce baseline chronic pain.6,7,71 For example, only 50% of an intravenous equivalent may need to be given to patients requiring oxycodone doses greater than 200 mg/d, morphine doses greater than 300 mg/d, or transdermal fentanyl doses greater than 150 ␮g/h. Opioid dosing may be increased as needed if patients do not experience adequate pain control. When pain is markedly reduced following successful spine surgery, neurolysis, or cordotomy, baseline opioid dosing should be gradually tapered rather than abruptly stopped to avoid withdrawal.6,7,90 Postoperative baseline or maintenance dose may be reduced 25%–50% and administered as divided doses. Dose tapering may proceed by 25%–50% every third day, until the daily dose

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Table 34.7: Guidelines for Perioperative Pain Management in Opioid Tolerant Patients Preoperative Evaluation: should include early recognition and high index of suspicion Identification: identify factors such as total opioid dose requirement, previous surgery/trauma resulting in undermedication, inadequate analgesia, or relapse episodes Consultation: meet with addiction specialists and pain specialists with regard to perioperative planning Reassurance: discuss patient concerns related to pain control, anxiety, and risk of relapse Medication: calculate opioid dose requirement and mode(s) of administration, provide anxiolytics or other medications: as clinically indicated Intraoperative Maintain baseline opioids (oral, transdermal, intravenous). Have patient take morning dose of sustained duration opioids the day of surgery Increase intraoperative and postoperative opioid dose to compensate for tolerance Provide peripheral neural or plexus blockade, consider neuraxial analgesic techniques when clinically indicated Utilize nonopioids as analgesic adjuncts Postoperative Plan preoperatively for postoperative analgesia; formulate primary strategy as well as suitable alternatives. Maintain baseline opioids Employ multimodal analgesic techniques Patient-controlled analgesia: as primary therapy or as supplementation for epidural or regional techniques Continue neuraxial opioids: intrathecal or epidural analgesia Continue continuous neural blockade Postdischarge If surgery provides complete pain relief, opioids should be slowly tapered, rather than abruptly discontinued Develop a pain management plan prior to hospital discharge; provide adequate doses of opioid and nonopioid analgesics Arrange for a timely outpatient pain clinic follow-up or a visit with the patient’s addictionologist Reprinted with permission from Mitra and Sinatra.7

has decreased to 10–15 mg of morphine equivalent, after which time it may be stopped.96 Alternatively, patients can be switched to an equianalgesic dose of methadone, which can then be slowly tapered. Transdermal fentanyl patches are easily maintained and replaced. In patients recovering from back procedures, surgical improvement in analgesia may allow fentanyl dose tapering of 25% within 24–48 hours. Further tapering may continue every 48 to 72 hours as tolerated by the patient. Application of clonidine transdermal patch 0.1–0.2 mg/h may help minimize some of the autonomic aspects of opioid withdrawal if symptoms should become distressing. Following hospital discharge, opioid-dependent patients should be scheduled for immediate follow-up visit with a pain specialist, who can optimize pain management during rehabilitation and facilitate opioid dose tapering. Some patients may require the expertise of an addictionologist and possibly enrolment into a buprenorphine detoxification program. Mitra and Sinatra7 suggested detailed guidelines for perioperative pain management in opioid-tolerant patients. A general guideline for the perioperative period is shown in Table 34.7.

the pain specialist are responsible for maintaining baseline opioid requirements and for providing effective multimodal analgesia. Withdrawal phenomena because of the abrupt discontinuation of other substances need also be identified and prevented or treated. Comprehensive, round-the-clock pain control remains the prime concern in the acute phase of management, relegating the issue of addiction treatment to a later phase once the patient is clinically more stable and pain free. Liaison with the patient’s addiction treatment system is important for this purpose. The liaison issue becomes vitally important in the case of acute pain management for those on methadone or buprenorphine maintenance therapy. The latter scenario (acute pain management in those on BMT) is especially likely to become more commonplace in future. Guidelines for management, as suggested in the accompanying tables, are often based on clinical experience, expertise of people working in this area, and anecdotes rather than rigorous scientific data. Future studies with appropriate methodology are warranted in this respect. Finally, it must be said that the cornerstone of management of these patients is achieving the balance between the administration of appropriate analgesia, on one hand, and close clinical monitoring for patient safety, on the other.

C O N C LU S I O N

In conclusion, it is important to emphasize that opioiddependent and substance-abusing patients have unique needs in the acute pain setting. Starting with the initial important goals of identifying and assessing such patients, the anesthesiologist and

R E P R E S E N TAT I V E C A S E M A NAG E M E N T

The following case reports offer insight and management guidelines for common issues observed in opioid-dependent patients,

Patients with Opioid Dependence and Substance Abuse

recognizing that alternative methods of treatment may be provided.

Case 1 Mrs RM, a 77-year-old, with a history of non-insulin-dependent diabetes mellitus, degenerative joint disease, and obesity, was scheduled for elective bilateral total knee arthroplasty. She has been taking oxycontin 20 mg twice a day for 2 years, which was recently increased to 40 mg twice a day. Her anesthesiologist used a combined spinal-epidural (CSE) technique. Intraoperatively she received 0.75% bupivacaine (15 mg) with 0.25 mg of preservative-free morphine (which reflect the standard spinal anesthetic/analgesic dose at our institution) and following completion of the procedure the epidural catheter was tested with 3 mL of 2% lidocaine. Approximately 45 minutes following her arrival in PACU, she began to complain of severe pain (VAS pain intensity of 9). At this point, an epidural bolus of 8 mL of 0.25% bupivacaine resulted in improved pain relief. An epidural infusion with hydromorphone (10 ␮g/mL) with 0.03% bupivacaine was started at a rate of 10 mL/h. However, within 60 minutes she again complained of severe pain. The pain specialist was notified and suspected that the inadequate level of analgesia noted by the patient was related to high-grade opioid tolerance. An epidural loading dose of hydromorphone (3 mg, usual loading dose is 1 mg), plus 8 mL bupivacaine (0.25%), reestablished effective pain control. A more concentrated epidural infusion containing hydromorphone (30 ␮g/mL) plus bupivacaine (0.1%) at 12 mL/h plus patient-controlled boluses of 3 mL every 10 minutes as needed maintained analgesia. In addition to neuraxial analgesia, IV morphine (5 mg every 2–3 h PRN) was prescribed to insure adequate central analgesic and sedating effects. Intravenous morphine was discontinued the evening following surgery and oxycontin (20 mg) was initiated. Multimodal analgesic supplementation included administration of a COX-2 inhibitor rofecoxib (50 mg every day), and application of a clonidine patch (0.1 mg every hour). The following morning, her dose of oxycontin was increased to 40 mg twice a day, the epidural infusion was discontinued 48 hours following surgery, and she was advanced to oral analgesics, oxycontin (80 mg twice a day) plus oxycodone (10–20 mg every 4 hours PRN) and rofecoxib (50 mg). The patient remained comfortable on this dose during her additional 2-day stay in the hospital. Following discharge her daily dose of oxycontin was gradually decreased to 20 mg twice a day over a period of 2–3 weeks and the dose of rofecoxib was decreased to 12.5 mg every day. The major error in this case was to have not recognized that, despite her age, Mrs RM was highly opioid tolerant, therefore doses of opioids employed for neuraxial analgesia should have been increased substantially and supplemented with judicious doses of IV or oral opioids as required.

Case 2 Mr RS is a 48-year-old with chronic low back pain of several years’ duration who presents for spinal fusion surgery with iliac crest bone graft. He has required treatment with opioid analgesics for several years and is currently prescribed transdermal fentanyl patch (Duragesic, Janssen; 100 ␮g/h) and oxycodone (5 mg) with acetaminophen. He was told by his orthopedic surgeon to discontinue transdermal fentanyl the night prior to

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surgery, as it might interfere with the general anesthetic. During the 3-hour operative procedure performed with an isofluranebased anesthetic, Mr RS received 400-␮g of fentanyl and 10 mg of morphine sulfate. On transfer to the PACU, he was noted to be tachycardic, hypertensive, and screaming in pain. The patient was given 20 mg of morphine in divided doses over a period of 5 minutes yet continued to experience severe pain (pain intensity score of 11 on a 0–10 VAS scale). He was then given an additional 250 ␮g of fentanyl yet continued to be hyperdynamic and agitated and complaining of severe pain. The pain management team took over care of the patient and titrated 8 mg of IV hydromorphone over a period of 10 minutes. At this time his pain score was reduced to 5 on a 0–10 VAS. The patient was started on IV PCA hydromorphone with a bolus dose of 0.6 mg every 6 minutes and a basal infusion of 0.6 mg/h. Two transdermal fentanyl patches (100 ␮g/h plus 50 ␮g/h; total 150 ␮g/h) were applied to reestablish baseline opioid requirements. In addition the patient was treated with rofecoxib (50 mg every day) and clonidine transdermal patch (0.1 mg/h). (Because rofecoxib has been withdrawn celecoxib [400 mg] offers a suitable alternative.) Approximately 12 hours after the fentanyl patch was applied, the patient was noticeably more comfortable, with a VAS score of 3, and somewhat sedated, therefore the PCA basal infusion was discontinued. The patient remained on PCA hydromorphone for 48 hours; thereafter he was converted to oral opioids. We calculated that he used 26 mg of hydromorphone each day, and converted him to oral hydromorphone 6 mg every 4 hours PRN for pain while continuing transdermal fentanyl (150 ␮g/h). Over the next 48 hours, his dose of oral hydromorphone was reduced to 2 mg every 4 hours and the transdermal fentanyl patch was reduced to 100 ␮g/h. Clonidine patch and oral rofecoxib were continued. Mr RS was discharged to home on this dose of opioid and scheduled for a follow-up visit in the pain clinic. The important point in this case is that patients treated with transdermal fentanyl are opioid tolerant. The patch should be maintained during the perioperative period and supplemented with higher than normal doses of IV or oral opioids for breakthrough pain.

Case 3 Mr JK is a 34-year-old heroin addict (for 5 years) who was otherwise healthy prior to his motor vehicle accident and femur fracture 5 weeks ago. Following open repair of the fracture, he has been off heroin and has been treated with fentanyl transdermal delivery system (Duragesic patch; 100 ␮g/h) for pain control. He was scheduled for replacement of hardware at the fracture site. The transdermal fentanyl patch was removed the morning of surgery. Intraoperatively, he received epidural anesthesia with 2% epidural lidocaine with fentanyl (100 ␮g). For postoperative pain control, he received an epidural infusion of bupivacaine 0.1% with fentanyl (5 ␮g/mL) at the rate of 10 mL/h plus epidural PCA. Mr JK’s postoperative pain relief was fair to good, but he used the maximum epidural PCA dose and required two rescue boluses of bupivacaine (0.25%). The next day, during the morning rounds, he was noted to be in moderate discomfort (VAS score of 5 of 10); however, he was also diaphoretic, tachycardic, and complaining of abdominal cramping and diarrhea. Infectious disease was called and a stool sample was obtained to rule out Clostridium difficile infection. The orthopedic surgeons suspected infection and possible sepsis and requested that

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the epidural be removed. The pain management team recognized that the patient was exhibiting classic signs of opioid withdrawal. He was immediately treated with IV hydromorphone (6 mg) and a clonidine patch (0.1 mg/h) was applied. In addition his preoperative dose of transdermal fentanyl was restarted. The patient’s symptoms subsided and he made a smooth transition from epidural analgesia to transdermal fentanyl plus oral hydromorphone as needed for breakthrough pain. The major message associated with this case is that, although neuraxial analgesia may provide effective pain relief, the dose of opioid administered may be too low to maintain baseline plasma concentrations and prevent systemic opioid withdrawal.

Case 4 Mr RM is a 35-year-old male presenting for a right total hip arthroplasty. He was involved in a motor vehicle accident 1 month prior with fracture and dislocation of his right hip. The patient’s past medical history is notable for substance abuse of opioids, marijuana, benzodiazepines, and tobacco. It was unclear as to when he last used benzodiazepines. He is otherwise healthy with no known cardiac, respiratory, gastrointestinal, or infectious issues. The patient has been on maintenance methadone, taking 110 mg every morning. He took his methadone on the morning of the operation. In the operating room, before the induction of general anesthesia, the patient had a lumbar L3-L4 epidural catheter placed. He was given 1 mg of hydromorphone epidurally along with local anesthetic intraoperatively before starting a continuous standard epidural infusion of 10 ␮g/mL of hydromorphone and 0.031% of bupivacaine at a rate of 12 mL/h. In the recovery room, the patient was in severe 10/10 pain, complained of muscle spasms, and was diaphoretic. The patient was given a bolus through the epidural pump of 20 mL of the standard epidural infusion with an increase in the rate of the epidural infusion to 18 mL/h. The concentration of the hydromorphone in the epidural infusion was increased to 30 ␮g/mL and the infusion was run at a rate of 12 mL/h. His pain score decreased to 5/10. On arrival to the surgical floor approximately 1 hour later, the patient again complained of 10/10 pain that was unbearable and associated with uncontrollable muscle spasms and rigors. The catheter was bolused with bupivacaine (0.25%) and 2 mg of hydromorphone, which provided some relief; however, the patient remained very anxious. Intravenous lorazepam (2 mg) was given in incremental doses. He eventually calmed down, and reported feeling much better at a pain scale of 4/10. The epidural infusion with repeated scheduled doses of lorazepam (2 mg every 4 to 6 hours) eventually provided adequate relief. This case illustrates how clinicians may focus on, and adequately compensate for, opioid tolerance while restricting or omitting other centrally acting agents that the patient may be dependent on. Placement of the epidural catheter and administration of high doses of hydromorphone was a good option for this patient; he, however, was troubled by excessive anxiety and agitation that worsened his perception of pain. Once his benzodiazepine dependence was uncovered, a nearly continuous administration of lorazepam significantly reduced his pain intensity and agitation. Given the magnitude of his anxiety component, scheduled doses of benzodiazepines should have been administered intraoperatively and in the early postsurgical period.

Case 5 The pain service was asked to consult for a 34-year-old patient suffering severe postoperative discomfort that could not be adequately controlled by the PACU nursing team and orthopedic surgical staff. The patient had a long history of substance abuse, including illicit use of heroin, oxycodone, and cocaine. He enrolled in an opioid detoxification program approximately 3 months prior to the present admission and has been treated with sublingual buprenorphine (8 mg) plus naloxone (Suboxone) daily. The last dose was taken the morning of surgery. He presented to the same-day surgical center with a diagnosis of a left knee meniscal tear with severe pain and underwent an arthroscopic repair with general anesthesia. Despite receiving 400 ␮g of fentanyl intraoperatively, he complained of severe discomfort (VAS of 10 of 10) that was unresponsive to PACU doses of morphine (15 mg), fentanyl (100 ␮g), and hydromorphone (3 mg). The pain service recognized that the patient was on BMT (Suboxone), and suspected that ongoing receptor antagonism may have reduced the effectiveness of the opioid-mediated analgesia. To overcome receptor blockade and rapidly gain pain control the patient was treated with sufentanil, a potent opioid with high receptor affinity. After receiving 50 ␮g in divided doses, he reported a reduction in pain intensity (VAS 8 of 10). The patient refused a femoral nerve block; however, he did agree to a single intra-articular injection of bupivacaine (0.25%, 8 mL) perfomed by the surgical team. He also received ketorolac (30 mg) to reduce the inflammatory aspects of his acute pain. The patient was admitted to the surgical care unit for overnight pain control. He was provided IV PCA hydromorphone (3-mg loading dose followed by 0.4-mg incremental bolus doses with an 8-minute lockout) and given single dose of celecoxib (400 mg) later in the evening. The following morning, he was converted to oral analgesics (oxycodone [10–15 mg] plus celecoxib [200 mg twice a day]). Methadone (10 mg twice a day) was substituted for suboxone. He was discharged uneventfully and maintained on this prescription for the next 72 hours, whereupon suboxone therapy was reinitiated by his psychiatrist. The patient and his caregivers were instructed that prior to future surgery, methadone should be employed as a temporary substitute for buprenophine/naloxone compounds and, if applicable, regional anesthesia/analgesia techniques should be strongly considered.

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SECTION IV

Specialist Managed Pain

35 Pain Management Following Colectomy: A Surgeon’s Perspective Theodore J. Saclarides

Colectomy, whether performed for benign or malignant disease processes, is a potentially morbid operation accompanied by a significant hospital stay, prolonged period of recovery, and extended time off from work. There has been considerable interest recently in determining ways to lessen complications and hasten recovery. Several centers have established clinical pathways and fast-track protocols that attempt to streamline the care of these patients from the minute they walk into the admissions department to the time the discharge order is written. Integral to the optimum management of patients undergoing colon resection is efficient pain control. In fact, pain specialists, whether they are anesthesiologists, nurse anesthetists, or nurse clinicians, have become important team members in these pathway committees. Successful relief of pain following major abdominal surgery invariably involves the use of parenteral and oral opioids; however, it is well known that narcotics contribute to the formation of an ileus, persistence of which may impair the recovery of patients with respect to restoration of normal bowel function. Consequently, clinicians have sought for ways to minimize the use of systemic narcotics, hasten recovery, and shorten hospital stay without compromising patient comfort or overall satisfaction with respect to their hospitalization. These efforts include neuraxial administration of opioids, using nonnarcotic analgesics, employing minimally invasive surgical techniques, and challenging traditional surgical practices with respect to nasogastric decompression, diet advancement, physical activity, and reliance on old criteria for discharge such as the passage of stool.

dinated bowel motility after surgical intervention, which prevents effective transit of intestinal contents or tolerance of oral intake.”2 Ileus is an expected complication following abdominal surgery and it may normally last for 3 to 4 days. The presence of a complication such as an intra-abdominal infection or anastomotic leak, however, may prolong an ileus. Ileus may follow other types of surgery, and can occur after urologic, gynecologic, orthopedic, and cardiothoracic procedures. It is a very common reason for prolonged hospital stay. According to 1999–2000 data from the Health Care Financing Administration, in the United States, the overall incidence of postoperative ileus after common abdominal operations was 8.5%. The incidence varies according to specific type of operation performed, being highest for surgery on the small bowel and colon, reaching almost 20%.2 The actual incidence may actually be higher because adequate documentation in the medical records may be lacking when a retrospective study of this nature is conducted. As stated previously, some reduction in gastrointestinal motility is to be expected during the first few days after an operation. Factors responsible for postoperative bowel dysfunction are outlined in Table 35.1. The various segments of the gastrointestinal tract recover their normal peristaltic activity at different times. The small bowel is the first to recover its normal motility and it does so usually within the first 24 hours postoperatively. In fact, small bowel peristalsis is visibly apparent during surgery in many cases, and jejunostomy tube feedings may be safely started immediately following completion of the operation. The stomach will recover next, usually within 48 hours. The colon is the last to recover and does so between 48 and 120 hours.1,3 Clinically, a patient with a postoperative ileus will complain of abdominal distention, cramping, nausea and vomiting, and delayed passage of flatus and stool. As a consequence of this, resumption of oral intake of nutrients may be delayed and parenteral nutrition may be required. Complications related to a central venous catheter could then occur. Other sequelae of an ileus include delayed ambulation, hypoalbuminemia, poor wound healing, reduced immune function, and nosocomial infections, including pneumonia. The end results are delayed

P O S TO P E R AT I V E B OW E L DY S F U N C T I O N

Opioid analgesics are associated with a number of undesirable side effects, including postoperative bowel dysfunction (POBD) and development of ileus. There is no standardized definition for ileus, but Livingston and Passar have defined it as the “functional inhibition of propulsive bowel activity, irrespective of pathogenic mechanism.”1 The Postoperative Ileus Management Council has defined postoperative ileus (POI) as “transient cessation of coor583

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Table 35.1: Factors Responsible for Postoperative Bowel Dysfunction Surgical manipulation Neurogenic: sympathetic hyperactivity Inflammatory: cellular and humoral factors, including endogenous opioid peptides Hormonal: corticotrophin releasing factor Pharmacologic pain management Exogenous opioids: used for pain prevention, but also act in the myenteric plexus to directly inhibit GI motility

Table 35.3: Surgical Techniques: Laparoscopy Duration of ileus is shortened after less invasive surgery Reduction in tissue injury leads to less inflammation and sympathetic response More rapid progression to a solid diet More rapid hospital discharge Several studies have shown favorable results These results may reflect earlier feeding and less reliance on opioid analgesia Holte and Kehlet. Drugs. 2002;62(18):2603–2615.5

Kehlet H, Holte K. Am J Surg. 2001;182 (5A suppl):3S–10S.

Baig MK, Wexner SD. Dis Colon Rectum. 2004;47:516–526.18

Holte K, Kehlet H. Drugs. 2002;62:2603–2615.5

discharge, increased hospital costs, and reduced overall patient satisfaction (Table 35.2). The neural regulation of the gastrointestinal tract is governed by both intrinsic (enteric) and extrinsic systems. The former establish the basic motility patterns, that is, the frequency with which migratory peristaltic contractions occur within each segment of the gut. Extrinsic control occurs through the sympathetic and parasympathetic nervous systems, whose function reflect what is occurring at any given moment for a particular patient.4 Stimulation of the sympathetic nervous system (surgical incisional pain, release of catecholamines as part of the normal response to stress) will have an inhibitory effect on gut function; enhanced parasympathetic activity will have the opposite effect. Alterations in either the intrinsic or extrinsic pathways may contribute to the development of postoperative ileus as may other factors such as infection, inflammation, the extent of surgical manipulation, and opioids. The inflammatory response produced by surgical manipulation and trauma results in activation of macrophages and mast cells that release various inflammatory mediators such as prostaglandins and nitric oxide, a potent inhibitor of gut function. Vasoactive intestinal polypeptide (VIP) and substance P are also released, both of which may contribute to ileus.5–7 Table 35.2: Clinical Impact of Postoperative Ileus Increased postoperative visceral pain Increased nausea and vomiting Increased risk of aspiration Need for Nasogastric intubation Prolonged time to oral intake and regular diet Delayed wound healing Increased risk of malnutrition and catabolism Prolonged time to mobilization Increased pulmonary complications Increased risk of DVT Prolonged hospitalization Impaired rehabilitation Increased health care costs From: Kurz A, Sessler DI. Drugs. 2003;63:649–671.

Endogenous opioids (endorphins, enkephalins, dynorphins) are released as part of the stress response that normally occurs after surgery. Exogenous systemic opioids are potent analgesics and are commonly prescribed following surgery. Both types of opioids activate the same receptor site within the bowel, the ␮receptor, and affect motility, secretion, and transport of fluids and electrolytes. They also profoundly inhibit peristaltic activity, delay gastric emptying, and intestinal transit. The total dose of exogenous opioid administered correlates significantly with the return of bowel function as measured by the return of bowel sounds, time to passage of first flatus, and time to first bowel movement. As expected, return of bowel function correlates with hospital length of stay.8–10 M I N I M A L LY I N VA S I V E S U RG E RY

Altering the surgical approach to incorporate minimally invasive technology will have beneficial effects on postoperative pain intensity, analgesic requirements, recovery of bowel function and length of hospital stay. Laparoscopic surgery has been studied extensively and has been compared to open surgery in a randomized fashion. In a meta-analysis of 12 randomized clinical trials published before 2002, 2512 patients were studied. Although laparoscopic surgery took an average of 32.9% longer to complete, there were fewer complications with this approach, specifically with respect to wound complications. The average time to passage of first flatus was reduced by 34% and to tolerance of solid food by 24%. Narcotic usage was reduced by 37%. At 6 hours, pain at rest decreased by 35% and during coughing by 35%. At 3 days, pain at rest was decreased by 63% and during coughing by 40%. Hospital stay was decreased by almost 21%. There were no significant differences in perioperative mortality or oncologic result.11 Benefits associated with minimally invasive surgery are outlined in Table 35.3. O P I O I D E F F E C T S O N B OW E L F U N C T I O N

When one considers the possible interventions physicians can introduce to shorten the duration of postoperative ileus, hasten return of gastrointestinal function, and shorten hospital stay, the use of opioids is probably one of the easiest and most important modifiable factors. Opioids decrease gastric motility and increase pyloric tone, potentially leading to anorexia, nausea, and vomiting (Table 35.4). They also decrease pancreatic and biliary secretions, reduce small bowel propulsion, and increase

Pain Management Following Colectomy

Table 35.4: GI Effects of Opioidsa

Table 35.5: Epidural Anesthesia/Analgesia

Pharmacologic Impact

Clinical Effect

Decreased gastric motility Inhibition of small intestinal propulsion Inhibition of large intestinal propulsion

Increased GI reflux Delayed absorption of medications Straining, incomplete evacuation, bloating, abdominal distension Spasm, abdominal cramps, and pain

Increased amplitude of nonpropulsive segmental contractions Constriction of sphincter of Oddi Increased anal sphincter tone, impaired reflex relaxation, rectal distension Diminished gastric, biliary, pancreatic and intestinal secretions. Increased absorption of water a

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Biliary colic, epigastric discomfort Impaired ability to evacuate bowel Hard, dry stool

If left untreated, opioid-induced bowel dysfunction can lead to pseudo-obstruction of the bowel, fecal impaction, poor absorption of oral drugs, and severe impairment of quality of life. (From: Pappagallo M. Am J Surg. 2001;182(suppl):11S–18S; Vanegas G, et al. Cancer Nurs. 1998;21:289–297; Kurz A, Sessler DI. Drugs 2003;63: 649–671.)

fluid absorption. Within the colon, opioids bind to, and activate, mu receptors in the myeteric plexus. Following activation, these receptors mediate decreased propulsion, increased nonpropulsive contractions, and increased fluid absorption leading to hard and dry stools, bloating, distention, and constipation. Virtually all anesthetics/analgesics may depress gastrointestinal motility, however the sympathetic blockade and opioid sparing effects associated with epidural local anesthetics may provide clinical benefits Epidural local anesthetics were first administered in the 1920s for the treatment of paralytic ileus. Several studies have demonstrated an improvement in outcome following surgery with respect to pulmonary function, blunting the surgical stress response, and better pain control. Reduced postoperative ileus is a significant benefit of epidural anesthetics/ analgesics when compared to general anesthesia and systemic opiates. In fact, bowel function may return 2 to 3 days earlier. This should be taken into consideration when planning clinical pathways and fast-tract protocols for shortening hospital stay. B E N E F I T S O F E P I D U R A L A NA LG E S I A

There are several mechanisms by which epidural anesthesia may promote recovery of gastrointestinal motility. These include blockade of noxious afferent fibers, blockade of thoracolumbar sympathetic nerves, release of parasympathetic inhibition, reduced need for postoperative opioids, and increased gastrointestinal blood flow (Table 35.5). It is probably the reduction in postoperative systemic opioids that has the most profound effect.12–16 Several randomized controlled trials comparing epidural anesthetics/analgesics versus systemic opioids have shown a benefit in favor of the former.17 Namely, there has been

Blocks sympathetic nervous system efferent tone responsible for inhibiting bowel motility Minimizes exposure to opioid analgesics Reduces effort dependent pain, encourages ambulation Inclusion of local anesthetics is important (Several studies have shown reduction in GI paralysis with epidural local anesthetics alone or combined with opioids as compared with opioids alone1,3 Sympathetic blockade with epidural local anesthetics is associated with a higher incidence of hypotension. (Patient must be well hydrated) Location of catheter important: thoracic application more effective than lumbar or low-thoracic Steinbrook RA. Anesth Analg.1998;86:837–844. Jorgensen H, et al. The Cochrane Library. Issue 3. 2004. Liu SS. Anesthesiology. 1995;83:757–765.

a demonstrable reduction in time to passage of first flatus, first stool, or both. Epidural infusions containing local anesthetics provide greater facilitation of bowel function but are more likely to precipitate hypotension in hypovolemic patients. Liu and coworkers15 reported that in patients recovering from colonic surgery, infusions containing local anesthetic or dilute local anesthetic plus opioid were associated with more rapid return of bowel function and met criteria for discharge sooner than either epidural solutions containing opioids alone or intravenous patient-controlled analgesia (IV PCA) (Table 35.6). Additional benefits from epidural anesthesia include improved perioperative pulmonary function, blunted surgical stress response, reductions in perioperative cardiac morbidity, and a lower incidence of pulmonary infections and embolism. Complications from epidural catheters include transient paresthesias and the rare case of epidural hematomas. Generally, epidural anesthesia is safe for patients undergoing bowel surgery. Studies have shown that epidurally administered local anesthetics maintain intestinal blood flow and mucosal pH and have a potentially beneficial effect on anastomotic healing rates.17 N S A I D S A N D C OX - 2 I N H I B I TO R S

Other pharmacologic methods of reducing systemic opioid use include the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase 2 (COX-2) inhibitors (coxibs), and peripheral ␮-receptor opioid antagonists. NSAIDs allow one to reduce the dose of systemic opioids by as much as 20%–30%. Blunting the inflammatory response with the use of NSAIDs may lead to a reduction in the influx of macrophages and mast cells into the area of surgical trauma and a reduction in nitric oxide, prostaglandins, and proinflammatory cytokines, all of which potentiate postoperative ileus. Inclusion of NSAIDs into a postoperative pain management protocol has become common, specifically with ketorolac trimethamine. This drug does not reduce colonic contractions, an effect noted with morphine. Postoperative analgesia with ketorolac may cause a faster resolution of ileus compared to analgesia with morphine and ketorolac.3,18–20 NSAIDs and coxibs provided additive postoperative analgesia and significant opioid-sparing effects following

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Table 35.6: Recovery of GI Function and Time until Hospital Dischargea Epidural Morphine plus Bupivacaine (MB)

Epidural Morphine (M)

Epidural Bupivacaine (B)

IV PCA Morphine (PCA)

43 ± 4b 67 ± 8b 96 ± 12

71 ± 4 102 ± 13 130 ± 14

40 ± 2b 62 ± 5b 101 ± 11

81 ± 3 96 ± 7 122 ± 9

Time until first flatus (h) Time until meeting discharge critera (h) Time until actual hospital discharge (h)

Note: values represent mean ± SE. Abbreviation: PCA = patient-controlled analgesia. a Liu SS et al: Anesthesiology. 1995;83;757–765. b Different from group M and group PCA (P < .005).

abdominal surgery. Grass and coworkers21 found that the addition of ketorolac (15 mg every 6 hours) reduced pain intensity scores and epidural PCA fentanyl requirements in patients recovering from bowel surgery. Patients assigned to the ketorolac group also benefited from faster time to oral diet and bowel movement. Many surgeons are concerned about platelet inhibition and increased risk of perioperative bleeding, with ketorolac and other nonselective NSAIDS. Coxibs have minimal impact on platelet function and have been advocated for postoperative analgesia. Perioperative doses of rofecoxib (50 mg every day) for 5 days reduced IV PCA morphine requirements by 30% while reducing pain intensity scores in patients recovering from abdominal surgery.22 Rofecoxib treated patients also benefited from significant reductions in sedation scores and more rapid return of bowel function. As rofecoxib has been withdrawn by the manufacturer, celecoxib in doses of 200 mg twice a day offers a suitable alternative P E R I P H E R A L O P I O I D A N TAG O N I S T S

The effects of opioids on gut function are mediated primarily through the ␮-receptors within the bowel. If one could block the peripheral effects of opioids on the bowel while maintaining their central nervous system effects on analgesia, gut function could be protected while maintaining pain relief. The drugs naloxone and naltrexone reduce opioid-induced bowel dysfunction but reverse analgesia. An ideal preventative measure or treatment of postoperative ileus would be a peripheral opioid ␮-receptor antagonist that reverses gut side effects without compromising pain control.

Naloxone does not achieve this. Although naloxone is a competitive ␮-receptor antagonist, it readily crosses the blood-brain barrier when given intravenously, reverses analgesia, and may induce opioid withdrawal. Its beneficial effects include reversal of opioid-induced central nervous system depression and respiratory depression, and it may decrease opioid-induced constipation. There are no data to support its use in the prevention or treatment of ileus. Emerging therapy for POBD and POI include two peripherally selective ␮-receptor antagonists, methylnaltrexone and alvimopam (Figure 35.1). Methylnaltrexone is a selective peripheral opioid receptor antagonist that has recently been approved for treatment of opioid induced bowel dysfunction (OBD). Addition of CH3 (methyl) group to naltrexone, a naloxone-derived, tertiary antagonist, prevents the drug from penetrating the bloodbrain barrier. Consequently, it reverses opioid-induced motility problems without reversing analgesia or inducing withdrawal. It is available as an injectable and is currently being evaluated in chronic and postoperative settings. The effectiveness of this compound provides support for concept that OBD and possibly POI areprimarily brought about by opioid receptors in the GI tract. Intravenous doses of 0.15– 0.3 mg/kg have been shown to rapidly initiate a bowel movement (Figure 35.2). While not approved for use in surgical settings, the IV formulation has been advocated for reversal of POI.

100

0.15 mg/kg

p < 0.0001

0.30 mg/kg Placebo

Quaternary Opioid Receptor Antagonists

%

50

0

0

1

2

3

4

5

Time (h)

Methylnaltrexone

Alvimopan

Figure 35.1: Emerging therapy for opioid induced bowel dysfunction: methynaltrexone and alvimopam.

Figure 35.2: Methylnaltrexone in patients with opioid-induced constipation. Time to laxation was significantly more rapid for patients treated with methylnaltrexone when compared to placebo group within the first 5 hours. From: Yuan CS, Israel RJ. Expert Opin Investig Drugs. 2006;15(5):541–552.

Pain Management Following Colectomy

Alvimopan is a peripherally acting ␮-opioid receptor antagonist.23 Its large molecular weight and polarity do not allow it to cross the blood-brain barrier and thus does not block central opioid receptors.24 It has a higher potency at the ␮-receptor than does morphine or methylnaltrexone and a longer duration of action than methylnaltrexone. Its side effects are currently under investigation and include abdominal pain, flatulence, and diarrhea.24 Alvimopan acts by reversing only the peripheral side effects of opioids without interfering with their central effects. Morphine, codeine, hydrocodone, oxycodone, and fentanyl relieve pain by crossing the blood-brain barrier and activating receptors of the central nervous system. This can also produce sedation, respiratory depression, and dependence. Concurrently, peripheral opioid receptors are activated such as those in the gastrointestinal tract potentially leading to alterations in bowel motility. Phases I, II, and III studies with alvimopan have been conducted, the phase III studies have also incorporated a fast-track protocol for all study subjects whereby all potentially innovative means to shorten hospital stay have been utilized. Such methods have included avoidance of nasogastric decompression, initiation of early feedings, and early ambulation. These methods, when employed in a clinical pathway approach, have been shown in a randomized controlled trial to shorten hospital stay when compared to traditional postoperative care. Patient satisfaction, pain control, and patient readmission rate because of complications or failure to progress satisfactorily have not been compromised.25–27 Alvimopan was studied in a double-blinded, randomized, placebo-controlled phase III trial involving 34 North American academic, public, and private medical centers to evaluate its effect on postoperative ileus. Enrollment included 510 patients in 3 different study arms: alvimopan (6 mg), alvimopan (12 mg), and placebo.27 All patients were over the age of 17 years who underwent segmental small or large bowel resection or radical total hysterectomy. All were scheduled to receive intravenous patient-controlled analgesia with opiates and all were scheduled to have the nasogastric tube removed at the completion of surgery. Study medications were given orally at least 2 hours before surgery and then twice a day until hospital discharge or up to 7 days. The primary efficacy end point was time to recovery of gastrointestinal function, as defined by the later of the times that the patient first tolerated solid food and that the patient first passes flatus or stool. An additional end point was the time to when the hospital discharge order was written. The time to recovery of gastrointestinal function was significantly accelerated by alvimopan at both doses compared to placebo; however, a more pronounced effect was noted with the 12-mg dose. The hospital discharge order was written approximately 20 hours earlier for patients receiving the 12-mg dose and 13 hours for those receiving the 6-mg dose. Interestingly, there were fewer instances of nasogastric tube insertion after surgery in patients treated with alvimopan compared to placebo. There were no differences in average daily opiate consumption between the treatment groups and daily and maximum postoperative pain scores were comparable.26 This is an important point to take note of: pain control and, hence, patient satisfaction was not jeopardized. The incidence of adverse events was similar among the 3 treatment groups, although the incidence of nausea and vomiting was slightly lower in the alvimopan treatment groups compared to placebo. In a second phase III study, similar results

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Table 35.7: Summary of Current Therapies for POBD At present there is no adequate treatment or prevention for POI Nonpharmacologic therapies have demonstrated no real value in the treatment of POI in clinical trials Techniques such as laparoscopy are complicated and may not be suitable for all patients Emerging management and treatment strategies include epidural and regional anesthesia/analgesia, use of COX-2 inhibitors (celecoxib), use of less invasive surgery, introduction of prokinetic opioid antagonists

were noted.25,27 When the results from the phase III studies are pooled, the alvimopan-treated groups had a lower incidence of nasogastric tube insertion, a lower incidence of postoperative ileus and early postoperative bowel obstruction, a reduction in hospital stay, and a trend toward a lower readmission rate. As stated, most patients undergoing colectomy require opioids for pain relief. It is not the intention of any of the maneuvers mentioned to totally eliminate the need for opioids, rather the goal of optimum patient management is to minimize the effects of systemic opioids on gut function. At the same time, a primary objective is to relieve patients of pain, eliminate unnecessary suffering, and ensure their satisfaction with their hospital stay. This is achieved by using analgesic techniques and adjuncts which lower the dose of opioid required to alleviate pain. Such therapy includes use of NSAIDs such as ketorolac or a Cox-2 inhibitor such as celecoxib, local anesthetic wound infiltration, oral or IV acetaminophen and epidural blockade. When postoperative gut function returns earlier, hospital stay is shortened. This could have significant implications on the cost of health care. In the United States, the annual burden of postoperative ileus on health care is $750 million to $1 billion per year.3 This is attributable to prolonged need for intravenous fluid administration, nasogastric decompression, extra hospital days, additional nursing care, and laboratory and radiologic tests. If one considers the number of laparotomies performed annually, if the hospital stay could be reduced by even 1 or 2 days for each patient, the cost savings could be enormous. Current strategies for minimizing POBD are outlined in Table 35.7. C O N C LU S I O N

Surgical concerns regarding postoperative pain management are often complicated by potential adverse effects of analgesics, such as impaired hemostasis with NSAIDs and POBD with opioids, as well as surgical related factors such as hypovolemia and anticoagulation that may contraindicate placement of neuraxial catheters. Nevertheless, the treating physician has a number of ways to reduce pain intensity, shorten hospital stay and hasten gut recovery following colectomy. One can consider altering the technique to include minimally invasive technology, but perhaps the most significant way is to employ a multidisciplinary approach to pain control. Epidural anesthetic agents, NSAIDs/ COX-2 inhibitors, and peripheral opioid-receptor antagonists all show promise in reducing the incidence and duration of postoperative ileus.

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REFERENCES 1. Livingston EH, Passar EP Jr. Postoperative Ileus. Dig Dis Sci. 1990;35:121–132. 2. Delaney CP, Wolff BG, Viscusi ER, et al. Alvimopan, for postoperative ileus following bowel resection. Ann Surg. 2007;245(3):355– 363. 3. Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg. 2003;138:206–214. 4. Goyal RK, Hirano I. The entire nervous system. N Engl J Med. 1996;334:1106–1115. 5. Holte K, Kehlet H. Postoperative ileus: progress towards effective management. Drugs. 2002;62:2603–2615. 6. Behm BW, Stollman NH. Postoperative Ileus: etiologies and interventions. Clin Gastroenterol Hepatol. 2003;1:71–80. 7. Bauer AJ, Schwartz NT, Moore BA, Turler A, Kalff JC. Ileus in critical illness: mechanisms and management. Curr Opin Crit Care. 2002;8:152–157. 8. Prasad M, Matthews JB. Deflating postoperative ileus. Gastroenterology. 1999:117;489–492. 9. Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus. Neurogastroenterol Motil. 2004;16(suppl 2):54–60. 10. Cali RL, Meade PG, Swanson MS. Freeman C. Effect of morphine and incision length in bowel function after colectomy. Dis Colon Rectum. 2000;43:163–168. 11. Abraham NS, Young JM, Solomon MJ. Meta-analysis of shortterm outcomes After laparoscopic resection for colorectal cancer. Br J Surg. 2004;91:1111–1124. 12. Ogilvy AJ, Smith G. The gastrointestinal tracts after anesthesia. Eur J Anaesthesiol. 1995;10(suppl):35–42. 13. Moraca RJ, Sheldon DG, Thirlby RC. The role of epidural anesthesia and analgesia in surgical practice. Ann Surg. 2003;238:663– 673. 14. Steinbrook RA. Epidural anesthesia and gastrointestinal motility. Anesth Analg. 1998;86:837–844. 15. Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia: their role in postoperative outcome. Anesthesiology. 1995;82:1474– 1506.

16. Ryan P, Schweitzer SA, Woods RJ. Effect of epidural and general anaesthesia compared with general anaesthesia alone in large bowel anastomoses: a prospective study. Eur J Surg. 1992;158:45– 49. 17. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg. 2000;87:1480–1493. 18. Baig MK, Wexner SD. Postoperative ileus: a review. Dis Colon Rectum. 2004;47:516–526. 19. Soybel DI, Zinner MJ. Ileus and the macrophage. Ann Surg. 2003;237:316–318. 20. Ferraz AA, Cowles VE, Condon RE, et al. Nonopioid analgesics shorten the duration of postoperative ileus. Am Surg. 1995;61: 1079–1083. 21. Grass JA, Sakima NT, Valley M, et al. Assessment of ketorolac as an adjuvant to fentanyl patient-controlled epidural analgesia after radical retropubic prostatectomy. Anesthesiology 1993;78:642– 648. 22. Sinatra RS, Boice J, Loeys TL, et al: Evaluation of perioperative rofecoxib treatment on pain control and clinical outcome in patients recovering from gynecologic abdominal surgery: a randomized, double-blind, placebo controlled clinical study. Reg Anesth Pain Med. 2005;31;134–142. 23. Azodo IA, Ehrenpreis ED. Alvimopan (Adolor/GlaxoSmithKline). Curr Opin Investig Drugs. 2002;3:1496–1501. 24. Schmidt WK. Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg. 2001;182(suppl 5A):27S–38S. 25. Taguchi A, Sharma A, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med. 2001;345:935–940. 26. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan Postoperative Ileus Study Group. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multi-center, randomized, double-blind, placebo-controlled phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004;240:728–735. 27. Delaney CP, Weese JL, Hyman NH, et al. Alvimopan Postoperative Study Group. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005;48:1114–1125.

36 Acute Pain Management in the Emergency Department Knox H. Todd and James R. Miner

Emergency physicians provide care for an extraordinary broad range of illnesses and injuries, the majority of which involve some degree of pain. Table 36.1 lists major categories of discharge diagnoses among those presenting to a multicenter emergency department (ED) network with a principal complaint of pain. Emergency physicians also frequently cause pain in the course of performing emergent therapeutic and diagnostic procedures. This chapter considers the prevalence of pain in the emergency department, barriers to its adequate treatment, as well as a variety of treatment modalities. Space limits prohibit a discussion of the wide variety of specific painful conditions that present to the ED. These can be found in other chapters of the text.

thus issues surrounding pain assessment should have primacy in our attempts to understand the pain experience. EDs employ a number of practical unidimensional pain assessment tools. Viewing pain as the “fifth vital sign” as encouraged by revised standards of the Joint Commission for Accreditation of Health Care Organizations has fostered the widespread use of such tools. For those without cognitive impairment, pain intensity can be assessed with either an 11-point numerical rating scale (NRS) or a graphical rating scale (GRS). The NRS is sensitive to the short-term changes in pain intensity associated with emergency care.4,5 GRS or picture scales are particularly useful for populations with limited literacy, including children.6,7 In one study of patients who have advanced cancer and pain, 81% were able to complete a picture scale, whereas only 75% could complete the VAS.8 In another study, the authors noted that male patients were uncomfortable with scales depicting severe pain using tears.9 Picture scales with such depictions might be avoided, because they may be biased in the direction of less severe pain in male patients. The visual analog scale (VAS) is used by some EDs; however, this instrument is more commonly employed in research settings. There is no advantage in using a VAS over an NRS in the ED settings; both are reliable and valid measures of pain intensity.10 In fact, certain patient populations find the NRS easier to complete, therefore it is preferred over the VAS for routine use.4,11 No matter the specific pain scale used, assessments should be repeated after therapeutic interventions and at the time of ED discharge. One multicenter study suggests that relatively few ED patients are reassessed after an initial pain score, finding that fewer than one-third of ED patients presenting with moderate to severe pain had repeat pain assessments while in the ED.12

P R E VA L E N C E A N D A S S E S S M E N T O F PA I N I N T H E E M E RG E N C Y D E PA RT M E N T

Pain is the presenting complaint for up to 78% of visits to U.S. EDs.1–3 Although making an accurate diagnosis and choosing the appropriate therapy to treat underlying conditions are principal goals for emergency physicians, those who present to the ED with pain seek recognition of their pain and rapid, effective interventions to control pain. In the United States, the ED serves as a safety net for our fragmented health care system, and pain is but one of many conditions for which emergency physicians not only treat acute clinical presentations but also care for those with chronic or recurrent painful conditions who are unable to access other parts of the health care system. Pain is inherently subjective and inevitably complex. Patients experience pain and suffering as individuals; clinicians assess it only indirectly. The emergency provider’s task is to use a commonly understood vocabulary and classification system in assessing pain so that our findings can be communicated consistently. Only by quantifying the pain experience in meaningful ways can we move beyond practices that are influenced by myth and opinion toward a scientific approach to our many questions regarding the pain experience. This challenge is at the root of our difficulties in treating pain, and not only in the ED setting;

T H E P R O B L E M O F E M E R G E N C Y D E PA RT M E N T O L I G OA NA LG E S I A

Notwithstanding the clinician’s duty to provide compassionate care, pain that is not acknowledged and managed appropriately causes anxiety, depression, sleep disturbances, increased 589

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Table 36.1: Major Categories of Diagnoses for 819 Patients Discharged from the ED after Presenting with Moderate to Severe Pain Diagnosis Wound, abrasion, or contusion Sprain or strain Back or neck pain Abdominal pain Fracture or dislocation Headache Chest pain (noncardiac) Upper respiratory infection Abscess or cellulitis Toothache Urinary tract infection Renal colic Other diagnoses Total

N (%) 91 (11) 90 (11) 85 (10) 71 (9) 48 (6) 47 (6) 40 (5) 30 (4) 25 (3) 19 (2) 16 (2) 14 (2) 243 (30) 819 (100)

From: Todd KH, Ducharme J, Choiniere M, et al. Pain in the emergency department: results of the Pain and Emergency Medicine Initiative (PEMI) Multicenter Study. The Journal of Pain 2007;8(6):460–466.12

oxygen demands with the potential for end organ ischemia, and decreased movement with an increased risk of venous thrombosis.13,14 Failure to recognize and treat pain may also result in dissatisfaction with medical care, hostility toward the physician, unscheduled returns to the ED, delayed complete return to full function, and, potentially, an increased risk of litigation.15 Although adequate analgesia in the ED is an important goal of treatment, the underuse of analgesics, termed oligoanalgesia by Wilson and Pendleton in 1989, occurs in a large proportion of ED patients.16–20 A variety of factors are felt to give provenance to pain undertreatment (Table 36.2).21 The very young or old often receive less intensive treatment for pain in the ED,22–24 and studies have documented oligoanalgesia among those of minority ethnicity.25,26 It has been suggested that patients’ expectations for pain treatment and perceptions of pain intensity do not differ by ethnic groups when patients are matched for socioeconomic factors.27–29 Differences have been noted, however, in the manner in which patients of different cultural backgrounds express their pain.29 Differences in the interactions of physicians and patients of different ethnic groups have been described and subtle differences within these interactions may affect the physician’s pain assessment.30,31 When affect, actual patient-MD interaction, and cultural expressions of ethnicity are removed from a case presentation, such as through written clinical vignettes, patients with similar pain tend to be similarly treated by physicians.32 Cultural discordance between the patient and the physician may hinder the ability of patients to confer an understanding of their pain to the physician. Of course, any treatment of pain is dependent on the physician’s accurate assessment of the patient’s pain. In fact, the only predictor of treatment that Bartfield and colleagues found for ED

Table 36.2: Factors Contributing to ED Oligoanalgesia Lack of educational emphasis on pain management Inadequate ED quality improvement systems Lack of ED pain research, particularly among geriatric and pediatric populations Emergency providers’ concerns regarding opioid addiction and abuse Fear of opioid adverse effects Racial and ethnic bias

patients with back pain was the physician’s assessment, regardless of the patients’ ethnicity, age, or insurance status.33 Disparities in the treatment of pain likely result from variations in assessment rather than variations in treatment among patients assessed as having a similar degree of pain. Although emergency physicians may be reluctant to accept patient report as the most reliable indicator of pain, and disparities between patient’s and physician’s pain intensity ratings may lead to inadequately treated pain, even patients themselves may be reluctant to report the presence of pain and its intensity. This may be because of low expectations of obtaining pain relief, fear of analgesic side effects, and perhaps the notion that pain is to be expected as part of an underlying disease or from medical treatments. Some patients exhibit an inappropriate fear of addiction when prescribed opioids, or fear the stigma associated with opioid use, even in the short term. Although federal regulators and state medical boards do not perceive emergency medicine as a specialty prone to inappropriate prescribing resulting in investigations and possible sanctions, emergency physicians express fears of such scrutiny or sanctions related to prescribing or administering opioids. In treating pain in patients receiving chronic opioid therapy, confusion over the concepts of physical dependence, tolerance, addiction, and pseudoaddiction may also constitute barriers to appropriate treatment. The use of standard definitions and widespread dissemination of these terms may be helpful in caring for patients managed with chronic opioids who present to the ED. ED personnel commonly identify patients who they feel are attempting to obtain opioids for illegitimate purposes. Although drug addiction occurs in all patient populations, it is likely that the ED sees a higher proportion of such patients than a typical office-based practice. Unfortunately, the true prevalence of addiction and aberrant drug-seeking behaviors in the ED is unknown and difficult to measure. When the prevalence of such problems is overestimated, oligoanalgesia is the predictable result. PA I N T R E AT M E N T A N D P RO C E D U R A L S E DAT I O N I N T H E E D

Effective pain management involves both pharmacologic and nonpharmacologic modalities. Simply asking about pain and validating the pain reports affects patients’ satisfaction with ED pain management. In one study, patient satisfaction with pain management was predicted more strongly by the perception that ED staff asked about pain than by the actual administration of an analgesic.34 Other nonpharmacologic modalities, such as

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reassuring the patient that pain will be addressed, immobilizing and elevating injured extremities, and providing quiet, darkened rooms for patients with migraine headaches are important aspects of quality pain management. Pharmacologic therapies should begin as soon as is practical after presentation to the ED. Analgesic protocols allowing early pain treatment can decrease the time to effective treatment and improve patient outcomes.35–37 Analgesics may be administered by a variety of routes; however, the vast majority of medications are administered by the oral or parenteral routes. Oral therapies are most commonly employed, as they are convenient and inexpensive for patients who can tolerate oral intake. When pain is severe, analgesics must be given immediately and titrated to effect, generally by parenteral routes. The intravenous (IV), rather than intramuscular (IM), route is indicated in this context. Intramuscular injections are painful, do not allow for rapid titration, and result in a slower onset of drug action; moreover, absorption is unpredictable. Unless intravenous access is elusive, there is little to recommend the intramuscular route. In general, it is inappropriate to delay analgesic use until a diagnosis has been made. In the case of acute abdominal pain, for which surgical dogma historically discouraged adequate analgesia, a large series of studies report no deleterious effect of intravenous opioid therapy on our ability to make appropriate diagnoses.38–44 S P E C I F I C T R E AT M E N T M O DA L I T I E S

A wide variety of analgesics are used in emergency medicine practice. In a recent -site survey of ED analgesic practice, a total of 735 doses of 24 different analgesics were administered to 506 patients receiving analgesics while in the ED. Analgesics administered to this cohort of ED patients are listed by prevalence in Table 36.3.12 The majority of analgesics administered were opioids (59%); morphine being the most commonly used analgesic (20%), followed by ibuprofen (17%). NONOPIOIDS

Commonly used ED analgesics include opioids, acectaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs). When opioids are required for pain treatment, nonopioids should be included to potentiate the opioid analgesic effect and decrease the severity of side effects. Unfortunately, nonopioid agents exhibit an analgesic ceiling effect and cannot be titrated to effect. This limits their usefulness in the setting of severe or fluctuating pain; however, they should be used as an adjunct to opioid therapies unless otherwise contraindicated. Acetaminophen is indicated for mild to moderate pain and is often combined with opioid agents. Acetaminophen, unlike NSAIDs, has no antiplatelet activity or anti-inflammatory effect. Although a great deal of attention has been paid to acetaminophen hepatotoxicity, especially in the setting of chronic malnutrition, alcoholism, or liver disease, such effects are uncommon, particularly when contrasted to the underappreciated high prevalence of NSAID-related adverse effects. NSAIDs, including salicylates, act to inhibit prostaglandin synthesis by interfering with cyclooxygenase (COX) enzymes. They cause platelet dysfunction and can precipitate renal failure in patients with renal insufficiency or volume depletion, a par-

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Table 36.3: ED Analgesics Administered to 506 Patients Presenting with Moderate to Severe Pain Analgesics Administered in the ED (735 doses given to 506 patients) Morphine Ibuprofen Hydrocodone/acetaminophen Oxycodone/acetaminophen Ketorolac Acetaminophen Hydromorphone Antacid Meperidine Fentanyl Metoclopramide Codeine/acetaminophen Oxycodone Naproxen Other Total

N (%) 148 (20.1) 127 (17.3) 93 (12.7) 83 (11.3) 60 (8.2) 53 (7.2) 36 (4.9) 26 (3.5) 24 (3.3) 23 (3.1) 13 (1.8) 12 (1.6) 10 (1.4) 9 (1.2) 18 (2.4) 735 (100)

From: Todd KH, Ducharme J, Choiniere M, et al. Pain in the emergency department: results of the Pain and Emergency Medicine Initiative (PEMI) Multicenter Study. The Journal of Pain 2007;8(6):460–466.12

ticular concern in the elderly or those presenting to the ED with hemodynamic instability. Ketorolac, the only parenteral available in the United States, is commonly used in the ED and is felt to be particularly useful in the setting of renal colic. One recent study of renal colic in the ED found that a combination or ketorolac and morphine resulted in superior analgesia and reduced adverse effects when compared to the use of either agent alone.45 OPIOIDS

Opioid combination analgesics are commonly used for moderate to severe pain. Although the opioid component in these agents does not exhibit ceiling analgesic effects, the nonopioid component dose must be limited; thus one cannot titrate these analgesics. The convenience of combination therapy must be balanced against this limitation. Hydrocodone and oxycodone combination agents are associated with less nausea and vomiting and are preferable to codeine combinations agents. Also, a significant proportions of the population are poor metabolizers of codeine, which must be metabolized to morphine to manifest analgesic effects, further limiting its effectiveness. The tramadol/acetaminophen combination agent is indicated for acute pain; however, experience with this agent in the ED setting is limited. In one recent trial of acute ankle sprains presenting to the ED, the tramadol/acetaminophen combination agent had comparable clinical utility to that of hydrocodone with acetaminophen.46 Tramadol’s mechanism of action is unclear: it binds only weakly to opioid receptors, but a metabolite is a more potent opioid and, in addition, it inhibits the reuptake of

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both norephinephrine and serotonin with analgesic effects like the tricyclic antidepressants. Opioids are the mainstay of ED therapy for moderate to severe pain and morphine is the standard of comparison for all agents of this class. If contraindicated because of allergy or other sensitivity, hydromorphone or fentanyl may be substituted. These opioids can be rapidly titrated intravenously to control severe pain, allowing early institution of an oral regimen. Fentanyl has the advantage being relatively short acting and is preferred in the setting of multiple trauma, head injury, and potential hemodynamic instability. Intravenous morphine is the standard of treatment for severe pain in the ED. Morphine (0.1 mg/kg bolus) has been found to be safe but not usually adequate to effect pain relief.47 Repeat boluses of 0.05 mg/kg every 5 minutes until pain relief represents a safe incremental strategy. Meperidine is a problematic opioid for a number of reasons. Many EDs have eliminated meperidine completely because of its metabolism to normeperidine, a toxic metabolite causing central excitation and seizures. In addition, meperidine is contraindicated in patients taking monoamine oxidase inhibitors as this combination may precipitate a serotonergic crisis.48 Historically, subtherapeutic doses of intramuscularly administered meperidine have been used to treat a wide variety of acute pain complaints by generations of physicians. The availability of other opioid agents of equal efficacy with fewer contraindications and less adverse effects argues against its routine use. Agonist-antagonist opioids, such as nalbuphine and butorphanol, have mixed effects on opioid receptor subtypes, exhibiting ceiling effects on both analgesia and respiratory depression. Because clinically important respiratory depression is distinctly rare in the setting of acute pain treatment, it is difficult to justify their routine use. One possible exception is for patients with advanced pulmonary disease. A particular drawback is that one cannot titrate these drugs to maximal effect because of analgesic ceiling effects. Additionally, these drugs are contraindicated and will induce withdrawal symptoms in patients who are physically dependent on opioids, either because of opioid therapy for chronic pain, methadone maintenance therapy, or active opioid addiction. PAT I E N T- C O N T RO L L E D A NA LG E S I A

The use of patient-controlled analgesia (PCA) has been described in emergency medicine for both adults and children.49,50 Although no specific advantage has been found over the titration of opioids, PCAs are at least as effective in relieving pain. In the setting of high demands on nursing resources, PCAs could serve to ensure that patients’ pain treatment needs are addressed in a timely fashion. In addition, patients admitted from the ED to inpatient hospital beds often experience a “pain window” between the last dose of an analgesic in the ED and the first dose administered on the hospital ward. Wider use of ED PCA might obviate this common problem. A LT E R NAT I V E D E L I V E RY RO U T E S

Multiple alternative delivery routes for the administration of pain medications have been described. The use of nebulized fentanyl has been described and holds promise as a route of

opioid delivery that can be initiated before an IV has been placed.51–53 Nebulized pain medications, especially for children who have severe pain but has not had an IV placed, could be of use in the ED. P RO C E D U R A L S E DAT I O N A N D A NA LG E S I A

Patients often present to the ED in need of painful or complex procedures that require patient cooperation and must be done emergently. Procedural sedation and analgesia (PSA) practices and policies have evolved rapidly in the ED and this is a growing area of emergency medicine research. Unlike most patients who are undergoing sedation in other settings, patients in the ED have unpredictable nil per os (NPO) status, often have concurrent severe systemic disease, and usually are in severe pain before the procedure begins. In addition, unpredictable concurrent events, as well as time and space constraints in the ED, can serve to complicate these procedures. The indications for ED PSA range from pain control for short painful procedures to the need for patient compliance with complex emergency procedure. Goals for level of sedation during ED PSA range from minimal through moderate to deep sedation, depending on the demands of specific procedures. Although it is acknowledged that deep sedation can inadvertently result in patient’s achieving a level of sedation consistent with anesthesia, this is not typically the goal of ED PSA. Minimal sedation, a drug-induced state during which patients respond appropriately to verbal commands (according to their developmental age), is generally performed for procedures that require patient compliance but are not typically intensely painful when performed with local anesthesia. Minimal sedation is typically used for lumbar puncture, evidentiary exams, simple fracture reductions (in combination with local anesthesia), and the incision and drainage of small abscesses. During minimal sedation, cardiovascular and ventilatory functions are generally well maintained, although patients should be monitored for inadvertent oversedation to deeper levels, using oxygen saturation monitors and close nursing supervision. Agents typically used for minimal sedation include fentanyl, midazolam, combinations of the two, and low-dose ketamine. Moderate sedation is performed on patients who would benefit from either a deeper level of sedation to augment the procedure or amnesia of the event itself. Moderate sedation is a drug-induced depression of consciousness during which patients respond to verbal commands (appropriately to their developmental age), either alone or with light tactile stimulation. Patients usually have an intact airway and maintain ventilatory function without support. As with minimal sedation, inadvertent oversedation to deeper levels can occur with moderate sedation. Appropriate assessments, including oxygen saturation, cardiac monitoring, and blood pressure measurements, should be done throughout the sedation, and direct observation of the patient’s airway should be maintained throughout the procedure. Agents used for moderate sedation in the ED include propofol, etomidate, ketamine, and the combination of fentanyl and midazolam. Deep sedation is performed on patients who would benefit from a deeper level of sedation, often to complete a procedure already begun. Generally, amnesia of the procedure is similar

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between moderate and deep sedation, and it is not necessary to sedate patients to a deep level only to obtain amnesia.54 Deep sedation is achieved in the ED with the same agents as moderate sedation; the difference is in the intended level of sedation. Monitoring requirements for deep sedation are similar to those for moderate sedation. End tidal carbon dioxide has also been described in ED PSA, but its utility over direct assessment of airway status has not been established.55 Deeply sedated patients can develop respiratory depression but generally maintain a patent airway and adequate ventilation. Patients sedated to this level can progress to a level of sedation consistent with anesthesia,56–58 and there is some evidence that this occurs more frequently in patients targeted for deep sedation than in those undergoing moderate sedation.59 For this reason, it is usually safer to use moderate sedation than deep sedation in the ED unless the procedure requires progressively deeper levels of sedation to complete successfully, such as the reduction of hip dislocations. Patients who progress to an unintended level of sedation consistent with general anesthesia are not arousable, even to pain. The ability to independently maintain ventilatory function is usually impaired, and patients often require assistance in maintaining a patent airway. Because patients can quickly progress to this level using agents commonly employed for moderate and deep sedation, physicians performing ED PSA must be prepared to provide ventilatory support until the patient has regained consciousness. To decrease the likelihood of aspiration, patients who are undergoing moderate or deep sedation in the ED should be kept NPO. It is difficult to find a consensus on the amount of time a patient should be kept NPO prior to PSA.60,61 Many departments use 3–6 hours as a minimum.62 ED PSA is necessarily used for patients who are medically stable (American Society of Anesthesiologists physical classes 1 and 2) and must be avoided in patients who are ASA 3 or 4. PSA for critically ill children has been described using ketamine63 and in adults using propofol or etomidate.64 The degree of respiratory depression noted in these patients was similar to patients with physical status scores of 1 or 2, but an increased rate of hypotension was seen in physical status 3 and 4 patients who received propofol. It may be that ketamine and etomidate are better suited for the emergent sedation of critically ill patients, but there is not yet sufficient data to make a definite recommendation. Both ketamine and propofol can have profound hemodynamic and respiratory effects in the more physiologically compromised patients. Sedated patients are generally monitored by pulse oximetry, which is a sensitive measure of oxygenation. If a patient receives supplemental oxygen prior to starting PSA, this monitor may not be as sensitive to changes in the patient’s ventilatory status.55,65,66 Preoxygenation is generally recommended for ED PSA; however, there is no evidence that it decreases the incidence of transient hypoxia that has been noted as a complication of PSA. End tidal carbon dioxide has been recommended as an additional modality for the monitoring of sedated patients.62,67 Monitoring expired carbon dioxide during PSA allows for a graphically display of the patients ventilatory status that can be a detector of respiratory depression before it becomes clinically apparent otherwise.55 In the event of hypoventilation, the end tidal CO2 value increases as the respiratory rate decreases. In the event of increasing airway obstruction, the baseline end tidal CO2 value decreases along with a blunting of the waveform as a result of

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increased mixing of the nasal expiratory sample with ambient air because of the turbulence from the obstruction. Ketamine use has been described in adults68 but is more commonly used for children undergoing ED PSA.69 Ketamine is a dissociative anesthetic that provides 15–20 minutes of sedation when given intramuscularly, with a return to baseline mental status in 30–60 minutes. It can be given in doses of 1 to 4 mg/kg IM and should be combined with atropine (0.01 mg/kg) to prevent hypersalivation. The addition of 0.1 mg/kg of midazolam to ketamine has been described to prevent emergence phenomena but is of unclear utility.70 The 1-mg/kg dose achieves light sedation sufficient for such procedures as lumbar puncture, dressing changes, and simple laceration repair. Doses from 2 to 4 mg/kg result in increasingly deeper levels of moderate to deep sedation. Patients sedated with ketamine usually maintain a patent airway and ventilate normally. Patients receiving ketamine should be monitored for respiratory depression and rare occurrences of laryngospasm.69,71 Emergence phenomena, unpleasant perceptual experiences as patients regain consciousness, have been described in both adults and children.70,72,73 Intravenous ketamine is also used for ED PSA at doses of 1 mg/kg IV with an onset of 1–2 minutes, followed by moderate sedation lasting 8 to 12 minutes. Side-effect profiles of IV ketamine are similar to those of IM use. The combination of fentanyl and midazolam has been used for minimal, moderate, and deep sedation in the ED.55,59,72,74,75 This combination results in longer periods of sedation than other agents and carries a higher rate of dose-related respiratory depression. Although adequate for minimal sedation, this combination is less useful for moderate to deep sedation and its use for these levels of sedation is not recommended. Dosing for minimal sedation has been described as 0.1 mg/kg IV midazolam followed by 0.05 mg/kg IV fentanyl, with repeated fentanyl boluses every 3 minutes until the patient is adequately sedated. The sedation typically lasts 30–60 minutes with a return to baseline mental status by 45 to 120 minutes. This method of PSA requires close respiratory monitoring. Pentobarbital is another agent resulting in similar durations of sedation but without analgesic properties. It is used for minimal to moderate sedation of children for radiologic procedures.76,77 The medicine is administered at 2.5 mg/kg IV, followed by 1.25 mg/kg IV every 5 minutes until adequate sedation is achieved. Pulse oximetry is required. The rate of respiratory depression is lower than that for other protocols but the sedation level is inadequate for most painful procedures.78 Methohexital has been used for moderate and deep PSA.79–81 It is a very short-acting agent with dense amnestic properties. It is administered at 1 mg/kg IV with 0.5 mg/kg repeat boluses every 2 minutes as needed. It has an onset of 30 seconds, with sedation lasting 2–4 minutes and returning to baseline within 10 to 15 minutes. It has been associated with respiratory depression and a quick progression to deeper levels of sedation than intended, it can cause oversedation even when carefully titrated, therefore close respiratory monitoring is required. When compared directly to propofol, methohexital is similarly effective and safe with single bolus use; however, it is less safe than propofol when multiple doses are required.79 It should be used principally for very brief procedures expected to last less than 2–4 minutes, such as the reduction of simple fractures and dislocations. Propofol is well described for ED PSA.55–59,64,79,82–86 It is administered as a 1-mg/kg bolus with repeat boluses of 0.5 mg/kg

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4. Effective physician and patient educational strategies should be developed regarding pain management, including the use of pain therapy adjuncts and how to minimize pain after disposition from the ED.

marked increases in both nonsteroidal anti-inflammatory agents and opioid analgesics (Figure 36.1).95 At the local level, adoptions of pain management guidelines and quality improvement processes have demonstrated dramatic improvements in practices. In one 3-site study, rates of ED analgesic treatment increased from 54% to 84% over 1 year as a result of individual and group feedback.96 In a recent study from one Swiss ED, educational programs and guideline implementation led to marked increases in pain intensity documentation, analgesic administration, reduction in pain intensity scores, and improved patient satisfaction over a 4-month period.97 We do not know the reasons for the rapid evolution of ED pain management practice. Policy and regulatory initiatives, institutional quality improvement programs, pharmaceutical marketing campaigns, educational efforts, and new knowledge from basic and clinical research are all likely to be influential factors. No matter the cause, emergency medicine pain research is increasing at a rapid pace, and ED pain management practices will continue to evolve.

5. Ongoing research in the area of ED patient pain management should be conducted.

REFERENCES

The majority of emergency department (ED) patients require treatment for painful medical conditions or injuries. The American College of Emergency Physicians recognizes the importance of effectively managing ED patients who are experiencing pain and supports the following principles. 1. ED patients should receive expeditious pain management, avoiding delays such as those related to diagnostic testing or consultation. 2. Hospitals should develop unique strategies that will optimize ED patient pain management using both narcotic and nonnarcotic medications. 3. ED policies and procedures should support the safe utilization and prescription writing of pain medications in the ED.

Approved by the ACEP Board of Directors March 2004. From: Anonymous. Pain management in the emergency department. Annals of Emergency Medicine. 44(2):198, 2004.

Figure 36.1: American College of Emergency Physicians policy on pain management.

every 3 minutes until the patient is adequately sedated. The sedation persists 2–5 minutes after a single bolus, and longer for patients receiving multiple boluses, with a return to baseline within 10–15 minutes. This medication has been associated with rates of clinically apparent respiratory depression from 4.0% to 7.7% in ED PSA, and, again, close respiratory monitoring is required. Propofol causes hypotension in critically ill patients and should be used with caution in hemodynamically unstable patients.64 Finally, etomidate is useful for ED PSA.64,87–92 It is given as a single bolus of 0.1 to 0.3 mg/kg, with an onset of sedation in 30– 60 seconds and sedation lasting 7–10 minutes. It is not associated with hypotension, thus is more commonly used when this is an issue; however, its use is associated with myoclonic jerking in up to 25% of patients. This adverse effect can complicate the procedure for which the patient has been sedated, making it a suboptimal sedative for healthy patients.64 Etomidate, in single boluses of 0.3 mg/kg, has been shown to cause transient adrenal suppression, but no significant changes in cortisol levels occur, and the significance of this finding remains unclear.93 E VO LV I N G E D PA I N M A NAG E M E N T P R AC T I C E S

Pain management practices in the emergency department continue to evolve. The American College of Emergency Physicians, emergency medicine’s principal specialty organization, established its first general policy statement regarding analgesic practices in 2004.94 Prior to this, data from the National Hospital Ambulatory Medical Care Survey showed that, from 1997 through 2001, there was an impressive 18% increase in analgesic use in US EDs (from 47.2 to 56.2 mentions per 100 visits), with

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Emergency Department 15. Furrow BR. Pain management and provider liability: no more excuses. J Law Med Ethics. 2001;29:28–51. 16. Wilson JE, Pendleton JM. Oligoanalgesia in the emergency department. Am J Emerg Med. 1989;7:620–623. 17. Stalnikowicz R, Mahamid R, Kaspi S, et al. Undertreatment of acute pain in the emergency department: a challenge. Int J Qual Health Care. 2005;17(2):173–176. 18. Pines JM, Perron AD. Oligoanalgesia in ED patients with isolated extremity injury without documented fracture. Am J Emerg Med. 2005;23(4):580. 19. Neighbor ML, Honner M, Kohn MD. Factors affecting emergency department opioid administration to severely injured patients. Acad Emerg Med. 2004;11(12):1290–1296. 20. Fosnocht DE, Swanson ER, Barton ED. Changing attitudes about pain and pain control in emergency medicine. Emerg Med Clin North Am. 2005;23(2):297–306. 21. Rupp T, Delaney KA. Inadequate analgesia in emergency medicine. Ann Emerg Med. 2004;43(4):494–503. 22. Jones JS, Johnson K, McNinch M. Age as a risk factor for inadequate emergency department analgesia. Am J Emerg Med. 1996;14(2):157–160. 23. Friedland LR, Kulick RM. Emergency department analgesic use in pediatric trauma victims with fractures. Ann Emerg Med. 1994;23(2):203–207. 24. Selbst SM. Managing pain in the pediatric emergency department. Pediatr Emerg Care. 1989;5(1):56–63. 25. Todd KH, Samaroo N, Hoffman JR. Ethnicity as a risk factor for inadequate emergency department analgesia. JAMA. 1993;269(12):1537–1539. 26. Todd, KH, Deaton C, D’Adamo AP, et al. Ethnicity and analgesic practice. Ann Emerg Med. 2000;35(1):11–16. 27. Miner J, Biros MH, Trainor A, et al. Patient and physician perceptions as risk factors for oligoanalgesia: a prospective observational study of the relief of pain in the emergency department. Acad Emerg Med. 2006;13(2):140–146. 28. Pfefferbaum B, Adams J, Aceves J. The influence of culture on pain in Anglo and Hispanic children with cancer. J Am Acad Child Adolesc Psychiatry. 1990;29(4):642–647. 29. Greenwald, HP. Interethnic differences in pain perception. Pain. 1991;44(2):157–163. 30. Tait RC, Chibnall JT. Physician judgments of chronic pain patients. Soc Sci Med. 1997;45(8):1199–1205. 31. Cooper-Patrick L, Gallo JJ, Gonzales JJ, et al. Race, gender, and partnership in the patient-physician relationship. JAMA. 1999;282(6):583–589. 32. Tamayo-Sarver JH, Dawson NV, Hinze SW, et al. The effect of race/ethnicity and desirable social characteristics on physicians’ decisions to prescribe opioid analgesics. Acad Emerg Med. 2003;10(11):1239–1248. 33. Bartfield JM, Salluzzo RF, Raccio-Robak N, et al. Physician and patient factors influencing the treatment of low back pain. Pain. 1997;73(2):209–211. 34. Todd KH, Sloan EP, Chen C, et al. Survey of pain etiology, management, and satisfaction in two urban emergency departments. Can J Emerg Med. 2002;4(4):252–256. 35. Zohar Z, Eitan A, Halperin P, et al. Pain relief in major trauma patients: an Israeli perspective. J Trauma. 2001;51(4):767–772. 36. Kelly AM. A process approach to improving pain management in the emergency department: development and evaluation. J Accid Emerg Med. 2000;17(3):185–187. 37. Fry C, Aholt D. Local anesthesia prior to the insertion of peripherally inserted central catheters. J Infus Nurs. 2001;24(6):404–408. 38. Attard AR, Corlett MJ, Kidner NJ, et al. Safety of early pain relief for acute abdominal pain. BMJ. 1992;305:1020–1021.

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39. Pace S, Burke TF. Intravenous morphine for early pain relief in patients with acute abdominal pain. Acad Emerg Med. 1996;3:1086–1092. 40. Vermeulen B, Morablia A, Unger PF, et al. Acute appendicitis: influence of early pain relief on the accuracy of clinical and US findings in the decision to operate: a randomized trial. Radiology. 1999;210:639–643. 41. Mahadevan M, Graff L. Prospective randomized study of analgesic use for ED patients with right lower quadrant abdominal pain. Am J Emerg Med. 2000;18:753–756. 42. Kim MK, Strait RT, Sato TT, et al. A randomized clinical trial of analgesia in children with acute abdominal pain. Acad Emerg Med. 2002;9:281–287. 43. Thomas SH, Silen W, Cheema F, et al. Effects of morphine analgesia on diagnostic accuracy in emergency department patients with abdominal pain: a prospective randomized trial. J Am Coll Surg. 2003;196:18–31. 44. Gallagher EJ, Esses D, Lee C, Lahn M, Bijur PE. Randomized clinical trial of morphine in acute abdominal pain. Ann Emerg Med. 2006;48:150–160. 45. Safdar B, Degutis LC, Landry K, Vedere SR, Moscovitz, HC, D’Onofrio G. Intravenous morphine plus ketorolac is superior to either drug alone for treatment of acute renal colic. Ann Emerg Med. 2006;48:173–181. 46. Hewitt DJ, Todd KH, Xiang J, Jordan DM, Rosenthan NR for the CAPSS-216 Study Investigators. Tramadol/acetaminophen or hydrocodone/acetaminophen for the treatment of ankle sprain: a randomized, placebo-controlled trial. Ann Emerg Med. 2007;49(4):468–480. 47. Bijur PE, Kenny MK, Gallagher EJ. Intravenous morphine at 0.1 mg/kg is not effective for controlling severe acute pain in the majority of patients. Ann Emerg Med. 2005;46(4):362–367. 48. Hershey LA. Meperidine and central neurotoxicity. Ann Intern Med. 1983;98(4):548–549. 49. Melzer-Lange MD, Walk-Kelly MD, Lea CM, et al. Patientcontrolled analgesia for sickle cell pain crisis in a pediatric emergency department. Pediatr Emerg Care. 2004;20(1):2–4. 50. Evans E, Turley N, Robinson N, et al. Randomised controlled trial of patient controlled analgesia compared with nurse delivered analgesia in an emergency department. Emerg Med J. 2005;22(1):25–29. 51. Fulda GJ, Giberson F, Fagraeus L. A prospective randomized trial of nebulized morphine compared with patient-controlled analgesia morphine in the management of acute thoracic pain. J Trauma. 2005;59(2):383–388. 52. Ballas SK, Viscusi ER, Epstein KR. Management of acute chest wall sickle cell pain with nebulized morphine. Am J Hematol. 2004;76(2):190–191. 53. Bartfield JM, Flint RD, McErlean M, et al. Nebulized fentanyl for relief of abdominal pain. Acad Emerg Med. 2003;10(3):215–218. 54. Miner JR, Bachman A, Kosman L, et al. Assessment of the onset and persistence of amnesia during procedural sedation with propofol. Acad Emerg Med. 2005;12(6):491–496. 55. Miner JR, Heegaard W, Plummer D. End-tidal carbon dioxide monitoring during procedural sedation. Acad Emerg Med. 2002;9(4):275–280. 56. Bassett KE, Anderson J, Pribble CG, et al. Propofol for procedural sedation in children in the emergency department. Ann Emerg Med. 2003;42(6):773–782. 57. Frazee BW, Park RS, Lowery D, et al. Propofol for deep procedural sedation in the ED. Am J Emerg Med. 2005;23(2):190–195. 58. Miner JR, Biros MH, Seigel T, et al. The utility of the bispectral index in procedural sedation with propofol in the emergency department. Acad Emerg Med. 2005;12(3):190–196.

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59. Miner JR, Biros MH, Heegaard W, et al. Bispectral electroencephalographic analysis of patients undergoing procedural sedation in the emergency department. Acad Emerg Med. 2003;10(6): 638–643. 60. Green SM. Fasting is a consideration – not a necessity – for emergency department procedural sedation and analgesia. Ann Emerg Med. 2003;42(5):647–650. 61. Agrawal D, Manzi SF, Bupta R, et al. Preprocedural fasting state and adverse events in children undergoing procedural sedation and analgesia in a pediatric emergency department. Ann Emerg Med. 2003;42(5):636–646. 62. American College of Emergency Physicians. Procedural sedation in the emergency department. Ann Emerg Med. 2005;46(1):103– 104. 63. Green SM, Denmark TK, Cline J, et al. Ketamine sedation for pediatric critical care procedures. Pediatr Emerg Care. 2001;17(4):244– 248. 64. Miner JR, Martel ML, Meyer M, et al. Procedural sedation of critically ill patients in the emergency department. Acad Emerg Med. 2005;12(2):124–128. 65. Hart LS, Berns SD, Houck CS, et al. The value of end-tidal CO2 monitoring when comparing three methods of conscious sedation for children undergoing painful procedures in the emergency department. Pediatr Emerg Care. 1997;13(3):189–193. 66. Bennett J, Peterson T, Burleson V. Capnography and ventilatory assessment during ambulatory dentoalveolar surgery. J Oral Maxillofac Surg. 1997;55(9):921–925; discussion 925–926. 67. Levine DA, Platt SL. Novel monitoring techniques for use with procedural sedation. Curr Opin Pediatr. 2005;17(3):351–354. 68. Chudnofsky CR, Weber JE, Colone PD, et al. A combination of midazolam and ketamine for procedural sedation and analgesia in adult emergency department patients. Acad Emerg Med. 2000;7(3):228–235. 69. Green SM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation in children. Ann Emerg Med. 2004;44(5):460–471. 70. Wathen JE, Roback MG, Mackenzie T, et al. Does midazolam alter the clinical effects of intravenous ketamine sedation in children? A double-blind, randomized, controlled, emergency department trial. Ann Emerg Med. 2000;36(6):579–588. 71. Green SM, Nakamura R, Johnson NE. Ketamine sedation for pediatric procedures: Part 1, A prospective series. Ann Emerg Med. 1990;19(9):1024–1032. 72. Kennedy RM, Porter FL, Miller JP, et al. Comparison of fentanyl/ midazolam with ketamine/midazolam for pediatric orthopedic emergencies. Pediatrics. 1998;102(4 Pt 1):956–963. 73. Green SM, Sherwin TS. Incidence and severity of recovery agitation after ketamine sedation in young adults. Am J Emerg Med. 2005;23(2):142–144. 74. Pena BM, Krauss B. Adverse events of procedural sedation and analgesia in a pediatric emergency department. Ann Emerg Med. 1999;34(4 Pt 1):483–491. 75. Dionne RA, Moore PA, Gonty A, et al. Comparing efficacy and safety of four intravenous sedation regimens in dental outpatients. J Am Dent Assoc. 2001;132(6):740–751. 76. Malviya S, Tait AR, Reynolds PI, et al. Pentobarbital vs chloral hydrate for sedation of children undergoing MRI: efficacy and recovery characteristics. Paediatr Anaesth. 2004;14(7):589–595. 77. Kienstra AJ, Ward MA, Sasan F, et al. Etomidate versus pentobarbital for sedation of children for head and neck CT imaging. Pediatr Emerg Care. 2004;20(8):499–506.

78. Karian VE, Burrows PE, Zurakowski D, et al. Sedation for pediatric radiological procedures: analysis of potential causes of sedation failure and paradoxical reactions. Pediatr Radiol. 1999;29(11):869–873. 79. Miner JR, Biros M, Krieg S, et al. Randomized clinical trial of propofol versus methohexital for procedural sedation during fracture and dislocation reduction in the emergency department. Acad Emerg Med. 2003;10(9):931–937. 80. Zink BJ, Darfler K, Salluzzo RF, et al. The efficacy and safety of methohexital in the emergency department. Ann Emerg Med. 1991;20(12):1293–1298. 81. Bono JV, Rella JG, Zink BJ, et al. Methohexital for orthopaedic procedures in the emergency department. Orthop Rev. 1993; 22(7):833–838. 82. Pershad J, Godambe SA. Propofol for procedural sedation in the pediatric emergency department. J Emerg Med 2004;27(1):11–14. 83. Burton JH, Miner JR, Shipley ER, et al. Propofol for emergency department procedural sedation and analgesia: a tale of three centers. Acad Emerg Med. 2006;13(1):24–30. 84. Symington L, Thakore S. A review of the use of propofol for procedural sedation in the emergency department. Emerg Med J. 2006; 23(2):89–93. 85. Guenther E, Pribble CG, Junkins EP Jr, et al. Propofol sedation by emergency physicians for elective pediatric outpatient procedures. Ann Emerg Med. 2003;42(6):783–791. 86. Havel CJ Jr, Strait RT, Hennes H. A clinical trial of propofol vs midazolam for procedural sedation in a pediatric emergency department. Acad Emerg Med. 1999;6(10):989–997. 87. Falk J, Zed PJ. Etomidate for procedural sedation in the emergency department. Ann Pharmacother 2004;38(7–8):1272–1277. 88. Hunt GS, Spencer MT, Hays DP. Etomidate and midazolam for procedural sedation: prospective, randomized trial. Am J Emerg Med. 2005;23(3):299–303. 89. Burton JH, Bock AJ, Strout TD, et al. Etomidate and midazolam for reduction of anterior shoulder dislocation: a randomized, controlled trial. Ann Emerg Med. 2002;40(5):496–504. 90. Vinson DR, Bradbury DR. Etomidate for procedural sedation in emergency medicine. Ann Emerg Med. 2002;39(6):592–598. 91. Keim SM, Erstad BL, Sakles JC, et al. Etomidate for procedural sedation in the emergency department. Pharmacotherapy. 2002;22(5):586–592. 92. Ruth WJ, Burton JH, Bock AJ. Intravenous etomidate for procedural sedation in emergency department patients. Acad Emerg Med. 2001;8(1):13–18. 93. Schenarts CL, Burton JH, Riker RR. Adrenocortical dysfunction following etomidate induction in emergency department patients. Acad Emerg Med. 2001;8(1):1–7. 94. Anonymous. Pain management in the emergency department. Ann Emerg Med. 2004;44(2):198. [Editorial] 95. McCaig LF, Burt CW. National Hospital Ambulatory Medical Care Survey: 2001 emergency department summary. Advance data from vital and health statistics. No. 335. Hyattsville, MD: National Center for Health Statistics; 2003. 96. Sucov A, Nathanson A, McCormick J, Proano L, Reinert SE. Peer review and feedback can modify pain treatment patterns for emergency department patients with fractures. Am J Med Qual. 2005;20(3):138–143. 97. Decosterd I, Hugli O, Tamch`es E, Blanc C, Mouhsine E, Givel J, Yersin B, Buclin T. Oligoanalgesia in the emergency department: short-term beneficial effects of an education program on acute pain. Ann Emerg Med. 2007.

37 The Nurse’s Perspective on Acute Pain Management Chris Pasero, Nancy Eksterowicz, and Margo McCaffery

lication of the first Agency for Health Care Policy and Research (AHCPR) guideline was a defining moment for those who managed acute pain because it emphasized the need to adopt an evidence-based approach to pain management and rely on individuals with unique expertise in the field to insure therapies are delivered safely and effectively. The American Nurses Association (ANA) and specialty professional nursing organizations, such as the American Society of PeriAnesthesia Nurses and the Oncology Nursing Society, have long supported the nurse’s role in pain management with the publication of standards, position papers, and guidelines for nursing care of patients with pain.5–7 However, in 1990, 7 nurses who at the time were serving as pain service coordinators in various parts of the country recognized the need for a professional nursing organization that could focus entirely on the optimal care of patients with pain and formed the American Society for Pain Management Nursing (ASPMN).1 This group recognized that increasing numbers of nurses were being employed to fulfill positions in pain management, especially acute pain management, without any formal preparation. The ASPMN is dedicated to the provision of pain education for professionals, development of standards, and the promotion of advocacy and research in pain management nursing. The ASPMN membership today consists of nearly 2000 registered nurses (RNs), most specializing in pain management. Recognizing the frontline nurse’s responsibility for implementation of effective pain care, the organization recently opened its membership to all licensed nurses. In 2005 RNs across the country sat for the first pain management nursing certification exam, which validated the specialty and achieved a goal of the organization since its inception.

Advances in pain research and technology since the late 1980s have resulted in an exciting expansion in nursing roles in the field of pain management. Although nurses have always cared for patients with pain, the specialty of pain management nursing is relatively new.1 Among the first to define the nurse’s role were nurses designated to coordinate newly established acute pain services in the late 1980s and early 1990s.2 Pain management is now identified as a nursing specialty3 that offers nursing certification in the field and a wide variety of opportunities for nurses who want to focus their careers on the care of people with pain, including in the areas of clinical practice, research, and education. One of the purposes of this chapter is to illustrate the growth and progress nurses have made in the field of acute pain management over the past several years. The chapter focuses on the various nursing roles that have emerged with the identification of pain as a specialty, including an in-depth discussion of the role of the acute pain service clinical coordinator and the education, credentials, and attributes necessary to adequately fulfill the role. The extensive responsibilities of the bedside nurse are also presented. Current pain management issues and challenges that nurses confront in their practices are described and solutions offered. G ROW T H A N D P RO G R E S S

In the late 1980s, anesthesiologists began to extend their services and expertise beyond the operating room to the postoperative setting. Their recognition of the key role bedside nurses would play in assessment and management of acute pain therapies, such as intravenous patient-controlled analgesia (IV PCA) and epidural analgesia, brought about the need for a nurse specialist who could link the two disciplines.2 Guided largely by anesthesiologists, hospitals across the country began to establish formal acute pain services and designate nurses to coordinate them. Support for this approach was found in publications, most notably the first clinical practice guideline on acute pain management in the United States, which described the importance of a multidisciplinary approach to the management of acute pain.4 The pub-

T H E AC U T E PA I N S E RV I C E C L I N I C A L C O O R D I NATO R

As acute pain services began to spring up across the country in the early 1990s, the number of nurses assuming the position of clinical coordinator grew rapidly. Nursing departments in community hospitals designated full-time coordinator positions. The department of anesthesiology often directly hired 597

598

Chris Pasero, Nancy Eksterowicz, and Margo McCaffery

Clinical Practice, Patient Care

Establish and Implement Patient Flow

Serve as Primary Resource for Bedside Nurses

Delineate Multidisciplinary Responsibilities

Acute Pain Service Clinical Coordinator

Develop and Implement Policies and Procedures

Provide Multidisciplinary and Patient Education

Participate in Marketing, Community Outreach Prepare and Execute Budget, Strategic Planning

Develop and Implement Continuous Quality Improvement

Figure 37.1: The role of the acute pain service clinical coordinator.

nurses to fill the role in academic settings and in some community hospital-based private practices. Today, the acute pain service clinical coordinator is a key figure in health care institutions and has a vast range of responsibilities, including most obviously the smooth implementation of acute pain therapies (see Figure 37.1). The clinical coordinator serves as the liaison between the pain service and bedside nurses as well as all of the other specialties and departments involved in the delivery of safe and effective pain treatment.

Characteristics of the Clinical Coordinator Most community hospitals require the acute pain service clinical coordinator to be an RN who holds a bachelor’s degree; often a master’s degree is preferred. A master’s or doctorate degreeprepared nurse is strongly recommended for the position in a large academic setting.2 Achievement of pain management nursing certification is desirable for all candidates. The clinical coordinator must have considerable prior experience caring for patients with pain, especially those with postoperative pain, in-depth knowledge of the anatomy and physiology of pain and pharmacology and principles of pain management, and expert assessment skills. The ideal candidate is one who has nursing management background with previous exposure to and understanding of hospital administration and policies as well as budget preparation. An appreciation of the roles of both management and day-to-day bedside nursing is essential for practical strategic planning. The ability to quickly and appropriately adapt to a wide range of scenarios is essential. Because the clinical coordinator must interface with almost every department in the hospital and gain the trust and support

of the many disciplines involved in pain treatment, the candidate must have excellent interpersonal skills. In addition to informal and in-the-moment instruction, formal education of both staff and patients is one of the coordinator’s primary responsibilities; therefore, teaching ability is a prerequisite. The safety and effectiveness of acute pain service therapies depend on the coordinator’s ability to insure that nurses in the clinical units individualize therapies to meet each patient’s unique needs. This requires the coordinator to have confidence in bedside nurses and the ability to foster a relationship of trust with them. Knowledge and appreciation of the challenges as well as the priorities of bedside nursing are vital to the clinical coordinator’s job.

Advanced Practice Registered Nurses There is a trend toward clinical nurse specialists, certified registered nurse anesthetists (CRNAs), and nurse practitioners electing to specialize in pain management. In most cases, these nurses have a master’s or doctorate degree and have achieved advanced practice certification. Advance practice registered nurses (APRNs) may be hired by the anesthesia department or by the institution or university to work with the anesthesia or nursing department to provide acute pain service therapies or coordinate a formal acute pain service. Depending on state regulations, the APRN may have a collaborative practice agreement with a physician or anesthesia group and be considered a licensed independent practitioner within the institution. These APRNs often are directly reimbursed for their services. Depending upon the State in which they practice, clinical nurse specialists may or may not bill directly for their services; however, they promote the hospital’s

The Nurse’s Perspective

mission and are recognized as clinical leaders within the institution. The APRN brings the advantage of complex practice skills such as catheter placement and prescribing authority to the service, which is beneficial, particularly in institutions where there is no formal anesthesia-driven acute pain service. Most have extensive clinical experience and an understanding of the challenges of bedside nursing. Bedside nurses tend to see the APRN as a valuable ally in the effort to better manage pain.

Organizational Structure There are several options for selecting the department under which the hospital-funded clinical coordinator position can be placed; most of these depend on the coordinator’s assigned responsibilities. The clinical coordinator must interface with a wide range of disciplines and departments through established channels of communication, representing anesthesiologists who have limited relationships with departments outside of the operating room. A good example of such interaction is with the department of nursing education. The clinical coordinator will spend a great deal of time educating and supporting the bedside nursing staff. It is, therefore, logical in many community hospitals to place the position under the authority of nursing services or directly under the department of nursing education. In academic settings, the acute pain service clinical coordinator is generally under the department of anesthesia in the organizational structure. The acute pain service clinical coordinator is a change agent, advising others about matters of significant consequence and influence. It is important that this person be seen as a clinical leader and should, therefore, answer to at least the director level of management in the organizational structure. This will allow the coordinator to confidently interact with a variety of disciplines and earn respect through participation in multidisciplinary educational programs and development of institutional policies and procedures. Clinical nurse specialists are often hired for the coordinator position through the patient care or nursing services department and report to a hospital director. In academic settings the clinical coordinator answers directly to the acute pain service medical staff director.

599

patient entry to health care system automatic or formal referral to acute pain service (licensed pain service consultation independent practitioner) (anesthesiologist, fellow, resident, nurse practitioner, development of pain treatment clinical coordinator) plan patient education (preadmission and admission acquisition of necessary supplies and personnel) equipment (pharmacy, sterile processing personnel) titration to comfort and initiation of therapy (PACU, ongoing ED, ICU, clinical unit personnel) transition to management (clinical unit personnel) alternate analgesia in preparation for discharge discontinue acute pain service therapy, discharge from acute pain service evaluate overall response and satisfaction (QI) Figure 37.2: Patient flow through the service.

The responsibilities of the acute pain service clinical coordinator are many and range from administrative duties to the provision of direct patient care. Following is a discussion that illustrates the clinical coordinator’s multifarious role.

Centralization of patient enrollment in the acute pain service will help insure smooth patient flow. Therapies can be initiated in a central location. For example, catheters can be placed in the holding area before surgery and IV PCA can be started routinely in the postanesthesia care unit (PACU) to assure seamless transition from one care area to another and optimal pain management. This process is facilitated when the clinical coordinator trains the preadmission nurses to provide patient education. The operating room (OR) or holding room staff is generally responsible for assisting anesthesiologists and CRNAs with catheter placement. The PACU nurses requisition analgesic infusion devices and drugs and insure therapies are initiated. Identification of a central location, such as the bioengineering or material distribution department, for cleaning, storing, dispensing, and tracking analgesic infusion devices is also recommended. Standardization of therapies as much as possible is a common characteristic of well-organized pain services. Nursing staff express a greater degree of confidence in their ability to manage pain therapies when they know what to expect. The pharmacy department will be able to more efficiently provide analgesic and anesthetic solutions and other medications when the acute pain service has designated standard formulations and side-effect medication regimens for the majority of the therapies it will offer. The use of standardized documentation and computerized or preprinted order forms helps to insure clarity of the treatment plan and better compliance with documentation requirements. Most important, such consistency may help to prevent confusion and error in the clinical setting.

Establish Patient Flow The first order of business for the clinical coordinator is to collaborate with the acute pain service medical staff director and establish an efficient mechanism for the delivery of therapies. An excellent place to start is to consider how patients will flow through the service so that every step before, during, and after treatment and the key personnel involved at each step can be identified (see Figure 37.2). How licensed independent practitioners will refer patients to the service must be determined. For example, surgeons in some community hospitals have an agreement with the anesthesia-based pain service to automatically manage their patients’ postoperative pain following certain surgical procedures, such as thoracotomy and total joint replacement. Others may require a formal request for consultation.

Delineate Responsibilities The clinical coordinator will need to partner with department managers and directors as well as frontline staff members to define personnel responsibilities in delivering analgesic therapies. For example, direct communication with the pharmacy is crucial; often the coordinator asks a pharmacist or doctor of pharmacy (PharmD) to serve as a liaison to the acute pain service and as a member of the pain care committee.8 Some of the many roles that must be described are those of the acute pain service medical staff director, anesthesiologists, CRNAs, licensed independent practitioners (eg, primary physicians, nurse practitioners, and physician assistants), clinical pharmacists, and bedside nursing staff (see Table 37.1). In academic settings, the involvement of residents, fellows, and

Responsibilities of the Clinical Coordinator

600

Table 37.1:

Chris Pasero, Nancy Eksterowicz, and Margo McCaffery Key Disciplines and Responsibilities for Acute Pain Services

Discipline

Key Responsibilities

Clinical Coordinator

1. Clinical practice ■ Conducts consultations and rounds ■ Assists with catheter placement and initiation of therapies ■ Assesses pain ■ Titrates and manages/evaluates therapies on an ongoing basis ■ Discontinues therapies ■ Manages side effects and complications ■ Operates and troubleshoots analgesic infusion devices ■ Documents therapies ■ Provides follow up with referring service as indicated ■ Serves as primary pain resource to all departments and disciplines ■ Coordinates pain resource nurse program 2. With medical staff director, makes decisions regarding implementation of the pain service 3. Develops and implements policies and procedures, standards, and guidelines 4. Provides multidisciplinary, patient, and community education ■ Pain resource nurse program ■ Nursing pain management competencies ■ Medical staff/resident education ■ Fellowships and preceptorships 5. Implements continuous quality improvement plan 6. Participates in research activities 7. Serves as pain committee chair or co-chair; represents pain service at departmental and committee meetings as indicated 8. Prepares and executes budget; strategic planning 9. Participates in marketing and community outreach activities

Pain Service Medical Staff Director

1. Clinical practice ■ Conducts consultations and rounds ■ Serves as primary pain medicine resource for residents/medical staff ■ Supervises and assists residents with patient management, procedures (e.g., catheter placement), and documentation 2. With clinical coordinator, makes decisions regarding implementation of pain service 3. Serves as primary contact for clinical coordinator regarding pain service issues 4. Provides input for development of policies and procedures, standards, and guidelines 5. Provides multidisciplinary pain education ■ Reviews (daily) components of the core curriculum for regional analgesia and pain management for residents ■ Participates in nursing education as indicated 6. Communicates or delegates responsibility for communicating patient status to referring service 7. Serves as pain committee chair or co-chair 8. Participates in continuous quality improvement activities as indicated 9. Oversees research activities 10. Represents pain service at departmental and committee meetings as indicated 11. Provides input into budget preparation and execution; strategic planning

Anesthesiologists/ CRNAs/Fellows/ Residents

1. Clinical practice ■ Conducts consultations and rounds ■ Places catheters ■ Prescribes therapies ■ Evaluates patient response to therapies ■ Manages side effects and complications ■ Discontinues therapies ■ Documents therapies ■ Provides follow up with referring service ■ Serves as a primary pain medicine resource ■ Serves as primary medicine contact for clinical coordinator and nursing staff regarding patient-specific issues 2. Provides multidisciplinary education 3. Provides input for development of policies and procedures, standards, and guidelines 4. Serves on pain committee as indicated 5. Participates in continuous quality improvement activities as indicated 6. Participates in research activities

The Nurse’s Perspective Discipline

Key Responsibilities

Pharmacist/Doctor of Pharmacy (PharmD)

1. Clinical practice ■

Conducts consultations and rounds Serves as primary pharmacology resource for medical and nursing staff Insures access to necessary analgesics and other requisite medications Provides multidisciplinary education Serves on pain committee Participates in development of policies and procedures, standards, and guidelines Participates in continuous quality improvement as indicated Participates in research activities ■

2. 3. 4. 5. 6. 7. Bedside Clinical Nurse

601

1. Clinical practice: primary pain manager, pain resource nurse ■

Assesses pain Assists with catheter placement ■ Titrates, initiates, and maintains therapies ■ Changes analgesic doses ■ Administers bolus doses ■ Monitors patients and therapies ■ Manages side effects and complications ■ Operates and troubleshoots analgesic infusion devices ■ Discontinues therapies ■ Documents therapies Provides patient education Serves on pain committee Provides input for development of policies and procedures, standards, and guidelines Participates in continuous quality improvement activities Participates in research activities ■

2. 3. 4. 5. 6.

medical students must be clarified. Other critical individuals are support personnel from the departments of material management, biomedical engineering, and accounting as well as those who will provide secretarial (clerical) assistance for the acute pain service. The importance of acquiring input from every department that will be involved in the delivery of therapies cannot be overemphasized as this will help to insure accurate work assignment and their ultimate cooperation and support of the service.

Establish Policies and Procedures The acute pain service clinical coordinator, with guidance from the medical staff director and others as appropriate, is responsible for establishing policies and procedures, standards, and guidelines for pain treatment. This involves researching the literature and networking with others in the field to determine current standard of care and insure an evidence-based approach is applied to the care of patients with pain. It often requires interfacing with the state board of nursing on scope of nursing practice issues. Policies and procedures should address the Joint Commission (JC) pain treatment and safety standards in hospitals that are surveyed by the JC. Coordinators who are inexperienced in writing policies and procedures and the JC survey process can seek assistance from those who are responsible for addressing these issues in the institution. Because many of the acute pain management policies and procedures influence and direct activity in other departments, the clinical coordinator should schedule time to meet with department directors to help insure accuracy and ultimate adherence. Among others, acute pain policies and procedures should address (1) patient flow through the service; (2) patientselection criteria for the various therapies; (3) prescribing

guidelines; (4) pain assessment; (5) therapy initiation, maintenance, and discontinuation processes; (6) patient monitoring; (7) side-effect and complication management; (8) medication, equipment, and supply acquisition; (9) infection control; (10) multidisciplinary education; and (11) patient education.

Clinical Practice Responses to an informal survey of 51 nurses who specialize in pain management and subscribe to a pain management nursing electronic-mail list service revealed that the majority of respondents (82%) spend most of their time in the clinical setting providing direct care to patients receiving analgesic therapies.9 This care is administered in diverse ways, including initial interviews and consultations, counseling patients and families, rounds both with and without medical and anesthesia staff, assisting bedside nurses in the clinical unit, and troubleshooting analgesic infusion device problems. Ideally, patient rounds include the acute pain service clinical coordinator, acute pain service anesthesiologist or medical staff director, and additional team members, such as a clinical pharmacist, at least once daily. The team should invite the bedside nurse to provide input on the patient’s status prior to or during rounds. At the time evaluations occur, titration decisions are made and orders are written. In the community setting, the coordinator is responsible for follow-up and evaluating changes in therapies, reporting back to the anesthesiologist and assuring that any additional changes in therapies are implemented. In an academic setting, the clinical coordinator works closely with the attending anesthesiologist and resident assigned to the acute pain service. As an integral member of the team, the coordinator orients each resident to the daily responsibilities and technical skills. Although the attending anesthesiologist

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Box 37.1: Nursing Education Content 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Adverse effects of unrelieved pain Anatomy and physiology of pain Pain assessment and goal setting Pharmacology of pain Selected pain therapies and delivery systems Population-specific considerations, e.g., labor, neonatal, pediatrics, geriatrics Side effect and complication management Transition to alternative analgesia and discontinuation of therapy Appropriate nondrug interventions Documentation Policy and procedure review Clinical skill requirements ■ Pain assessment ■ Titration to comfort prior to therapy ■ Initiation and maintenance of therapy ■ Evaluation of patient response, decision making, and dose adjustment ■ Discontinuation of therapies; removal of various infusion catheters ■ Analgesic infusion device operation

supervises the resident during preoperative catheter insertions, the coordinator covers the incoming pages, assists with patient positioning, and facilitates setting up equipment as needed. The coordinator and resident conduct a second set of patient rounds to evaluate therapy changes. The follow-up rounds also provide the resident with the additional information needed to give an accurate account of the pain treatment plan to pass off to the covering resident. A significant amount of the clinical coordinator’s time is spent serving as a resource to beside nurses as they manage the acute pain service patients’ pain. This involves assisting with pain assessment and decision-making with regard to the need for changes in the patient’s pain treatment plan, validating psychomotor skills such as analgesic infusion device operation and removal of the various infusion catheters, and managing side effects and complications. The coordinator documents therapies and insures that others document appropriately. Thorough documentation is essential because it ensures continuity of the pain management plan, captures reimbursement, and provides information for quality improvement.

Multidisciplinary Education A major responsibility of the clinical coordinator is to educate all of the disciplines involved in the delivery of acute pain therapy. Bedside clinical nurses initiate, monitor, maintain, and discontinue acute pain therapies. Their knowledge and skill at completing these activities will determine the safety and effectiveness of the acute pain service. The clinical coordinator is the primary pain nursing resource for the bedside nurses

and responsible for providing the initial and ongoing education required to fulfill their role as primary pain managers. In addition to formal lectures, the coordinator conducts much of the instruction in the clinical unit, often at the bedside, validating the nursing staff’s decision-making and skills. It is imperative that the clinical coordinator work with the institution’s nursing education department to determine how nurses will achieve their educational requirements (see Box 37.1). The pain service medical staff director helps identify important pain content and clinical skill requirements for the nursing staff; medical staff directors and anesthesiologists or CRNAs often provide lectures for the nursing staff. In the academic setting, the acute pain service medical staff director oversees the residents’ educational process, and the clinical coordinator assists in providing them with both formal and informal education (see Box 37.2).

Box 37.2: Resident Education Content 1. Adverse effects of unrelieved pain; benefits of specific analgesic therapies 2. Anatomy and physiology of pain 3. Patient selection criteria and indications for various therapies 4. Prescribing guidelines ■ Analgesics, anesthetics ■ Adjuvant medications ■ Side-effect management ■ Patient population considerations 5. Initiation of therapies ■ Discuss plan with acute pain service attending and clinical coordinator ■ Discuss plan with referring service as indicated ■ Obtain consent ■ Catheter placement procedures 6. Evaluation of patient response to therapies ■ Pain: evaluate at rest and activity ■ Achievement of functional goals ■ Side effects ■ Analgesic use during past 24 hours ■ Concurrent medication use ■ Problem-oriented physical exam ■ Patient satisfaction 7. Complication management 8. Appropriate nondrug interventions 9. Discharge preparation ■ Transition to alternative analgesia ■ Discontinuation of therapy ■ Transfer care to referring service 10. Communication with nurses, patients, families, referring service 11. Documentation 12. Analgesic infusion device operation

The Nurse’s Perspective

Patient Education One of the primary reasons for the management of acute postoperative pain is to optimize postoperative patient outcomes, and the patient’s active participation in the achievement of recovery goals is critical to this process. This is enhanced when patients understand what they can expect from the health care team and what the team expects of them during the postoperative period. The clinical coordinator must develop and implement a means by which patients receiving acute pain treatment are educated about these important points. Although not always possible, every effort should be made to conduct education prior to initiation of therapy. Educationally appropriate reading material can be provided to the patient and family to review at home after the surgical planning visit. References and resources for additional details are usually included in these materials. Some acute pain services provide videos or DVDs that can be either shown in the surgeon’s office or given to the patient to be viewed at home. A central location, such as the preadmission testing area, for the majority of in-person patient education is convenient; however, patient education can be reinforced anywhere, including in the preoperative holding area and in the clinical units. Enlisting nursing staff to routinely include defined pain management content in their teaching sessions will help to insure patient education is provided and will ease the clinical coordinator’s workload. Important content includes a review of the adverse effects of pain, an explanation of the pain treatment plan, establishment of realistic comfort-function goals,10 and, if indicated, a demonstration and return demonstration of PCA equipment. Continuous Quality Improvement The development and implementation of a continuous quality improvement (CQI) plan that focuses on process and performance will help to insure safe and effective acute pain management is delivered. The clinical coordinator must work with the QI and risk management departments to address among other indicators: (1) pain assessment; (2) analgesic effectiveness (pain reduction and control, goal achievement and outcomes, patient satisfaction); (3) treatment and reduction of side effects; (4) prevention of infection, complications, and safety hazards; (5) multidisciplinary performance; and (6) compliance with JC pain treatment and safety standards. Data collection can consume a significant amount of time. It is, therefore, advised that the acute pain service clinical coordinator work with the clinical unit managers to incorporate monitoring of pain management indicators into their unit-specific CQI plans. Key to the ongoing and systematic monitoring of these indicators, is the analysis of findings and implementation of action plans aimed at improving care when problems or potential problems are identified. Other General Responsibilities The effective acute pain service clinical coordinator becomes the voice for patients with pain in the institution by serving as the nursing representative at pertinent committee meetings and whenever a decision must be made that will affect or be affected by pain management. The coordinator often chairs or cochairs (with the acute pain service medical staff director) the pain committee, which focuses on building institutional commitment to improvements in pain management. They serve on or prepare and present reports to various other committees such as infection

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control, pharmacy and therapeutics, professional development, and strategic planning. Input from the acute pain service clinical coordinator and medical staff director on the development of clinical practice guidelines is essential. Other general responsibilities include budget preparation, insuring appropriate evaluation and acquisition of analgesic infusion devices and other pain service equipment and supplies, and working with the marketing department on a variety of activities, including development of patient information material and community outreach programs. D I V E R S I T Y O F T H E N U R S E ’ S RO L E

Changes in health care have brought about interesting diversity in the role of nurses who specialize in pain management. With the advent of managed care in the mid-1990s and subsequent budget cuts across the country, many community hospitals discontinued their formal acute pain services and several clinical coordinators lost their jobs. Others were retained but were assigned additional responsibility for patient care in other areas of the hospital, such as in the PACU or intensive care unit (ICU). Several were assigned responsibility for global institutional pain management issues, such as JC compliance and process improvement rather than as the coordinator of an acute pain service. With the widespread acquisition and merging of hospitals, many clinical coordinators now distribute their time among some or all of the hospitals in the health care system. As a result, the nurse’s role in pain management is diverse, and creative strategies for improving pain management and insuring the safe and effective administration of pain therapies have been developed. Following are some examples.

Pain Resource Nurse Programs Nurses who care for patients in the clinical units have been described as primary pain managers by virtue of their assessment abilities and 24-hour presence.11 They have a tremendous impact on the delivery of acute pain management therapies. Their involvement spans the continuum of care and encompasses multiple responsibilities (see Table 37.1). One of the most creative approaches to prepare and support bedside nurses in their role as primary pain managers and to generally improve the management of pain in institutions is the pain resource nurse (PRN) program.8 The implementation of a PRN program involves the designation of at least one nurse, preferably an RN, per shift on every clinical unit in the hospital to serve as a resource to the other members of the nursing staff regarding pain management issues. PRNs complete an extensive educational program, which is specifically designed to teach them about pain management as well as how to serve as a support person and role model for their peers. This is followed by validation of skill requirements in the clinical setting. The City of Hope National Medical Center in Duarte, California, has presented annual PRN educational programs since the early 1990s and prepared nearly 2000 nurses to assume the PRN role or return to their institutions to establish their own PRN programs.12 Common pitfalls of PRN programs are that PRNs often feel as though they do not have enough time to perform educational activities and that they are stretched to address their own patients’ pain, much less the pain problems of their coworkers’

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patients.8 Sustained success of a program depends on administrative commitment to it, which involves periodically providing additional staffing so that the PRNs have adequate time to educate and assist other nurses in their clinical unit with pain management issues. Programs spearheaded by an identified full-time nurse coordinator are much more likely to succeed.8 Quite often this coordinator is based in a clinical unit such as the PACU or ICU. If available, the acute pain service clinical coordinator or APRN who specializes in pain often provides the educational support and serves as the point person for the PRNs. The ultimate goal of all PRN programs should be to target every nurse on the clinical unit, rather than a select few, to become proficient in the management of pain.2,8

the consistent provision of patient education, ongoing evaluation of their patients’ responses to pain treatment, and reliable management of complex pain issues as major benefits of the service. NURSING ISSUES

As a result of an increased commitment to the management of pain, a number of issues that directly affect nurses have come to the forefront. Most of these are universal among all nurses; however, some have arisen from the needs of specific patient populations. Following is a brief discussion of some of these issues; recommendations and solutions are offered.

Role Model Programs and Preceptorships One of the best ways to teach others is through role modeling.8 A variety of role modeling programs have been offered nationwide over the years whereby dyads of physicians and nurses or other colleagues attend a conference to learn how to improve pain management processes in their institutions. The University of Wisconsin at Madison sees the nurse as the primary change agent in a health care facility and offers the Practice Change Program to prepare nurses for this role. A few hospitals with particularly well-organized pain services offer preceptorships for nurses who want to observe the service in action. These programs tend to last 2 to 4 days and provide didactic as well as clinical exposure. Attendees are given support materials such as policy and procedure templates to use when they return to their institutions. Those who attend preceptorships consistently cite the firsthand observation of patient flow through a well-managed pain service as invaluable.13

Nurse-Based Pain Programs Nurse-based pain programs have sprung up around the country in response to the need for improved pain management in institutions that do not offer an anesthesia-based acute pain service. Most often a master’s-prepared nurse or APRN hired by the health care facility and based in a clinical unit, such as the PACU or ICU, or directly under nursing administration leads the service and works with medicine and surgery colleagues to establish a mechanism for referral to the service. Medical direction may be provided by a variety of specialties, most often the anesthesia or surgery department. Any licensed independent practitioner may request a formal consultation with the nurse-based pain service; some have established automatic referral for certain surgical procedures and medical conditions. In most institutions the nursing staff may ask for an informal consultation with the nurse-based pain service, which usually leads to treatment recommendations and problem resolution or a formal referral. Some nurse-based pain services have a staff of nurses available 24 hours a day, who round regularly on referred patients, and all rely on the bedside nurses to provide the majority of care. Similar to the clinical coordinator, the nurses who manage and work for the nurse-based PCA service serve as the bedside nurse’s primary pain management resource and provide education and skill development for them. The pharmacy department usually works closely with the service to provide standardized analgesic solutions and side-effect medications as well as patient consultations. Physicians who utilize the nurse-based service often cite

Pain Assessment in Nonverbal Patients The introduction of the JC pain treatment standards in 2000 resulted in recognition of the need for better pain assessment in health care facilities nationwide, even in those that were not JC accredited (see Chapter X). The use of the 0-to-10 numeric pain rating scale quickly became the standard tool for obtaining the patient’s report of pain intensity and was incorporated into routine nursing care nationwide. However, it soon became clear to nurses in certain clinical areas that the 0-to-10 scale was inappropriate for many of their patients because of an inability to report pain, such as unconscious, ventilated patients in the ICU.14 ICU nurses and those who care for infants, toddlers, and cognitively impaired patients expressed frustration with the unrealistic expectation that a pain rating be recorded for every patient under their care. There was also concern that pain assessment seemed to have become reduced to recording a number in the medical record.14 In response to this issue, the ASPMN appointed a task force to develop guidelines on the assessment of pain in the nonverbal patient (anyone who could not use a customary selfreport pain assessment tool).15 This included infants, toddlers, the cognitively impaired, and unconscious, ventilated patients. The guideline describes the use of a hierarchy of pain measures, which involves assessment of ■

■ ■

■ ■

Self-report in patients who can provide it or documentation why the clinician cannot use self-report; single most reliable indicator of pain Presence of underlying pathology or procedure that is thought to be painful Behavioral indicators of pain, such as grimacing and restlessness, or use of behavioral tools such as the Critical-Care Pain Observation Tool (CPOT)16 and the Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC)17 Surrogate (parent, significant other, or caregiver) report of possible pain behaviors Analgesic trial whereby analgesia is administered and any changes in identified behaviors help to confirm the presence of pain

The hierarchy provides nurses with a multidimensional method for assessing pain in patients who are unable to provide a report using a customary self-report tool and establishes a basis for formulating a pain treatment plan. Further, this approach led to the approval in institutions nationwide of the acronym APP

The Nurse’s Perspective

(assume pain present) for documentation for patients in whom pathology, behaviors, or other indicators suggest pain.14

Patient Monitoring The emphasis on providing better pain management has led to an increase in the use of opioid analgesics and concerns over an apparent subsequent increase in opioid-induced respiratory depression.18,19 This, in turn, has led to recommendations for increased patient monitoring, particularly during parenteral and intraspinal opioid therapy.19 Because nurses provide the bulk of patient monitoring and are responsible for insuring patient safety during opioid therapy, any new recommendations will directly impact their practice. The observation that increased sedation precedes opioidinduced respiratory depression suggests that more frequent nurse assessment of sedation level during opioid therapy is of the utmost importance.11 Responses to an informal survey of 63 nurses (representing 66 hospitals) who specialize in pain management and subscribe to a pain management nursing electronic mail list service revealed that 99% of those responding were using some type of sedation scale during IV and intraspinal opioid therapy, the most common being the Pasero Opioidinduced Sedation Scale (POSS) (see Box 37.3).20 However, only 9% incorporated recommendations for nursing actions at the various levels of sedation.

Box 37.3: Pasero Opioid-Induced Sedation Scale (POSS) with Interventions S = Sleep, easy to arouse Acceptable; no action necessary; may administer opioid dose 1 = Awake and alert Acceptable; no action necessary; may administer opioid dose 2 = Slightly drowsy, easily aroused Acceptable; no action necessary; may administer opioid dose 3 = Frequently drowsy, arousable, drifts off to sleep during conversation Unacceptable; decrease opioid dose by 25 to 50%; suggest administration of a nonsedating, opioid-sparing nonopioid, such as acetaminophen or a nonsteroidal antiinflammatory drug; monitor respiratory status and sedation level closely until sedation level is less than 3 and respiratory status is satisfactory. 4 = Somnolent, minimal or no response to physical stimulation Unacceptable; stop opioid administration; consider administering naloxone; notify pain service, licensed independent practitioner, house officer, or first-response team for orders; monitor respiratory status and sedation level closely until sedation level is less than 3 and respiratory status is satisfactory. When opioid is resumed, decrease the initial dose by 50%.

Used with permission. Copyright, C. Pasero, 1994. Acute Pain Management Service: Policy and Procedure Guideline Manual. Los Angeles (CA): Academy Medical Systems.

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This survey indicates that nurses understand there is a link between increased sedation and impending opioid-induced respiratory depression and recognize the importance of sedation assessment. Nurses also verify that sedation assessment is simple, convenient, and cost-effective. However, the increase in the incidence of clinically significant opioid-induced respiratory depression also indicates that nurses are not held accountable for sedation assessment and acting when dangerous increased sedation is detected. It is imperative that all opioid prescriptions be accompanied by clear monitoring guidelines for nursing staff that include sedation assessment at least every 2 hours during at least the first 24 hours of opioid therapy and the expectation that nurses will immediately decrease the opioid dose as soon as a dangerous level of increased sedation is detected (see sedation level 3 in Box 37.3).11,21 Further, nurses should be expected to observe respiratory status (depth, regularity, rate, and noise during respiration) at this same frequency. Sleeping patients with unacceptable respiratory depth, regularity, or rate and those with noisy respirations (eg, snoring) must be aroused for further assessment. The use of a simple scale, such as the POSS, that focuses solely on opioid-induced sedation and does not include agitation indicators is recommended for assessment of opioid-induced sedation.21

Analgesia by Catheter Techniques Analgesia delivered by catheter techniques, such as intraspinal analgesia and perineural infusions, is common for the management of acute pain. However, there has been some confusion and inconsistency nationwide with regard to the extent to which nurses can monitor and manage these therapies.22 Nurses often report that they are able to provide complete care for patients receiving analgesia by catheter techniques in one clinical care area but not in another. For example, RNs within the same institution may be allowed to increase the rate of an epidural analgesic infusion in a neonate but are prohibited from doing so in a labor patient. In response to this issue, the ASPMN developed a position statement reinforcing that it has long been within the scope of nursing practice for an RN to administer analgesia and stating their belief that this scope includes analgesia by catheter techniques such as intraspinal, perineural, and interpleural administration.22 Personal perception or bias unsupported by scientific evidence is not adequate justification for refusing to care for patients receiving analgesia by catheter techniques. The organization emphasizes that bedside RNs are critical to ensuring safe and effective analgesia by these methods and provides monitoring and management recommendations for the licensed independent practitioner, health care facility, and the RN.

Range Order Administration Range orders are defined as a medication order in which the dosage or time period or both are specified according to a range.23 As-needed range orders have been considered an essential method for the management of acute pain for decades.23,24 In response to JC and other accrediting organizations’ concerns about the safety of this practice and the nurse’s associated role, the ASPMN and the American Pain Society (APS) issued a consensus statement that reinforced their belief that competent

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RNs can safely interpret and implement properly written analgesic range orders.24 The development of prescribing guidelines and a protocol that outlines patient monitoring and facilitates the nurse’s decision making with regard to appropriate dose selection is recommended.25 Insuring RN competency through didactic and psychomotor skill validation is essential.

Alternative Agent-Controlled Analgesia There is general acceptance that effective use of PCA requires patients to understand the relationships among pain, selfadministration of a dose of pain medication, and pain relief and be cognitively and physically able to use the PCA device (see Chapter X).11,26 There are many patients who would benefit from PCA but are denied the therapy because they do not meet these criteria. A solution to this dilemma is the authorization of a competent alternate agent, such as a parent or significant other, who is capable of assuming responsibility for using the PCA device to administer analgesic doses to a loved one.26 The agent is taught how to recognize pain and whether it is safe to administer a dose. With nurse-activated dosing, the patient’s primary nurse serves as the alternate agent and utilizes the PCA device to deliver analgesic doses. This is an ideal therapy in the ICU where patients are too ill to manage their own pain using PCA. A continuous infusion (basal rate) can be administered and the nurse can press the demand button to administer supplemental doses for breakthrough pain and to prepare the patient for painful procedures. This method saves nursing time and assures that the correct opioid dose is administered.26 These alternative uses of analgesic infusion devices have been safely administered for several years in both children and adults.8,26 In 2007, the ASPMN published clinical recommendations in a position statement supporting the nurse’s role in the use of these effective pain management methods.27

REFERENCES 1. Pasero C, Reed B. The formation and early history of the American Society for Pain Management Nursing. ASPMN Pathways. 2003;12(12):2, 8. Available at: http://www.aspmn.org/ Organization/history.htm. Accessed January 12, 2007. 2. Pasero C, Preble LM. Role of the clinical nurse coordinator. In: Sinatra RS, Hord AH, Ginsberg B, Preble LM, eds. Acute Pain. Mechanisms & Management. St Louis, MO: Mosby;1992;552–559. 3. St Marie B, ed. Core Curriculum for Pain Management Nursing. St Louis, MO: Saunders; 2002. 4. Agency for Healthcare Policy and Research (AHCPR). Acute Pain Management: Operations or Medical Procedures and Trauma. Clinical Practice Guideline. Rockville, MD: U.S. Public Health Service, AHCPR Publication 92-0032. 5. American Nurses Association (ANA). Position statement on the role of the registered nurse (RN) in the management of analgesia by catheter techniques (epidural, intrathecal, intrapleural, or peripheral nerve catheters). Washington, DC: ANA. Available at: http://www.nursingworld.org/readroom/position/joint/jtcathet. htm. Accessed January 12, 2007. 6. Krenzischek D, Wilson L. Introduction to the ASPAN pain and comfort clinical practice guideline. J Perianesth Nurs. 2003; 18(4):228–231.

7. Oncology Nursing Society (ONS). ONS Publications. Retrieved January 10, 2007 from http://www.ons.org/publications/. 8. Pasero C, Gordon DB, McCaffery M, Ferrell BR. Building institutional commitment to improving pain management. In: McCaffery M, Pasero C, eds. 2nd ed. Pain: Clinical Manual, St Louis, MO: Mosby; 1999;711–744. 9. Pasero C. Electronic-mail communication with the American Pain Society Nursing Special Interest Group email list service subscribers, February 26 through April 1, 2007. 10. Pasero C, McCaffery M. Comfort-function goals. Am J Nurs. 2004;104(9):77–78, 81. 11. Pasero C, Portenoy RK, McCaffery M. Opioid analgesics. In: McCaffery M, Pasero C, eds. Pain: Clinical Manual. 2nd ed. St Louis, MO: Mosby; 1999;161–299. 12. Pasero C. Electronic-mail communication with Betty Ferrell, PhD, RN, Research Scientist, City of Hope National Medical Center, Duarte, CA on March 24, 2007. 13. Pasero C. Personal communication with Joan Beard, MS, RN, Director of Pain and Palliative Care, Mercy Medical Center, Des Moines, IA, September 13, 2006. 14. Pasero C, McCaffery M. No self report means no pain intensity. Am J Nurs. 2005;105(10):50–53. 15. Herr K, Coyne P, McCaffery M, et al. Pain assessment in the nonverbal patient: position statement with clinical recommendations. Pain Manag Nurs. 2006;7(2):44–52. 16. Gelinas C, Fillion L, Puntillo KA, Viens C, Fortier M. Validation of critical-care pain observation tool. Am J Crit Care. 2006;15:420– 427. 17. Fuchs-Lacelle S, Hadjistavropoulos T. Development and preliminary validation of the pain assessment checklist for seniors with limited ability to communicate (PACSLAC). Pain Manag Nurs. 2004;5(1):37–49. 18. Vila H, Smith RA, Augustyniak MJ, et al. The efficacy and safety of pain mnagement before and after implementation of hospitalwide pain management standards: is patient safety compromised by treatment based solely on numerical pain ratings. Anesth Analg. 2005;101:474–480. 19. Weinger MB. Dangers of postoperative opioids. APSF Newslett. 2006–2007;21(4):63–68. 20. Pasero C. Electronic mail communication with the American Pain Society Nursing Special Interest Group email list service subscribers, March 1 through April 10, 2006. 21. Pasero C, McCaffery M. Monitoring opioid-induced sedation. Am J Nurs. 2002;102(2):67–68. 22. Pasero C, Eksterowicz N, Primeau M, Cowley C. Registered nurse management and monitoring of analgesia by catheter techniques. Pain Manag. Nurs. 2007;8(2):49–55. 23. Manworren RCB. A call to action to protect range orders. Am J Nurs. 2007;106(7):30–33. 24. Gordon DB, Dahl J, Phillips P, Frandsen J, Cowley C, Foster RL, Fine PG, Miaskowski C, Fishman S, Finley RS. The use of “as needed” range orders for opioid analgesics in the management of acute pain: a consensus statement of the ASPMN and the APS. Pain Manag Nurs. 2004;5(2):53–58. 25. Pasero C, Manworren RCB, McCaffery M. IV opioid range orders. Am J Nurs. 2007;107(2):52–59. 26. Pasero C, McCaffery M. Authorized and unauthorized use of PCA pumps. Am J Nurs. 2005;105(7):30–33. 27. Wuhrman E, Cooney M, Dunwoody C, Eksterowicz N, Merkel S, Oakes L. Authorized and unauthorized (“PCA by proxy”) dosing of analgesic infusion pumps: position statement with clinical practice recommendations. Pain Manag Nurs. 2007;8(1):4– 11.

38 Role of the Pharmacist in Acute Pain Management Leslie N. Schechter

Today’s pharmacist responsibilities have expanded beyond the traditional roles of compounding, filling, dispensing prescriptions with accuracy and appropriateness, and pharmaceutical supply management. Pharmacists have been identified as part of a collaborative team that provides appropriate medication therapy management. This team approach benefits patients that receive medications for the treatment of acute pain. Pharmacists also ensure proper preparation of sterile products, adhering to the United States Pharmacopeia (USP) 797 recommendations.1 In addition, pharmacists provide drug information and critical evaluations of new drug products or devices to the Pharmacy and therapeutics (P&T) Committee. Additional roles for the pharmacist include quality assurance data collection, development of proper medication labeling, medication error reporting, and the development of policies and procedures for appropriate opioid control systems.

legal responsibilities have been expanding since 1990, when most states implemented a federal standard contained in the Omnibus Budget Reconciliation Act of 1990.5 The Act mandated that pharmacists perform prospective drug use reviews as a condition of participation in the federally funded, but stateadministered, Medicaid program. The Act required pharmacists to screen for drug duplication, drug-disease contraindications, drug-drug interactions, incorrect dosage or duration of drug treatment, allergic reactions, and clinical abuse/misuse.5 Once a problem is identified, the pharmacist contacts the prescriber, initiating a collaborative relationship that will lead to a resolution of the problem. Patient counseling is an expected service provided by pharmacists to ensure that patients have the information needed to use their medications properly.6 More recently, with the passage of the Medicare Modernization Act of 2003 and the Medicare Prescription Medication Benefit (Part D), the federal government has begun to develop a plan that incorporates pharmacists, in collaboration with physicians, as being responsible for medication therapy management (MTM).6 This team approach benefits patients that receive medications for the treatment of acute pain. MTM has been defined by the pharmacy profession as “a distinct service or group of services that optimize therapeutic outcomes for individual patients that are independent of, but can occur in conjunction with, the provision of drug product.”7 With implementation of MTM, patient outcomes should include appropriate medication use, enhanced patient understanding of their medication regimens, increased patient compliance with prescribed medications, reduced risks for adverse events associated with medication administration, and reduced medical costs.7 Some states are authorizing collaborative drug therapy management so that pharmacists can order and interpret laboratory tests, modify drug dosage, and initiate new drug therapy under a plan approved by the patient’s physician.8 To date, these types of collaborations are found mostly within hospitals and other institutions but are beginning to extend into community pharmacies and other independent practices.

M E D I C AT I O N T H E R A P Y M A NAG E M E N T

Pharmacists are well situated in the medication use process to influence patient outcomes from drug therapy.2 They are usually the last health care provider whom a patient comes in contact with before using a new medication. In addition, communitybased pharmacists are easily accessible to patients. Therefore, pharmacists are in a unique position to optimize patient outcomes by identifying, resolving, and preventing medication therapy problems. Medication therapy problems include improper drug selection, subtherapeutic dosage, overdosage, adverse drug reaction, drug interaction, failure to receive the drug, and drug use without an indication.3 Drug-related morbidity is costly and prevalent. In 2000, an estimated $177.4 billion was spent in the United States to manage direct costs associated with drug-related morbidity in the ambulatory setting.4 Pharmacists are in a unique position to help identify, resolve, and prevent drug-related morbidity, thereby optimizing patient outcomes in pain management. Federal and state regulations have catalyzed the expanding responsibilities of pharmacists in patient care. Pharmacists’ 607

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Another unique role for the pharmacist is with medication reconciliation. Medication reconciliation is defined by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) as the “the process of comparing the medications that the patient/client/resident is currently taking with the medications that the organization is planning to provide.”9 The intent of medication reconciliation is to provide continuity of care for patients with regard to medication use as they transition in the health care system and to avoid errors in transcription, omission, duplication of therapy, drug-drug and drugdisease interactions. Cornish and colleagues reported that over 50% of patients admitted to a general internal medicine hospital floor had at least one unintended discrepancy between the physician’s admission medication orders and a comprehensive medication history obtained through an interview.10 This has tremendous implications for chronic pain patients treated with complicated regimens, including high-dose opioids, who will be having surgery and experiencing acute on chronic pain. Data from the USP MEDMARX program from September 2004 to July 2005, indicated that more than 2000 medication errors were attributed to failures of medication reconciliation; 22% occurred during hospital admission, 66% during transition/transfer to another level of care, and 12% at hospital discharge.11 The Joint Commission National Patient Safety Goal 8 requires that through a collaborative effort, the organization, the patient and/or family, the patient’s primary physician, and outpatient pharmacy develop a complete list of medications that the patient is currently taking on admission to the organization.9 The list must include over-the-counter and alternative therapies as well as prescription medications. The medications must then be compared to the medications ordered at admission and any differences or potential problems, such as omissions, dose changes, duplication of therapy, or drug interactions, must be reconciled. On discharge or transfer to another health care provider, the list is to be given to the patient and to the next care provider. This JCAHO requirement is not intended just for inpatients. Medication reconciliation should occur any time the patient enters a health care organization where medications will be administered. The standard does not specify who must perform the reconciliation or specify any particular documentation. However, a formal and systematic approach to reconciling a patient’s medications across the continuum of care with multidisciplinary input from key organizational departments/services is imperative.11 Pharmacists are critical to establishing an effective medication reconciliation program. They can ensure that medications used for the treatment of pain are continued or converted to an appropriate alternative when transitioning from one organization to another. If a pharmacist notes that a patient is on a long-acting opioid at home and is admitted for surgery, ensuring that the opioid dose is considered in the postoperative pain regimen is crucial. The pharmacist can assist the surgeon with appropriate conversions to intravenous opioids during the immediate postoperative period and then again when the patient is tolerating oral medications. Pharmacists play an important role in improving the management of acute pain by ensuring that analgesic drug therapies are reconciled, prescribed, dispensed, and administered properly. The need to assess and treat pain appropriately has evolved into the fifth vital sign; that is, pain assessment is documented at a minimum of every eight hours when other vital signs are taken. JCAHO requires organizations to recognize

patients’ rights to appropriate assessment and management of pain.12 Healthcare providers must assess the existence, nature, and intensity of pain in all patients and record the results in a way that facilitates regular reassessment and follow-up. In addition, JCAHO requires policies and procedures that support appropriate ordering of pain medications. Patient needs must also be addressed by providing education for patients and families about effective pain management, both in the hospital setting and on discharge. Opportunities for pharmacists to improve pain management may begin with efficient dispensing but must also include becoming a team member in managing the overall care for the patient with pain. Empirical evidence supports this type of collaboration as an effective means to improve therapeutic outcomes, reduce health care costs, and relieve patient suffering.8 PA I N M A NAG E M E N T E D U C AT I O N F O R P H A R M AC I S T S

The topic of pain management is not adequately presented and developed in the curricula of many United States schools of pharmacy. Although pain management is included in some format, it is usually covered in a fragmented way, usually as part of presentations on diseases with pain as a prominent feature, such as cancer.13 Some schools have specific courses in pain management, but these are usually elective courses, taken by a small percentage of the student body. In addition, instruction about the diagnosis of pain, patient assessment, and physical examination is minimal.13 Therefore, clinical training of pharmacists in the field of pain management, as with other professionals, needs to be further developed and refined for pharmacists to be effective members of a pain service. JCAHO pain management standards require education about pain management for all relevant clinical staff, including physicians, nurses, and pharmacists. Educational and competency based programs will ensure that pharmacists become competent in pain management. A program should be available to evaluate the pharmacist’s communication skills in effectively talking to patients regarding pain management. In addition, pharmacists must have a basic knowledge of various analgesic medications and their place in pain management. It is imperative that pharmacists understand the differences between addiction, pseudoaddiction, dependence, and tolerance and are able to address patient concerns regarding these topics. This will help to alleviate misconceptions regarding the use of opioids for the management of pain. Pharmacists must also be familiar with the equianalgesic dosing tables and competent in providing guidance to other health care professionals converting patients from one opioid analgesic to another. Although there are clinical pharmacy pain specialists, all pharmacists should be minimally competent in providing effective pain management for their patients. M A NAG E M E N T O F S C H E D U L E I I NA RC OT I C S

Controlled substances are placed in one of five schedules. Schedule I is for those abusable drugs that are deemed to have no medical utility (eg, heroin). Schedules II through V are for drugs with

Role of the Pharmacist

abuse potential that currently have acceptable medical uses. The lower the schedule number (eg, Schedule II), the higher the risk of abuse. The federal Controlled Substances Act requires all registrants, including pharmacists, to keep complete, accurate, and detailed records of the acquisition and disposition of all controlled substances.14 These records are to be maintained in a readily retrievable manner so that the inspectors of the Drug Enforcement Administration (DEA) can easily review them. When dispensing controlled substances, pharmacists have a legal responsibility to verify that all prescriptions for controlled substances have been written by a prescriber in the usual course of that prescriber’s legitimate medical practice.14 Violations of the Controlled Substances Act and DEA regulations can subject pharmacists to a variety of sanctions, ranging from an administrative letter of admonition to licensure suspension to criminal prosecution.14 The collaborative effort between physicians and pharmacists could have a significant affect on the treatment of patients who are prescribed controlled substances such as opioids for acute pain management. Pharmacists are acutely aware of their “gatekeeper” or “drug police” positions at the end of the drug distribution chain and of their responsibility not to provide drug diverters or addicts with easy access to controlled substances.8 However, pharmacists are equally mindful of their responsibilities for the appropriate medication therapy management of their patients. Pharmacists strive to fill valid prescriptions and to refuse purported prescriptions, but discerning between the two is not an easy task and some error may occur. Traditionally, physicians and pharmacists have had a confrontational relationship regarding scheduled narcotics because of stringent regulatory controls over these substances and pharmacists’ sometimes unjustified fear of disciplinary action.8 Even today, some pharmacies will not stock particular medications that have high “street” value. Other pharmacists question the overuse of opioids by the physicians who prescribe them. Just as physicians continue their reluctance to prescribe adequate medications for pain, pharmacists are similarly reluctant to dispense high doses of opioid medications. Accountability for narcotics within a hospital system must be a coordinated effort among pharmacists, nurses, and physicians. Pharmacists are responsible for ordering and maintaining an adequate central stock of controlled substances within the hospital. When controlled substances are distributed to the patient care areas, nursing personnel are then accountable for conducting controlled substance inventory review and reconciliation every shift, ensuring proper documentation for patient administration and narcotic wastage. When controlled substances are distributed directly to anesthesiology personnel, they are then accountable for the controlled substances. The pharmacy department is ultimately responsible for reviewing nursing and anesthesiology records for accuracy and potential diversion issues. Replacing this relationship of confrontation with a collaborative agreement would place the responsibility for patient outcomes in the hands of both physician and pharmacist.8 Together they would determine the appropriate pain management therapy for each patient, based on objective clinical practice guidelines. This will not only assure that patients get the most appropriate medication therapy management but also provide an avenue through which physicians and pharmacists can manage the risk of regulatory scrutiny.8

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D RU G F O R M U L A RY M A NAG E M E N T A N D P O L I C Y D E V E LO P M E N T

Drug Formularies Drug formularies are in place at the hospital, community, and national levels.15 At the hospital level, the formulary is a list of available drugs meeting the medication needs of the patients serviced at the hospital. This formulary will provide a list of drugs that are considered by the P&T Committee to be the most useful in patient care and provides guidelines for drug use.16 When formularies were first created in hospitals, they were lengthy lists of all the drugs available for use in a hospital. Modern formularies not only include this list but also reflect organizational policies and procedures for rationale drug use and cost considerations.17 Hospital formularies may be open with unrestricted prescribing, closed with prescribing strictly controlled and therapeutic substitution as a standard of practice, or mixed.17 Many hospitals limit therapeutic classes of drugs to specific agents. The decision for selecting one or two drugs in a therapeutic class is usually based on clinical efficacy, safety, and cost factors.15 At the community level, general practitioners and pharmacists have implemented formulary programs as a mechanism to ensure the use of cost-effective therapy.15 In addition, in the community, insurance companies have developed formularies, usually with tier levels. A level one medication will have the lowest copay. The insurance copays increase as the tier level increases. At the national level in many European countries, the formulary is defined by the health authority as the list of drugs that are reimbursable by the national health program.15 Drugs not included on the list must be paid for by the patient. In addition, certain drugs may be restricted to patients with certain documented pathologies where the additional benefit justifies the additional cost. In the hospital setting, opportunities for pharmacists to improve MTM in managing pain begin with the availability and dispensing of pain medications. Efficacy and safety are among the primary concerns of the Food and Drug Administration (FDA) before a new drug or device is approved. When a new drug is commercially available, it is the responsibility of the P&T Committee to evaluate the new drug entity based not only on safety and efficacy but also on cost and outcome considerations.17 The pharmacist’s role in evaluating new drugs and drug delivery technologies for formulary addition may involve searching the published literature for clinical trial reports, obtaining additional information from the manufacturer, critically reviewing the data, and preparing drug monographs and reports to the P&T Committee. Pharmacists should be members of the P&T Committee and Institution Review Board (IRB). As a member of the IRB, pharmacists will have the opportunity to become familiar with new drugs before their approval by the FDA. When reviewing a medication for hospital formulary addition, the P&T Committee should not only review its safety and efficacy based on the results of randomized, controlled trials but also review the pharmacoeconomics (ie, the scientific discipline that compares the value of one pharmaceutical drug or drug therapy to another), pharmacoepidemiology (ie, the use and effects of drugs in large numbers of patients), and outcomes from using the drug. Outcomes should include side effects and therapeutic failure as well as desired therapeutic endpoints. The

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Table 38.1: Functions and Scope of the P&T Committee16,18 Developing, maintaining, and approving a formulary of medications accepted for use in the organization. Establishing programs and procedures that help ensure effective, safe, and cost-effective drug therapy; if a medication is only indicated for epidural administration, it should be restricted to those practitioners competent in spinal drug administration, primarily anesthesiologists Establishing or planning educational programs on medication use for all professional staff Initiating or directing medication use evaluations to optimize medication use Participating in quality improvement activities to minimize medication errors

Medication Guidelines Development of medication guidelines offers health care providers valuable information on the indications, dosing, monitoring, and equivalencies within therapeutic categories. The development and implementation of pain management guidelines offers prescribers a reference of evidence-based treatment for pain. The guidelines should include important phone numbers for consultations, available formulary medications, including the doses and important prescribing information in all therapeutic classes used to treat pain, medications used to treat side effects, and equivalency tables for converting patients from one opioid to another. These guidelines are approved by the P&T Committee and an educational program is designed to train prescribers on its appropriate use. INFUSION DEVICE SELECTION C O N S I D E R AT I O N S

drug under consideration is compared to other drugs in the same class or for the same indication. Comparable efficacy and adverse event profiles must be critically evaluated, as well as reviewing the cost. The cost of the medication should be assessed using a pharmacoeconomic analysis, taking into account not only the price of the drug but also the impact of therapy on other institutional factors such as laboratory testing, staff time management, impact on length of hospital stay, and patient satisfaction and quality of life. For example, the use of a new drug may reduce the adverse effects, nursing staff time, patient recovery time, and the duration of hospitalization compared with other drugs, resulting in cost savings that more than offset the higher cost of the new drug. Pharmacists also have knowledge of special drug acquisition costs and pricing programs. These incentives should be a consideration in the pharmacoeconomic analyses. The functions and scope of the P&T Committee are listed on Table 38.1.16,18

Therapeutic Substitution Programs Developing therapeutic substitution programs and educating prescribers on the use of these policies and protocols can yield substantial cost savings.19 When two or more drugs have been proven to be therapeutically equivalent, many hospitals and some insurance formularies apply a policy of automatic drug exchange or interchange. In addition, a therapeutic interchange program can be implemented to convert patients receiving intravenous therapy to oral therapy as soon as the patient is able to tolerate oral intake. The decision to have a therapeutic interchange is determined by both the medical and pharmacy staff and approved by the Medical Executive Committee. Generally, hospital pharmacists automatically implement the drug interchange so that the transition to the selected product occurs quickly. This may impact acute pain management if an institution has a therapeutic interchange program for opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), or local anesthetics. Physicians and pharmacists must work together closely to ensure that a therapeutic interchange program will not adversely impact patients that may require a specific drug within a certain drug class. There can be exceptions to therapeutic interchange if a patient does not tolerate the therapeutically equivalent interchange drug.

Although the P&T Committee is responsible for the maintenance of medication policies, the New Products Committee is responsible for evaluating and introducing new devices into the hospital setting. This is generally a multidisciplinary committee consisting of representatives from various departments within the hospital. Medical, nursing, pharmacy, biomedical, and hospital administration staff may all be represented. Any new device is presented to the committee and evaluated similarly to a new medication. Efficient use of technology to ensure that medications are readily available for the patient is imperative. The use of patient-controlled analgesia (PCA), epidural, and local anesthetic delivery devices along with medication storage units should be evaluated. Device selection should be based on safety, accuracy, reliability, ease of use, cost, and compatibility with selected drugs.20 Appropriate staff education must be provided after a decision is made to purchase or lease new devices. Many devices are available with differing mechanisms for drug delivery, including syringe pumps, peristaltic devices, and elastomeric reservoir pumps. Syringe pumps are used to deliver the contents of the syringe over a given period of time or on patient activation.20 The contents of the syringe may be delivered over several hours or several days. This is the most common type pump for PCA use in the treatment of acute postoperative pain. There are commercially available morphine (1 mg/mL) and meperidine (10 mg/mL) prefilled syringes in standard concentrations for use in these types of PCA pumps. When other opioids such as hydromorphone and fentanyl, or when variant concentrations of morphine are used, the pharmacist is responsible for preparing these syringes. Peristaltic devices deliver drug from a flexible reservoir via administration tubing that is mechanically squeezed to allow the delivery of the drug.20 These pumps are traditionally used for the administration of IV fluids but have been modified for the administration of epidural infusions. Peristaltic devices can accommodate larger volume infusion solutions because they use a flexible reservoir bag.21 The capacity of these bags range from 50 mL to 1000 mL. Flow rate capabilities range from 0.1 to 999 mL/hr. Elastomeric reservoir pumps are usually disposable devices that consist of an inflatable balloon reservoir surrounded by a protective shell with a medication entry port and permanently attached tubing. After the balloon is filled with medication and

Role of the Pharmacist

Table 38.2: Considerations for Selecting Infusion Devices Patient population using the device The maximum reservoir volume The range of administration rates Ability to lock a reservoir if the medication contained in the device is a controlled substance Design of occlusion and end-of-infusion alarms Cost of disposables Cost of the pump (renting, leasing, buying)

the tubing is primed, pressure created by the inflated balloon forces the medication through the tubing and into the patient.22 The flow rate is controlled either by using calibrated lengths of small-bore tubing or with a flow-restricting device located near the end of the tubing.22 Elastomeric devices are available in different flow rates (50 to 250 mL/hr) and volume capacities (50 to 500 mL). Several devices are available for instillation of local anesthetic into surgical incisions. When evaluating or selecting any infusion device, many variable issues should be considered. As described previously, safety, accuracy, reliability, and ease of use are imperative. Other important considerations are included in Table 38.2. Many institutions are evaluating “smart” pumps, infusion devices with drug libraries and decision support.23 Smart pump technology enables health care providers to set limits in the pumps to help eliminate over- and underadministration of medications. Pharmacists should help to determine the minimum and maximum rates and drug concentrations to be programmed into smart pumps. Pharmacists are a valuable resource for determining stability and proper container size for various pumps. Education programs must be designed to ensure that new technologies are not utilized unless proper education and training of staff is provided. Pharmacists who become knowledgeable about these technologies should be involved in the development of educational programs and policies and procedures (see also Chapter 19, Patient-Controlled Analgesia Devices and Analgesic Infusion Pumps). RO U T E O F A D M I N I S T R AT I O N C O N S I D E R AT I O N S F O R T H E T R E AT M E N T O F PA I N

Traditionally, the treatment for acute pain has been intermittent oral, intramuscular (IM), or intravenous (IV) injections. PCA and the use of epidural injections of opioids are improvements in pain management modalities, yet all have limitations. Intermittent analgesia is frequently associated with “analgesic gaps,” that is, time periods when the patient’s pain level is higher than desired.24 In addition, IM injections may be painful and provide variable absorption of the medication. Oral medications may be valuable as transition agents but may not be usable in the postoperative setting if a patient cannot take anything by mouth. Because of these limitations, nursing administered intermittent administration of pain medications is usually not recommended. Intravenous PCA offers convenience by eliminating the need for intermittent dosing by nursing personnel and gives patients some autonomy in the treatment of their pain.25 Patients deter-

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mine when they are ready for a dose, press the PCA administration button to receive the dose, eliminating the waiting time for a nurse to assess the patient, and then obtain and administer the opioid. Different PCA pumps have different configurations. Usually there is a syringe or cartridge containing the analgesic, locked into the PCA pump, that is then programmed to allow administration of a small bolus dose at specified time intervals, with or without an accompanying continuous IV infusion.26 When the technique of epidural and intrathecal administration was developed, it was standard of practice to administer these agents as a single bolus or multiple as-needed bolus injections.21 However, this technique is usually not recommended because it may result in periods of inadequate pain control and has been associated with a higher frequency of side effects resulting from temporary peak levels of drug.27 Current methods now allow for initial bolus doses followed by a continuous infusion with or without patient-controlled epidural analgesia (PCEA).28 Like PCA, PCEA allows for infusion of a fixed dose of analgesic with incremental patient demand doses during periods of inadequate pain relief. This method allows for individualization of treatment, increased patient satisfaction, and convenience.20,28 Regional anesthetic techniques are also available and widely used for the management of acute postoperative pain. These techniques involve either intermittent or continuous infusions of local anesthetics through an epidural-like catheter directly into nerve sheaths or incision sites.27,29–31 There is evidence that this method of pain control may be effective in inhibition of the sensitization phenomena associated with postinjury hyperalgesia.27 A mechanism must be designed to identify patients receiving local anesthetics epidurally or into incisional wounds. Traditionally, anesthesiologists insert and manage epidural infusions while surgeons insert peripheral catheter devices that infuse local anesthetic directly into the surgical wound site. If local anesthetics are used in both peripheral and epidural sites, caution is warranted because of the potential risk for toxicity with dual administration sites. Pharmacists should be aware of all local anesthetics administered to patients and report any duplication of therapy to both prescribing physicians. Nurses, physicians, and pharmacists should be aware of all pain modalities for any given patient. Methods must be in place to document and identify patients that have received intraspinal analgesics, patients with a continuous infusion through an epidural catheter, and patients with surgical incision site infusions of local anesthetic. I N T R A S P I NA L S O LU T I O N P R E PA R AT I O N , S TA B I L I T Y, A N D S T E R I L I T Y

Pharmacists must be familiar with the preparation, dosing, and administration techniques for all routes of pain medication administration. Any drug injected or infused into the epidural or intrathecal space must be free of neurotoxic preservatives.28,32 Injectable drugs that contain preservatives such as methylparaben, benzyl alcohol, methylhydroxybenzoate, propylhydroxybenzoate, phenol, and formaldehyde must be avoided. Although infection of the epidural or intrathecal space is rare, it can have a high morbidity or be fatal. Preparation of all intraspinal solutions should be performed with strict adherence to sterile aseptic technique. On January 1, 2004, chapter 797 of the USP became the nation’s first enforceable standard

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for the compounding of sterile preparations.1 This standard was developed in response to a growing demand to hold pharmacies accountable for preparations that are compounded outside of a controlled environment.33 The chapter provides procedures and requirements for compounding sterile preparations. Sterile compounding requires a clean facility, specific training and testing of personnel in principles and practices of aseptic manipulations, air quality evaluation, and knowledge of sterilization and solution stability principles and practices.1 The FDA considers chapter 797 an enforceable standard and JCAHO is using it as a standard when surveying hospitals.33 Therefore, whenever possible, the preparation of any solution being administered in the epidural or intrathecal space should be prepared within the pharmacy, in accordance to USP 797 guidelines. Most pharmacies prepare sterile products in a clean room, within a laminar flow hood. The stability of morphine, fentanyl, sufentanil, and hydromorphone alone or in combination with bupivacaine, ropivacaine, clonidine, or epinephrine in a variety of syringes and reservoirs has been studied.34–38 All solutions studied were stable for up to 30 days. However, the risk of microbial contamination in preservative-free solutions is still considered problematic.21 Guidelines and recommendations from the Centers for Disease Control and Prevention (CDC) and the American Society of Health-System Pharmacists recommend that preservative-free infusion solutions be completely used or discarded within 24 hours of preparation when not refrigerated.28,39–40 These guidelines also recommend that preservative-free mixed solutions should be stored under refrigeration for no more than seven days.39–40 After the solution is dispensed for patient use, a 24hour expiration date must be applied to the label.39–40 D RU G S E L E C T I O N , D O S AG E , A N D A DV E R S E E F F E C T S

Nonopioid Analgesics Nonopioids such as aspirin, acetaminophen, and NSAIDs are traditionally used for the treatment of mild to moderate pain and may be combined with opioid analgesics for the treatment of moderate to severe pain. Pharmacists should evaluate postop order sets and ensure that at least one nonopioid analgesic is available to the patient for pain management. In addition, pharmacists should evaluate the number of medications ordered that contain acetaminophen. Opioid combination formulations may contain 500 mg of acetaminophen per tablet. If a patient is receiving two tablets every four hours, this will exceed the recommended maximum daily dosage of acetaminophen (4 grams). Patients may have acetaminophen ordered for elevated temperature. Additional acetaminophen doses may unintentionally be administered, exposing the patient to potential hepatotoxicity. For these reasons, it may be appropriate to prescribe opioids and acetaminophen as separate entities. Although all NSAIDs have similar mechanisms of action and adverse effect profiles, they do differ in potency, time to onset of action, duration of action, and interpatient tolerance variations.41 Pharmacists and physicians need to evaluate the efficacy, therapeutic end points, and side-effect profiles of various NSAIDs to determine which NSAIDs will be on the hospital formulary for the treatment of acute pain. Consideration for the inclusion of ketorolac on the formulary, the only injectable NSAID approved in the United States, will be impor-

Table 38.3: Equianalgesic Opioid Conversions Based on Injection Sitea Drug Morphine Hydromorphone Fentanyl a

Oral (mg)

Parenteral (mg)

Epidural (mg)

Intrathecal (mg)

30 7.5

10 1.5 0.1

1 0.15 0.001

0.1

Adapted from Krames ES.42 These equivalencies are not supported by large-scale, double blinded studies, and are meant as a reference for identifying appropriate conversions.

tant for patients unable to take oral medications. Pharmacists must ensure that ketorolac is ordered appropriately based on the patient’s age, renal function, and history of gastrointestinal bleeding. In addition, ketorolac therapy is limited to five days.26

Opioids Opioids are the cornerstone of treatment for moderate to severe acute pain. The choice and dosage for an opioid depends on the patient’s pain severity, whether the patient is opioid na¨ıve or tolerant, the route of administration, pharmacokinetics, patient preference, adverse effects, and cost.26 The pharmacokinetics of the various opioids are important in designing the dosage and frequency of opioids. Pharmacists must assess postoperative pain order sets to ensure the proper dosing and dosing intervals are utilized. Routes of administration for opioids include oral, sublingual, nasal, intramuscular, intravenous, transdermal, rectal, inhalation, and intraspinal. Depending on the route of administration, the dose of opioid will vary. Pharmacists must be familiar with dosing for all routes of administration. When an opioid is administered epidurally, there will be a maximum infusion rate secondary to the physical characteristics of the epidural space. Administration rates may vary from 4 to 18 mL/ hr, and rates above 20 mL/hr are generally not indicated.21 Administration via the intrathecal route is rarely indicated for acute pain and has even lower infusion rates. Understanding the difference in dosing depending on the route of administration is imperative. Individual hospitals should develop ranges for all medications that may be administered epidurally or intrathecally. Table 38.3 provides a guideline for equianalgesic opioid conversion for intravenous, epidural, and intrathecal routes.42 Pharmacists should also be involved in helping physicians select the most appropriate opioid for the treatment of acute pain. Historically, meperidine was commonly used for the treatment of acute pain. It remains one of the most frequently prescribed opioids for procedural sedation; however, its use should be limited for extended treatment of acute pain because of its neurotoxicity, short duration of action, and lower potency relative to morphine. Normeperidine, the major metabolite of meperidine, accumulates with repeated dosing and seizures have been observed even in patients with normal renal function.43 The American Pain Society now recommends avoiding meperidine for the treatment of acute pain whenever possible.44 Pharmacists can educate and recommend alternative opioids when meperidine has been included in postoperative order sets. When there is no alternative for meperidine, its use should be limited to 48 hours and no more than 600 mg may be administered per day.44

Role of the Pharmacist

Propoxyphene is generally prescribed for mild to moderate pain. However, because of the risk for toxicity associated with the metabolite norpropoxyphene that may occur in patients with diminished renal function, repeated doses, and in the elderly, its use should be avoided.45,46 Propoxyphene has no clinical advantage over nonopioid analgesics and has a higher incidence of adverse effects.47 Again, pharmacists can educate and recommend alternatives to propoxyphene for the treatment of acute pain. Codeine is generally considered an opioid for mild to moderate pain, with a higher incidence of significant adverse effects such as nausea and constipation compared to other opioids at equianalgesic doses.44 In addition, codeine must be converted to morphine via the cytochrome P450 2D6 pathway to provide analgesia. A substantial percentage of Caucasians are poor metabolizers due to deficiencies in this isoenzyme.48 These patients will not be able to convert the codeine to morphine and will therefore receive no analgesic benefit. If codeine is part of a postop order set, pharmacists should ensure that other opioids are ordered for those patients that do not obtain relief from codeine. Methadone is a unique opioid option. Methadone is a mureceptor agonist and an N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptors can decrease mu-receptor’s response to opioids. This added activity may be useful during opioid rotation or when treating known drug abusers for acute pain. Methadone’s duration of analgesic action following a single dose is four to six hours.49 However, because of its high volume of distribution, there can be a substantial increase in duration of action following chronic dosing.49 Methadone has a long, unpredictable half-life and, with tissue accumulation, serious, life-threatening toxicity can occur. There is limited knowledge on titrating doses and equivalencies. Many equianalgesic tables use equivalencies based on single-dose studies. In reality, studies have indicated that methadone’s potency increases in patients on higher doses of opioid.50 Equianalgesic tables many times fail to consider these unique properties and dose conversion based on the listed ratio may result in a drastic overdose. It is recommended that conversion ratios be based on the total daily dose of morphine (or its equivalent) and adjustments in conversion ratios adjusted as opioid doses increase.50 Pharmacists and physicians must be cautious when converting patients to methadone and appropriate monitoring is imperative. Pharmacists play an important role in identifying drug allergies. Many patients state that they have an allergy to a particular opioid, yet genuine allergies to opioids are rare. In many cases, the patient reports an allergy because they experienced a side effect from the opioid. The diagnosis of an opioid allergy is further complicated because many opioids can cause histamine release, manifesting as a drug allergy. Therefore, it is important for the pharmacist to illicit the reaction a patient had with the implicated opioid and determine its significance. Identifying which opioid a patient has tolerated in the past often helps with prescribing opioids for the treatment of new acute pain syndrome. Pharmacists also play a role in identifying potential adverse effects from opioids and ensuring orders have been placed and processed to help treat opioid-related side effects. Differences in side effects may be related to the opioid ordered, the surgical procedure, the type of anesthesia, and individual patient characteristics. The most frequently reported side effects from opioids are respiratory depression, sedation, nausea, vomiting, consti-

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pation, urinary retention, and itching.48 Other adverse effects include confusion, hallucinations, nightmares, and dizziness. These adverse effects can have a negative impact on recuperation, participation in rehabilitation, and potentially prolong hospital stay. Factors such as age, extent of disease or surgery, concurrent administration of other drugs, prior opioid use, and route of administration can also increase the risk of opioidrelated adverse effects.46 Respiratory depression is the most serious adverse effect of opioids. When it occurs, it is often in an opioid-na¨ıve patient. The patient generally experiences sedation and mental clouding prior to developing the respiratory depression.45,48 Patients at increased risk for respiratory depression include obese patients and patients with a history of sleep apnea or airway disease. These patients require additional monitoring that may include pulse oximetry, capnography, and more frequent assessment of sedation levels. This monitoring should be incorporated into all postop order sets. Treatment for respiratory depression may include an opioid antagonist such as naloxone. The pharmacist should ensure that the proper dose of naloxone is administered for the reversal of respiratory depression. The dose used for the treatment of opioid overdose (0.4 to 2 mg IV) is not appropriate for reversing opioid side effects. These doses will also reverse the analgesic effects of the opioid. Initiating administration with small doses of a diluted solution of naloxone (diluting 0.4 mg to a concentration of 0.04 mg/mL) and administering 20 mcg (0.5 mL) to 40 mcg (1 mL) every minute until the respiratory rate increases above 10 per minute is a more appropriate method to reverse respiratory depression. If naloxone doses need to be continued, a naloxone infusion may be started. Doses of 0.25 mcg/kg/hr have been effective in reducing opioid-related side effects while maintaining adequate analgesia.51–52 This dose offers a starting point for reversal of side effects. The infusion rate may be increased if the patient’s status warrants. Opioid-induced gastrointestinal side effects such as nausea/ vomiting and constipation are the most common and, from the patient’s perspective, the most troubling postop adverse effect.53 Switching opioids or route of administration may be beneficial, but most importantly, prevention and treatment should be part of an opioid order set. Transdermal scopolamine, metoclopramide, droperidol, phenothiazines, and serotonin type 3 receptor antagonists have all been used for treatment of nausea and vomiting. Regimens to treat opioid-induced constipation should include stimulant laxatives. Stool softeners and bulk laxatives offer minimal effects. Although not indicated for the management of opioid-induced constipation from short term use of opioids, two peripheral opioid antagonists, methylnaltrexone and alvimopan, have recently been approved by the FDA. In April 2008, methylnaltrexone was approved to help restore bowel function in patients with late-stage, advanced illness who are receiving opioids on a continuous basis for pain management.54 In May 2008, alvimopan was approved to accelerate the restoration of normal bowel function in patients 18 years and older who have undergone partial large or small bowel resection surgery.55 In addition, as part of alvimopan’s approval under the FDA’s new Risk Evaluation and Mitigation Strategy (REMS) rules, it may be given only in hospitalised patients at specially certified facilities.56 More studies are needed before either agent may be used for the treatment of constipation from the short-term administration of opioids in the post-op setting. Administering opioids for acute pain management is a balancing act. Patients should be provided with the best pain

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Table 38.4: Frequency of Reported PCA Error Events from MAUDE Database62

Table 38.5: Frequency and Types of PCA Errors Reported to MEDMARX and USP MER Programs

Reported Error

Frequency

Possible Causes of Error

Type of Error

Device related

79.1%

Battery, display board, software failures Failure to deliver drug on demand Faulty alarm system Lack of free-flow Error code Defective patient on-demand device

Indeterminate events

12.5%

Excessive delivery of drug Underdelivery of drug

Improper dose/quantity Unauthorized drug Omission error Prescribing error Wrong administration technique Extra dose Wrong drug preparation Wrong time Wrong patient Wrong dosage form Wrong route Deteriorated/expired product

Possible operating errors

6.5%

Pump programming error (dose, concentration, rate) Failure to clamp-unclamp tubing Improperly loading syringe or cartridge Not responding to safety alarms Battery improperly inserted Pharmacy medication error

Possible adverse drug reaction

1.2%

Nausea/vomiting Sedation Respiratory depression Pruritus Urinary retention

Possible patientrelated error

0.6%

Misunderstanding instructions for PCA use

management available, with minimal side effects. Treatment for potential side effects from pain medications should be included in order sets. R O L E O F T H E P H A R M AC I S T I N R E D U C I N G PA I N M E D I C AT I O N E R R O R S

Medication error prevention is the responsibility of all healthcare providers. However, pharmacists must understand the unique role they have in preventing, detecting, and reporting errors that occur during the medication use process. This should include a systems approach to design an optimum drug delivery system and education of patients and other healthcare providers to ensure a better understanding and compliance with prescription and over-the-counter medications.57 When evaluating medication error rates, it is difficult to analyze the literature because different end points are used in various studies. However, the Institute for Safe Medication Practices (ISMP) identified morphine as one of six medications on the very first List of High-Alert Medications published in 1989. In the most current publication of the ISMP’s List of High-Alert Medications,59 opiates remain as a class of drugs that bear a heightened risk of causing significant patient harm when they are used in error. One major error that is reported frequently is inadvertent substitution of hydromorphone for morphine.60 Many times the error is related to the misconception that hydro-

Percentage Frequency (%) 38.9 18.4 17.6 9.2 4.8 4.7 4.2 3.3 2.5 1.6 0.6 0.3

morphone is the generic name for morphine. A misunderstanding of equivalencies may lead to administration of high hydromorphone doses (1.5 mg of hydromorphone intravenously is approximately equal to 10 mg of morphine).49 This inadvertent substitution has resulted in patient death.61 Several steps may be taken within an institution to help prevent this error. When possible, use tall man lettering to emphasize the Hydro portion of Hydromorphone on pharmacy labels, auxiliary labels, medication administration records, and drug listings on computer screens or automated dispensing cabinets.61 When computer physician (or prescriber) order entry (CPOE) is available, an information screen can be designed describing the equivalency of hydromorphone to morphine. In conjunction with opiate medication errors, device errors can also be dangerous and potentially fatal. The Manufacturer and User Facility Device Experience (MAUDE) maintains a database of reports of adverse outcomes for medication devices that is publicly available.62 PCA-related adverse events were analyzed from the MAUDE database from January 1, 2002, to December 31, 2003. Table 38.4 describes the frequency of reported PCA error events and the possible causes. Adverse events included respiratory depression/arrest (9%), excessive sedation (3%), death (19%), and naloxone administration (58%).62 PCA errors are also reported to the USP-ISMP Medication Errors Reporting (MER) Program and MEDMARX, a national, Internet-accessible database that hospitals and health care systems use to track and trend adverse drug reactions and medication errors. Five thousand one hundred and ten PCA errors were reported and analyzed from September 1, 1998, through August 31, 2003.63 Table 38.5 lists the frequency and types of PCA errors reported to MEDMARX and USP MER programs. ISMP had identified how PCA errors occur (Table 38.6). To help prevent PCA errors, ISMP recommends performing a failure mode and effects analysis (FMEA). FMEA is a procedure for analysis of potential failure modes within a system for the classification by severity or determination of the failure’s effect on the system.65 When using FMEA, consider whether the PCA pump can be programmed easily to deliver desired concentrations, if the pump operation intuitive for the clinician and patient, and if the information displayed appears in logical sequence.64 Mechanisms to help prevent PCA errors are included on Table 38.7.66

Role of the Pharmacist

Table 38.6: How PCA Errors Occur64 Error

Special Considerations

PCA by proxy

Family members and health professionals may not realize the implications of activating the PCA button This may result in oversedation, respiratory depression, and death

Improper patient selection

Inadequate monitoring

Elderly patients should be evaluated carefully prior to initiating PCA Patient must be cognitive and psychologically competent to manage their own pain. Ensure guidelines are established for routine monitoring, especially for the first 24 hours and at night. Consider pulse oximetry or capnography monitoring

Inadequate patient education

Ensure patient is educated prior to surgery Ensure patient is able to identify and utilize the PCA button

Drug product mix-ups

Separate Hydromorphone from morphine Separate syringes with standard concentrations of opioid from special concentrations

Practice-related problems and inadequate staff training

Misprogramming of PCA pump Incorrect transcription of prescriptions Calculation errors

Device design flaws

Default opioid concentrations Use of mL versus mg Pumps that do not require users to review all settings prior to initiation Activation button may look like the nurse call bell Patient does not know if they received a dose when they push the button

Prescription errors

Opioid conversion errors Prescribed inappropriate opioid Dosing errors

615

Table 38.7: Mechanisms to Help Prevent PCA Medication Errors Require health care provides to undergo competency testing for prescribing and programming PCA pumps Establish one standard concentration for each opioid used in PCA Design standard order sets that include: Standard concentrations of opioids Patient monitoring Frequent monitoring of respiratory rate and sedation level If patient is at risk for respiratory depression (eg, history of sleep apnea), provide more intense monitoring Treatment for side effects or adverse events Avoid ordering doses in mL; dose opioids in mcg or mg Establish patient selection criteria Ensure patient education prior to surgery and patient competence to utilize PCA postoperatively Maintain standard PCA syringes in one narcotic storage area. Separate morphine from Hydromorphone Custom PCA concentrations should be stocked away from the standard concentrations Require two health care providers to double check right patient, order, drug concentration, and pump settings

Table 38.8: Strategies for Preventing Epidural and Intrathecal Infusion Errors Pump considerations Consider using distinctly different pumps for epidural infusions Use “smart pumps” that incorporate drug protocol and maximum dosing limits Add a large visible label marked “epidural pump” on the pump infusing the epidural solution Avoid the use of dual chamber pumps for both IV and epidural infusions Consider placing IV pump and epidural pumps on opposite sides of the patient bed

Epidural medication errors have frequently been reported in the literature and to ISMP.28,67,68 In fact, ISMP added epidural and intrathecal medications to the 2007 LT High-Alert Drug List after practitioners were surveyed and requested the addition.69 Drugs including potassium chloride, theophylline, and antibiotics intended for intravenous administration have been accidentally administered into the epidural or intrathecal space.28,67,68 Several reports have described infusion rate issues when epidural pumps are identical to IV infusion pumps.68 Nurses mistakenly set the rate of the epidural pump to the rate that is supposed to be on the IV infusion pump. To help prevent epidural or intrathecal medication errors, Table 38.8 describes strategies for prevention. Pharmacists should identify opportunities to promote proved strategies to minimize medication errors. Working with physicians and nurses to promote efficient drug ordering, distribution, and administration will help to prevent medication errors.

If possible, discontinue the IV fluid and insert a heparin lock Epidural tubing Consider infusion tube distinction by either using colored tubing or labeling the tubing with brightly colored “for epidural use only” stickers. Stickers should be placed at distal connecting sites Epidural tubing should have no injection ports Limit the volume of the epidural solution (prepare 100- to 200-mL bags)

D E V E LO P M E N T O F S TA N DA R D O R D E R S E T S

Pharmacists and the P&T committee are often involved in the development and review of physician order sets, whether for traditional paper charts or CPOE. Order sets should be carefully evaluated for appropriate selection of medications, accuracy of

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Leslie N. Schechter

Table 38.9: Important Elements for Epidural Analgesia Orders Sets21

Table 38.10: Equianalgesic PCA Opioids Used at Thomas Jefferson University Hospital Opioid

Concentration

Drug(s), concentration(s)

Morphine

1 mg/mL

Instructions for administration

Fentanyl

0.01 mg/mL (10 mcg/mL)

Patient name, birth date, medical record number, room number

Bolus doses Drug with dose to be bolused

Hydromorphone

0.2 mg/mL

Meperidine (avoid using)

10 mg/mL

Interval between bolus injections Infusions Loading dose Infusion rate Treatment for breakthrough pain Maintenance of intravenous site for administration of fluids and for access for emergency administration of reversal medications if necessary Order to prevent other services from prescribing CNS depressants Monitoring instructions for opioid and/or local anesthetic administration. Specific observations that should be immediately communicated to the anesthesiologist (respiratory rate less than 6, systolic blood pressure less than 90 mm Hg) Instructions and treatment options for side effects Contact information if problems occur Date, time, and physician signature

dosing, and appropriate patient monitoring based on medications ordered. For pain management, different classes of pain medications should be available to treat pain. Acetaminophen or an NSAID may be used for mild pain. An oral combination product with hydrocodone or oxycodone may be used for moderate pain and injectable opioids may be used for severe pain. If epidural analgesia is employed, the anesthesiologists monitoring the effectiveness of this modality should also be responsible for ordering breakthrough pain medications. Pain assessment and reassessment of the adequacy of the pain medication should be evaluated on a regular basis. Adjustments should be made to drug regimens when adequate pain relief is not obtained. In addition to the appropriate pain medications, order sets should also include medications to treat the potential adverse effects attributed to these medications. There are several classes of drugs that may be chosen to treat nausea and vomiting, constipation, respiratory depression, and pruritus caused by opioid administration. The age of the patient, patient history, and the adverse effects of these drugs should be taken into consideration. Naloxone orders should include the appropriate dose for reversing respiratory depression while maintaining analgesia, as described previously. One of the recommendations from the ISMP to help prevent medication errors is to standardize concentrations of injectable medications.66 Based on this recommendation, PCA syringes, opioid infusions, and epidural solutions should be prepared using standard concentrations. Pharmacists should be familiar with the standardized dosing ranges and carefully evaluate orders that deviate from the established ranges.

Epidural Infusions The final volume and concentrations for epidural solutions must be considered when standardizing epidural infusions. Decisions regarding standard epidural preparations must take into consideration safety, cost, time for preparation, narcotic accountability, and the reservoir capacity in the infusion device. When possible, using whole rather than partial ampules or vials and using available package sizes of the drugs used in preparation of epidural infusions help to minimize waste.21 This process is also beneficial in helping to keep narcotic inventories accurate and minimizing the need to document of waste. When establishing standard epidural solutions, physician preference and stability considerations should be assessed. With adjustments in rate, the majority of patients may be prescribed a standard solution. In patients with a history of opioid use or in patients not receiving adequate analgesia from a standard epidural, a specialized solution may need to be prepared. The anesthesiologist should communicate with the pharmacist regarding the deviation from standard protocol. Table 38.9 provides important elements for epidural analgesia order sets.21

PCA Orders Standardization of PCA orders is imperative to help prevent medication errors. Most institutions will use a standard incremental PCA dose of 1 mg of morphine sulfate every six to eight minutes.26 Examples of equianalgesic opioid concentrations for PCA syringes that were developed at Thomas Jefferson University Hospital are listed in Table 38.10. An optional nursing bolus or loading dose equal to twice the incremental dose may be administered for breakthrough pain. Another feature of PCA pumps is the “lockout” or maximum dose that may be administered over a specified period of time. The lockout period may be a design feature within the device or may be programmed. A continuous or basal infusion may also be programmed into the PCA pump for patients with higher opioid requirements, particularly the opioid-tolerant patient. A basal or continuous infusion is not recommended for opioid-naive patients because of an increased incidence of respiratory depression. When designing an order entry form or computer program, all of the above criteria must be included. In addition, appropriate patient monitoring and treatment options for side effects such as respiratory depression, itching, and gastrointestinal disturbances must part of the order set. Table 38.11 lists important elements for PCA order sets.21 If a patient has higher opioid requirements and a higher concentration of opioid is required in the PCA syringe, a nonstandard PCA syringe will be compounded. This syringe will need to be stored in a different location from the standard concentration

Role of the Pharmacist

Table 38.11: Important Elements for PCA Order Sets21 Patient name, birth date, medical record number, room number Drug(s), concentration(s) Pump settings Incremental dose (PCA dose) Lockout interval (time between PCA doses) Total hourly limit Basal infusion (for opioid tolerant patients) Nursing bolus doses for breakthrough pain Initial loading dose instructions Maintenance of intravenous site either as heparin lock or for administration of fluids (access for emergency administration of reversal medications if necessary) Order to prevent other services from prescribing CNS depressants Monitoring instructions Specific observations that should be immediately communicated to the anesthesiologist (respiratory rate less than 6, systolic blood pressure less than 90 mm Hg) Instructions and treatment options for side effects Contact information if problems occur Date, time, and physician signature

syringes to avoid its inadvertent use in another patient, resulting in a potentially major medication error. S U M M A RY

The pharmacist is a valuable resource in the provision of appropriate pain management strategies. Pharmacists’ responsibilities are expanding beyond the roles of compounding, filling, and dispensing prescriptions with accuracy and appropriateness, and pharmaceutical supply management. As a member of a medication management team, the pharmacist can assist in the appropriate treatment for patients with acute pain. Pharmacists can ensure proper preparation of sterile products, adhering to the USP 797 recommendations. Pharmacists can facilitate the identification of medication errors and adapt corrective measures to prevent future misadventures. Having the guidance of an experienced pharmacist as a member of a medication management team can ensure patients receive the most appropriate pain management.

REFERENCES 1. Pharmaceutical compounding-sterile preparations. In: United States Pharmacopeia, and National Formulary, (USP 31-NF 26), Suppl 2. Rockville MD: United States Pharmacopeial Convention; 2008;3700–3734. 2. Hepler CD, Grainger-Rousseau TJ. Pharmaceutical care versus traditional drug treatment: is there a difference? Drugs. 1995;49:1– 10.

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3. Strand LM, Cipolle RJ, Morley PC. Drug-related problems: their structure and function. DICP Ann Pharmacother. 1990;24:1093– 1097. 4. Planas LG, Kimberlin CL, Segal R, et al. A pharmacist model of perceived responsibility for drug therapy outcomes. Soc Science Med. 2005;60:2393–2403. 5. Huang SW. The Omnibus Reconciliation Act of 1990: redefining pharmacists’ legal responsibilities. Am J Law Med. 1998;24(4):417–442. 6. McGivney SM, Meyer SM, Duncan-Hewitt W, et al. Medication therapy management: its relationship to patient counseling, disease management, and pharmaceutical care. J Am Pharm Assoc. 2007;47(5):620–628. 7. American Pharmacists Association, National Association of Chain Drug Stores Foundation. Medication therapy management in community pharmacy practice: core elements of an MTM service. Version 1.0. J Am Pharm Assoc. 2005;45:573–579. 8. Brushwood DB. From confrontation to collaboration: collegial accountability and the expanding role of pharmacists in the management of chronic pain. J Law Med Ethics. 2002;29:69–93. 9. F. The Joint Commission. FAQs for the 2008 National Patient Safety goals (updated March 2008). Available at: http://www. jointcommission.org/NR/rdonlyres/F770FD7F-C0F2-4454B4F8-C8D38D4559BB/0/2008 FAQs NPSG 08.pdf. Accessed September 08, 2008. 10. Cornish PL, Knowles SR, Marchesano R, et al. Unintended medication discrepancies at the time of hospital admission. Arch Intern Med. 2005;165:424–429. 11. Santell JP. Reconciliation failures lead to medication errors. Jt Comm J Qual Patient Saf. 2006;32(4):225–229. 12. The Joint Commission. History tracking report: 2009 to 2008 requirements. Chapter: provision of care, treatment, and services. Available at: http://www.jointcommission.org/NR/rdonlyres/ 5DA65D95-B0E4-42E6-ACAF-F867A9A8CDDB/0/OBS PC 09 to 08.pdf. Accessed September 08, 2008. 13. Singh RM, Wyant SL. Pain management content in curricula of US schools of pharmacy. J Am Pharm Assoc. 2003;43(1):34– 40. 14. Branding FH. The impact of controlled substance federal regulations on the practice of pharmacy. J Pharm Prac. 1995;8:130–137. 15. Scroccaro G. Formulary management. Pharmacotherapy. 2000; 20(10pt2):317S–321S. 16. American Society of Hospital Pharmacists. ASHP guidelines on formulary system management. Am J Hosp Pharm. 1992;49:648– 652. 17. Schechter LN. Advances in postoperative pain management: the pharmacy perspective. Am J Health-Syst Pharm. 2004;61:S15–S21. 18. American Society of Hospital Pharmacists. ASHP statement on the pharmacy and therapeutics committee. Am J Hosp Pharm. 1992;49:2008–2009. 19. Schachtner JM, Guharoy R, Medicis JJ, et al. Prevalence and cost savings of therapeutic interchange among U.S. hospitals. Am J Health-Syst Pharm 2002;59:529–533. 20. Kwan JW. Use of infusion devices for epidural or intrathecal administration of spinal opioids. Am J Hosp Pharm. 1990;47:S18– S23. 21. Carfagno ML, Schechter LN. Regional anesthesia and acute pain management: a pharmacist’s perspective. Techn Reg Anesth Pain Manag. 2002;6(2):77–86. 22. Schleis TG, Tice AD. Selecting infusion devices for use in ambulatory care. Am J of Health-Syst Pharm. 1996 53(8):868– 877. 23. Rothschild JM, Keohane CA, Cook EF, et al. A controlled trial of smart infusion pumps to improve medication safety in critically ill patients. Crit Care Med 2005;33:533–540.

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24. Carr DB, Reines HD, Schaffer J, et al. The impact of technology on the analgesic gap and quality of acute pain management. Reg Anesth Pain Med 2005;30:286–291. 25. Viscusi ER. Emerging treatment modalities: balancing efficacy and safety. Am J Health-Syst Pharm. 2007;64(suppl 4);S6– S11. 26. Strassels SA, McNicol E, Suleman R. Postoperative pain management: a practical review, part 1. Am J Health-Syst Pharm. 2005;62:1904–1916. 27. Holder KA, Dougherty TB, Porche VH, et al. Postoperative pain management. Int Anesthesiol Clin. 1998;36:71–86. 28. Littrell RA. Epidural analgesia. Am J Hosp Pharm. 1991;48:2460– 2474. 29. Peng PWH, Chan VWS. Local and regional block in postoperative pain control. Surg Clin North Am. 1999;79:345–370. 30. Paut O, Sallabery M, Scheiber-Deturmeny E, et al. Continuous fascia iliaca compartment block in children: a prospective evaluation of plasma bupivacaine concentrations, pain scores, and side effects. Anesth Analg. 2001;92:1159–1163. 31. Zohar E, Fredman B, Phillipov A, et al. The analgesic efficacy of patient-controlled bupivacaine wound instillation after abdominal hysterectomy with bilateral salpingo-oophorectomy. Anesth Analg. 2001;93:482–487. 32. Shafer Al, Donnelly AJ. Management of postoperative pain by continuous epidural infusion of analgesics. Clin Pharm. 1991;10:745– 764. 33. Candy TA, Schneider PJ, Pedersen CA. Impact of Unites States Pharmacopeia chapter 797: results of a national survey. Am J Health-Syst Pharm. 2006;63:1336–1343. 34. Tu YH, Stiles ML, Allen LV. Stability of fentanyl citrate and bupivacaine hydrochloride in portable pump reservoirs. Am J Hosp Pharm. 1990;47:2037–2040. 35. Oster Svedberg K, McKenzie J, Larrivee-Elkins C. Compatibility of ropivacaine with morphine, sufentanil, fentanyl, or clonidine. J Clin Pharm Ther. 2002;27(1):39–45. 36. Christen C. Johnson CE. Walters JR. Stability of bupivacaine hydrochloride and hydromorphone hydrochloride during simulated epidural coadministration. A J Health-Syst Pharm. 1996;53(2):170–173. 37. Johnson CE. Christen C. Perez MM. Ma M. Compatibility of bupivacaine hydrochloride and morphine sulfate. Am J HealthSyst Pharm. 1997;54(1):61–64. 38. Priston MJ, Hughes JM, Santillo M, Christie IW. Stability of an epidural analgesic admixture containing epinephrine, fentanyl, and bupivacaine. Anaesthesia. 2004;59:979–983. 39. Centers for Disease Control. Guideline for prevention of intravascular device-related infections. Am J Infect Control. 1996;24:262– 293. 40. Anonymous. ASHP guidelines on quality assurance for pharmacyprepared sterile products. American Society of Health System Pharmacists. Am J Health-Syst Pharm. 2000;57(12):1150– 1169. 41. Moote C. Efficacy of nonsteroidal anti-inflammatory drugs in the management of postoperative pain. Drugs. 1992;44(suppl 5):14– 30. 42. Krames ES. Practical issues when using neuraxial infusion. Oncology. 1999;13(suppl 2):37–44. 43. Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review. Am J Ther. 2002;9:53–68. 44. Ashburn MA, Lipman AG, Carr D, et al. Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Pain. 5th ed. Glenview, IL: American Pain Society; 2003. 45. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain. 2002;18 (suppl 4):S3–S13.

46. Strassels SA, McNicol E, Suleman R. Postoperative pain management: a practical review, part 2. Am J Health-Syst Pharm. 2005;62:2019–2025. 47. Carr DB, Jacox AK, Chapman CR, et al. Clinical practice guideline number 1: acute pain management: operative or medical procedures and trauma. Rockville, MD: Agency for Health Care Policy and Research, AHCPR publication no. 92-0032; 1992. 48. Gutstein HB, Akil H. Opioid analgesics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2007;569– 619. 49. Anderson R, Saiers JH, Abram S, et al. Accuracy in equianalgesic dosing: conversion dilemmas. J Pain Sympt Manage. 2001;21:397– 406. 50. Ripamonti C, Grof L, Brunelli C, et al. Switching from morphine to oral methadone in treating cancer pain: what is the equianalgesic dose ratio? J Clin Oncol. 1998;16:3216–3221. 51. Gan TJ, Ginsberg b, Glass PS, et al. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology. 1997;87(5):1075–1081. 52. Maxwell LG, Kaufmann SC, Bitzer S, et al. The effects of a small-dose naloxone infusion on opioid-induced side effects and analgesia in children and adolescents treated with intravenous patient-controlled analgesia: a double-blind, prospective, randomized, controlled study. Anesth Analg. 2005:100(4):953– 958. 53. Macario A, Weinger M, Carney S, et al. Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg. 1999;89:652–658. 54. U.S. Food and Drug Administration. FDA approves Entereg to help restore bowel function following surgery. Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01838.html. Accessed September 12, 2008. 55. U.S. Food and Drug Administration. FDA approves Relistor for opioid-induced constipation. Available at: http://www.fda.gov/ bbs/topics/NEWS/2008/NEW01826.html. Accessed September 12, 2008. 56. Lavine G. New drug to restore bowel function approved under new FDA rules. Am J Health-Syst Pharm. 2008;65:1204. 57. Mangino PD. Role of the pharmacist in reducing medication errors. J Surg Oncol. 2004;88:189–194. 58. Davis NM, Cohen MR. Today’s poisons: how to keep them from killing the patients. Nursing. 1989;89:49–51. 59. Institute for Safe Medication Practices. ISMP’s List of HighAlert Medications. Available at: http://www.ismp.org/Tools/ highalertmedications.pdf. Accessed September 12, 2008. 60. Institute for Safe Medication Practices. High alert medication feature: reducing patient harm from opiates. Available at: http:// www.ismp.org/Newsletters/acutecare/articles/20070222.asp. Accessed September 12, 2008. 61. Institute for Safe Medication Practices. An omnipresent risk for morphine-hydromorphone mix-ups. Available at: http://www. ismp.org/Newsletters/acutecare/articles/20040701.asp. Accessed September 12, 2008. 62. U.S. Food and Drug Administration. Manufacturer and User Facility Device Experience Database – (MAUDE). Available at: http://www.fda.gov/cdrh/maude.html#files. Accessed September 12, 2008. 63. U.S. Pharmacopeia Quality Review. Patient-controlled analgesia pumps. Available at: http://www.usp.org/pdf/EN/patientsafety/ qr812004-09001.pdf. Accessed September 12, 2008. 64. Institute for Safe Medication Practices. Safety issues with patientcontrolled analgesia: part I – how errors occur. Available at:

Role of the Pharmacist http://www.ismp.org/Newsletters/acutecare/articles/20030710. asp. Accessed September 12, 2008. 65. Anonymous. Failure mode and effects analysis: a hands-on guide for healthcare facilities. Health Devices. 2004;33(7):233– 243. 66. Institute for Safe Medication Practices. Part II – How to prevent errors – safety issues with patient-controlled analgesia. Available at: http://www.ismp.org/Newsletters/acutecare/articles/ 20030724.asp. Accessed September 12, 2008. 67. Institute for Safe Medication Practices. IV potassium given epidurally: getting to the “route” of the problem. Available at:

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http://www.ismp.org/Newsletters/acutecare/articles/20060406. asp. Accessed September 12, 2008. 68. Institute for Safe Medication Practices. Epidural-IV route mixups: reducing the risk of deadly errors. Available at: http://www. ismp.org/Newsletters/acutecare/articles/2008070360406.asp. Accessed September 12, 2008. 69. Institute for Safe Medication Practices. ISMP 2007 Survey on high-alert medications: differences between nursing and pharmacy perspectives still prevalent. Available at: http://www.ismp. org/Newsletters/acutecare/articles/20070517.asp. Accessed September 12, 2008.

SECTION V

Pain Management and Patient Outcomes

39 Economics and Costs: A Primer for Acute Pain Management Specialists Amr E. Abouleish and Govindaraj Ranganathan

Healing is an Art. Medicine is a Science. Healthcare is a Business. – Author unknown

worth the risk. Because the plan is about the future, there must be assumptions made in the plan. Assumptions are based on either “current market conditions” (based on surveys or current contracts) or economic studies. The most common studies are cost minimization, cost-benefit, or cost-effective studies. The studies are focused on a specific issue and are not the same as business plans. Further, other assumptions may be considered the best estimate (or “guess”). Therefore, to understand and develop business plans, one must understand the issues of revenue, costs, and economic studies.

As much as each one of us would like to concentrate only on our patients and their families, the reality is that health care is a business. In addition, your treatment decisions will affect not only your revenue and costs but often the costs of other parties, including your patients, the hospital, and third-party payers. Because these other parties have an economic interest in your medical decisions, if you are not involved in and do not understand the economic issues, then others will make policies and rules that will significantly affect how you practice and what treatment options are available to your patients. Economics is defined as the science that deals with the production, distribution, and consumption of goods and services. The underlying fact is that resources are limited. Therefore, the economic problems faced by all of us are (1) the goods and services produced, (2) how they will be distributed, and (3) who will consume or use them. These economic questions are not limited to health care and acute pain management; they also exist for us as a society and for each of us personally. The goal of this chapter is not to present brand new concepts but to explain concepts and principles that each of us use in everyday life and show how these same concepts also exist in our professional life. In addition, the chapter should also provide the right terminology to explain and understand the economic issues in acute pain and health care.

PERSPECTIVES

Figures don’t lie, liars figure. There is much truth to this colloquial saying. The basic understanding of perspectives when dealing with economic analysis – business plans, economic studies – is a requirement to avoid drawing the wrong conclusions. Without this understanding, you are at the mercy of the person who is doing the analysis. Perspective is defined as the following: in any economic analysis, the revenue and costs included depend on what is determined as relevant. This concept of perspective – personally, professional, hospital, patient, society – will be seen throughout this chapter and is the underlying principle you must understand! REVENUE

Because a business plan is based on both costs (present and ongoing) and revenue (future), we will cover both of these topics. From the professional perspective, the increase in revenue should be directly proportional to an increase in services as long as those services are billable. The major determinants of the revenue expected are the estimated payer mix, either current or predicted, and the estimated number of procedures. For example, if you predict that you will do 10 epidural catheter placements with initial consult and one follow-up, and the payer mix will be

BUSINESS PLANS VERSUS ECONOMIC STUDIES

Before proceeding, the differences in the concepts of business plans and economic studies must be discussed. Simply, business plans are used to convince a person or group of persons that spending money today will result in a return of that money and more in the future, that is, the “return on investment” (ROI) is 623

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Table 39.1: Estimated Revenue CPT

Fee Weighted Average

Medicare 25%

Medicaid 25%

Commercial 50%

99253

$112.78

$108.67

$72.83

$134.80

Epidural catheter placement

62319

$238.25

$89.96

$150.02

$356.50

Follow-up

01996

$92.82

$54.63

$46.65

$135.00

$443.84

$253.26

$269.50

$626.30

Consult

Total per epidural Total for 10 epidurals

$4438.40

Note: Medicare and Medicaid fees are for 2007 Texas; commercial rates are estimates.

25% Medicare, 25% Medicaid, and 50% commercial, then the evaluation would be as in Table 39.1. However, taking the hospital perspective, the additional acute pain procedure does not change the hospital revenue, that is, the “per diem” payment (commercial payers) or “DRG” payment (governmental payers). Therefore, why should the hospital incur the additional costs and risks of the additional services? The adequate management of acute pain is important for hospitals for three major economic reasons. First, the Joint Commission on Accreditation Health Care Organizations (JCAHO) has made pain management important in 2000 with the publication of Pain Management Standards for hospitals.1 Because of these JCAHO standards, hospitals must now incorporate acute pain management in policy and procedures throughout the facility. Therefore, hospitals must commit financial resources toward pain management. Although no direct increase in revenue may occur from an increase in acute pain management services, there is still a nonfinancial benefit to the services. Further, by having

acute pain specialists at the facility, the hospital can rely on them to help with education of staff on pain management. The second reason is that improved acute postoperative pain management can result in increased patient mobility.2 Increased mobility has been shown to reduce postoperative complications, (eg, pneumonia, ileus) and length of stay.3 Further, with adequate pain management, including with the use of regional blocks and indwelling catheters, surgical procedures that have traditionally required inpatient postoperative care can be performed as ambulatory surgery.4,5 Although there is no change in hospital revenue (assuming the revenue is relatively fixed by procedure), as discussed below, the ambulatory patient reduces the cost and hence the net profit per procedure increase.6 Finally, the third reason is that improved acute pain management can be used for marketing of the hospital as well as the all-important “word-of-mouth.” What can be a better marketing tool than “painless” surgery. In fact, a surgeon, who may

Perspective Everyday Example A school decides that a half-day school day (with the other half for staff education) costs the school district nothing and results in no loss of revenue. In fact, there is an added-value of staff education and satisfaction without any costs! The administrators make this conclusion because they focus only on the school’s perspective. A half-day results in the same costs as a full day. The revenue from taxes and the government is the same, because it is considered a day of school. So having a half-day does not cost the district anything and, at the same time, allows them to have staff education time (added value to the school employees). However, if the perspective of parents is considered, the conclusions would be different. Working parents must make child care arrangements or even take the day off work, all resulting in costing the parents money and even lost salary. Hospital Example A hospital administrator determines that 24-hour epidural services for obstetric patients is a good business decision. The administrator determines that even though there is a small cost (cost of medications and epidural kit), the increase in revenue from increase in market share will easily outweigh the cost. However, if the physician (anesthesiologist) perspective is included in the hospital administrator’s evaluation, the costs of providing the service must include the costs of 24-hour on-call services even when no cases are done. From a laboring parturient’s perspective, there is no real increase in cost (covered by the patient’s third-party payer). Hence, solely from the patient’s perspective, the 24-hour labor epidural service is all benefit without cost.

Economics and Costs

Cost Centers Everyday Example Hospital economics are similar to those of a restaurant that offers all-you-can-eat buffet meals. For the restaurant, once the customer has paid his/her entrance fee, the goal is to serve the patient at a cost less than the entrance fee. If the restaurant is successful, then the restaurant makes a profit. Hence, the restaurant manager must view the buffet as a “cost center” rather than a “revenue-center.” Fortunately for the restaurant, if the manager calculates the costs correctly, then he/she can set the entrance fee higher than the costs. Without an understanding of costs, the restaurant manager is only guessing (and praying) that he/she set the entrance fee correctly.

be reluctant to have pain management procedures to be done on his or her patients may become the best proponent of the procedures if the benefits of this “word-of-mouth” increases the number of referrals to his or her practice. COSTS

Unlike revenue, the costs of services is often much more difficult to determine. The final cost analysis is very much dependent on which costs are included and which are excluded (perspective). Without an understanding of costs, you cannot evaluate any business plan properly nor can you be effective in cost analysis projects initiated by your hospital or other entities (eg, government or third-party payers). As noted above, for many hospitals, the revenue from a patients’ procedure or hospitalization is fixed. That is, once the patient arrives at the hospital, one cannot change the revenue expected. Hence, the management challenge is to reduce and control costs to improve the net profit from the stay. For health care providers, one must know what the costs of a service are to be able to determine what fee is needed to earn a profit. Without understanding costs, the provider is only guessing that the service is profitable or the negotiated fee is a good contract. Unfortunately, with government payers, negotiations are not possible, and one must either reduce costs below the government fee or lose money on every patient.

Costs Definitions7–9 Simply viewing costs as the cost of buying a product is incorrect and simplistic. Further, whoever determines what costs are included or excluded will have great influence on the findings of the analysis. Therefore, an understanding of how costs are defined and categorized will allow one to have the tools to be able to participate in any cost analysis efforts effectively.

Costs Are Not Charges Because hospital costs have not been easy to determine, many analysis have relied on charges and the estimate of costs by the

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cost to charge ratio. Unfortunately, by using charges, improper findings can occur. Charges may or may not be related to revenue, but they are not related to actual costs, because a consistent cost to charge ratio does not exist between hospital services.7 In a study evaluating the cost of inpatient surgeries, Marcario et al used a cost information system to determine costs of hospital services and the charges associated with each. The overall ratio of cost to charge was 0.42, but this ratio was not consistent. For those departments with a high ratio, charge analysis using the overall ratio would underestimate the costs of these services. For instance, if the departmental ratio was 0.8, then the costs were 80% of the charges. But when the overall ratio is used, the cost of the department would be calculated as 42% of charges and hence underestimating the actual costs. Similarly, a department with a low ratio would be incorrectly viewed as having higher costs. For anesthesia services, the ratio was 0.29 and hence in the past with charge-based analysis, the anesthesia services’ costs were overestimated. Fortunately, many hospitals have begun to use cost-accounting systems to track estimated costs rather than simply relying on charge data.

Explicit, Implicit, and Total Cost Costs can be simply defined is what someone is willing to sacrifice for a good or services. Explicit costs are the monetary payment for the goods or services. In contrast, implicit costs occurs when no monetary transaction occurs. The total cost is the sum of explicit and implicit costs. Explicit costs are easy to determine; simply what someone is willing paying for the good or service. If you are the provider of the good or service, you set the price (or cost to the buyer) based on the market demand and supply. With the introduction of Ebay and other internet selling Web sites, determining value of a good has been simplified! However, implicit costs are not as easily identifiable and are often overlooked. In addition to implicit and explicit cost categorization, costs can be grouped in two other ways: direct, indirect, and intangible and then fixed and variable. Each grouping is important for evaluating the economics of a project or service.

Total Costs = Explicit + Implicit Costs Everyday Example: The Cost of Landscaping Your Yard If you do it yourself, often you only include the explicit costs, that is, the amount you pay at the nursery for supplies (bushes, flowers, dirt, etc). Often, you forget to include your implicit costs (eg, cost of your own labor and the cost of acute back pain). Acute Pain Management Example: The Cost of IV PCA Often, the cost of IV PCA is quoted to be a small number (eg, $8 per patient). This cost is limited and includes only one of the explicit costs (ie, the acquisition cost of the morphine PCA cartridge). (Some additional explicit costs are the cost of the actual pump and the tubing.) Implicit costs are often overlooked, for example, labor costs, including nursing (2 nurses are required to check the PCA settings, evaluation of the pain control), pharmacy, biomedical engineering, and transportation.

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Direct, Indirect, and Intangible Costs Acute Pain Management Example Direct costs: Labor costs of patient care (physician, nurse practioner, physician assistant, resident, nurse’s aide), medications, hospital room (bed days), catheters and kits, IV equipment Indirect costs: Laundry, security, hospital president, billing office, loss of workdays (patient and family), loss of livelihood Intangible costs: Pain and suffering, stress on family from inadequate pain relief, stress on nursing staff

Direct, Indirect, and Intangible Costs Direct costs are the costs related to directly with the service or goods produced. For health care, these are costs directly involved with patient care. Indirect costs are not related directly to patient care but support patient care. Finally, intangible costs are costs that are difficult to quantify but are important depending on the perspective of the cost analysis. When evaluating the net profit (as defined as revenue minus costs), if only direct costs are included, there may be a profit, but when indirect costs are included, there may be a loss. Unfortunately, often a decision is made to close a unit or clinic because of overall loss. This decision may be a poor economic one, if direct costs show a profit. The reason is that the clinic to be closed helps pay some of the allocated indirect administrative costs. Without the clinic, all the other services must now cover this cost. By closing the clinic, one may actually lead to the other clinics going from net profit to net loss because of the increase in indirect costs that are allocated! As one can see, which costs are included can change the final answer. Further, which intangible costs and how to quantify them becomes extremely important to the analysis. Again, the only way to be assured the costs that you feel are important are included is to be involved in the planning. When asked by an administrator to be involved with committees that examine patient care or budgets, you should respond with a resounding yes. Fixed and Variable Costs A fixed cost does not change with a change in the quantity of the goods or services provided. In contrast, a variable cost does change directly with a change in quantity. For health care, a variable cost increases with each service provided. The most commonly identifiable variable costs are medications. However, fixed costs do not increase with a change in the number of patients. An example is the cost of an anesthesia machine. Labor costs over the short run are fixed. That is to staff a unit or a pain management service for the next month, the staffing costs are fixed. However, over the long run, staffing can be adjusted. So if there is a projected increase in staff next year, one can vary the staffing given enough time. The use of locums tenens or agency staffing allows for some flexibility but for most positions the above is true. One of the greatest mistakes that cost analysis studies do is to assume that fixed costs are variable costs. In anesthesia care, we see this mistake when newer agents or equipment wish to tout

that their increase costs are offset by saving minutes or even an hour of a stay in a unit, for example, the operating room (OR) or postanesthesia care unit. Just because the hospital charges or allocates costs by time (cost per minutes of stay), this does not mean the actual costs are variable by the minute. If a hospital determines that an OR is to be staffed, then the staffing for that OR is fixed. It does not matter if 1 patient is scheduled for 1 hour or 2 hours, the staffing costs are the same for that day.

Total, Average, and Marginal Costs The total cost of a service has been defined above as the sum of explicit and implicit costs. Another way is to define it as the sum of fixed and variable costs. In this situation, the term average total costs is used to signify that the fixed costs is spread out among all the services produced. For example, if in the morning, the fixed costs for an OR staffing is deteremined. If one patient is done, then the fixed costs associated per patient is the fixed costs

Fixed or Variable Costs? It is not often that scientific journals allow sarcasm to illustrate a point, but the editors of Anesthesiology made a great decision when they chose to publish the following letter to the editor: Cost Savings in the Operating Room by Jay B. Brodsky, MD To the Editor: Because of the growing costs of medical care, we have been asked to modify our practices to be more fiscally responsible. In our area, the operating room, we have undergone periodic operations improvement (OI) efforts to reduce unnecessary expenses. Nurses have been replaced with technicians, and physicians have been asked to work “more efficiently.” We have found a simple way to significantly reduce expensive operating room time without jeopardizing patient care. Rather than moving patients on the count of three (“1-2-3” move) as had been our practice, we now count only to two (“1-2” move). Because for every case, each patient is moved to and then from the operating room table we now save 2 s per patient. We have 30 operating rooms, each with an average of 3 operations per day, so our projected savings are 180 s or 3 min per day. Approximately 600 min can be saved over the course of a year by this simple maneuver. Our operating room time costs $20/min. Thus, we can save $12,000 per annum by counting only to two. More importantly, the additional 10 h of operating room time is sufficient for another three to five cases to be performed. With the acceptance and success of the “move-ontwo” maneuver, we have initiated a pilot study of a “move-on-one” maneuver. Initial reports suggest that this can be just as safely and successfully done and will lead to a doubling of efficiency (i.e., saving time and money) over the next fiscal year. Anesthesiology 1998;88:834

Economics and Costs

Total

Costs

Average Fixed Costs Marginal

1

A

Number of Patients Figure 39.1: Total, average, fixed, and marginal costs.

divided by 1. However, if 3 patients are done, then the fixed costs is divided by 3 and hence the fixed cost per patient is reduced. The marginal cost is the change in total costs that results in providing 1 more service. Generally, this is simply the variable costs associated with the additional service. Continuing with the above example, the marginal cost of taking care of 1 more patient once the OR is staffed is simply the variable costs. Hence, the average total cost per patient is the average fixed costs + variable costs (Figure 39.1).

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For a given range, this average total costs will continue to decrease as the number of patients increases (a spread of the fixed costs among more patients). At some point, the number of patients will result in a need for increasing staffing (could be a second OR or afternoon shift), and hence the fixed costs will go up. This situation is also true for clinics (hiring more staff and leasing additional space) and for acute pain services (hiring more staff). The most difficult decision is when to hire the additional staff. Does one hire the additional staff to meet expected growth? In this way, one keeps the good level of service that has been seen in the past, but, on the other hand, one takes the risk that the volume will not grow to cover the costs. Or does one wait until the demand is too much for current staff and then hire the additional staff. In this way, one does not take a risk of increased staffing but does risk losing business because of inability to meet the demands in timely manner. In Figure 39.1, this point is “Point A” in the x axis. The average costs per patient continues to decrease because the fixed costs are spread among more patients. At point A, there is a need to hire more staff and/or more space.

Opportunity Costs The final category of costs is opportunity costs. The definition is simply stated, “If you spend it here, you can’t spend it there.” Because resources are limited, the decision spend resources on a service or good over another service or good is an example of opportunity costs.

Total, Average, Marginal Costs Everyday Example An athletic club is a great example of fixed and marginal costs. When the owners build and equip an athletic club, most of the costs are fixed. The costs of the exercise machines, free weights, the aerobics room, the locker room, and the utilities are fixed. They do not change if one person comes and works out or if 100 do. The staffing costs over the short run are fixed as well. So what is the cost of having 1 more member? That is the marginal cost associated with one more member, which include administrative costs (member data entry, billing), small utilities costs, and maybe some maintenance costs. Hence, each new member will result in profit when examining the marginal costs and the new revenue. If the owner looks at the total costs, initially, each new member will be assigned a net loss because of the fixed costs. But it would be incorrect to say that the owner should then not sign up new members. In fact, in the business plan, the owner has a break-even point where the fixed costs is spread among enough members that the monthly dues result in no loss when total costs are included. In another example of spreading the costs over a large period is the example of home decorating, specifically, window treatments. We are confident that in many households, the argument for accepting the high cost of window treatments is that the cost is not really for 1 year but for the lifetime of the house (decades and decades). The cost per year is not much. (The same argument is made about furniture and kitchen appliances.) Anesthesiology Example When looking at professional charges for anesthesia care, base units per case can be viewed as the fixed “cost” and time units as the “variable costs.” The average units billed per hour care is very dependent on surgical duration. For a short case, the base units per case is only spread out over a short period, whereas for long cases, the base units is spread out over many hours. For example, a 1-hour 7-base unit case has an average ASA units per hour of 11 units (7 base + 4 time units divided by 1 hour). However, the same 7-base unit case that takes 4 hours has an average ASA units per hour of less than 6 units (7 base + 16 time units divided by 4 hours).11

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Opportunity Costs Everyday Example Everyday, we make many decisions where we are limited with a resource and decide to spend it on one activity or good over another. These include decisions that require spending or saving money. But we also make these decisions in our time management because time is a limited resource; for example, should I spend time writing a chapter or play golf or play with the kids?

In health care, opportunity costs may be explicit costs (ie, spending dollars on staffing or equipment instead of another service or equipment). Although staffing costs are considered fixed over the short run, what the staff spends time doing can also illustrate opportunity costs. For example, if a patient has adequate pain management from a regional block, then the floor nurse will spend less time managing the patient’s pain (eg, assessing pain, answering questions of the family, contacting physician, administrating medications, and even witnessing medicationsbeing wasted) and have more time doing other activities (eg, patient education, quality improvement projects, finishing nursing documentation during the shift rather than after the shift is over). Although the improved pain management may not show up as cost savings on the hospital accounts, the opportunity costs of having to spend time on pain management may end up leading to increased costs in long run (eg, with staff dissatisfaction, having to recruit and train new staff).

are not the same, then a cost-benefit or cost-effective study must be performed.

Cost Minimization The underlying assumption of a cost minimization study is that the end points of care are the same. Hence, the question is which intervention will allow one to get there for the least amount of money. The major advantage is that these studies are easy to understand and do. The major disadvantages are that the equal end points assumption may be disputed and that the costs included or excluded may also be questioned. Often, the only costs included in the study are explicit costs (ie, the costs that the accounting system can identify as money spent). The most common example in the hospital is the evaluation of which medication should be on the formulary. If there are two types of medications that provide the same effect, then the hospital often focuses only on the acquisition costs. The costs of administrating the medications are often ignored (even when one is once a day and another 3 times a day). In addition, for many medications, the end points are not necessarily identical. A worse situation is when this type of analysis is done to two different types of services focused on the same problem. In acute pain management, an administrator may want to do a cost minimization study comparing IV PCA with continuous femoral nerve catheter infusion for acute pain management after total knee replacement surgery. Clearly, these two “services” do not lead to identical end points (as defined as pain management, mobility, physical therapy). But still the analysis may be done. Adding insult to injury, the analysis may only look at acquisition costs rather than total costs!

Cost-Benefit and Cost-Effective PERSPECTIVES AND SYSTEM THINKING

As one can see, the costs included in any analysis and possible benefits depend on what perspective is used. Specifically, in examining acute pain management, a larger perspective than simply the service provided should be examined. The improvement in acute pain management improves many aspects of the health care provided and outcomes. Although direct cause and effect is often difficult to establish, even the JCAHO recognizes the connection. When taking a larger perspective, then one begins to use system thinking. Although it is easier to view everything from one’s own perspective, we all work in a system. For example, if better acute pain management is provided, there may be less chance of developing a chronic pain condition and the associated costs (direct health care costs and indirect in loss of work and livelihood). In the discussions of economic studies, the concepts of system-thinking and perspective will determine what kind of study is performed, and many times, the outcome of the study. ECONOMIC STUDIES

Three types of economic studies or cost analyses can be done. They are categorized as cost minimization, cost-benefit, and cost-effective. Cost minimization is the easiest to do and understand, but requires that the end point or benefits of treatment are identical between the therapies evaluated. If the end points

If the end points are not the same, then a cost-benefit or a costeffective study should be performed. They are relatively the same except that in the benefit studies, the outcomes are assigned a monetary value, whereas in the effectiveness studies, the outcomes are converted to arbitrary units. The advantage is that these types of studies can be used to compare different benefits and the respective costs. The disadvantage is the valuation of costs, benefits, and outcomes are often very subjective.

Cost Minimization versus Cost-Benefit/Cost-Effective Studies Everyday Example What kind of car do you drive to work? How do you decide which car to drive? If you believe that any working car will suffice because the end point (ie, arriving to work on time) is identical, then you should use a cost minimization analysis to choose the car. This way you will choose the least expensive car that you can find. If you choose to spend more money on the car, then you have done a cost-benefit or cost-effective analysis without even realizing it. Further, in determining which of the extra features to get with the new car, you also weighed in the opportunity costs.

Economics and Costs

It is very important to note that these studies are done only if the more expensive service or therapy is more effective or has more benefits. In other words, if the better service or therapy costs less, then why do an analysis? Only when it costs more does one need to determine if it is worth the money spent. Some of the end points used in cost-effective studies include quality adjusted life-years (QALYs), life-years gained, and days off work. Because QALY is used in looking at long-term outcomes, one needs to be familiar with the term. QALY is used to report on the quality of everyday life (as based on medical conditions) and not simply survivability. In studies that use QALY, a numeric value for a year of life is given with the value of a year of life ranging from 1 (perfect health) to 0 (equivalent to death). The basis of this valuation is the patient. That is, the patient is asked to value what a year living with the medical condition is compared to living a year in perfect health. In most cases, this measurement is used looking at chronic pain conditions (eg, chronic back pain). Most valuations are done using a health survey. In a study comparing surgery to rehabilitation, patients who chose surgery for chronic back pain valued their current state at 0.35 QALY (ie, each year with the pain = 0.35 year of perfect health) and those that chose nonsurgical therapy valued their state at 0.41 QALY.11 In evaluating costs of therapy, improvements in QALY is used as a denomitator to compare $spent/QALY. For acute pain, this benefit study would be used in the examination of preventing chronic pain syndromes.12 In contrast, a cost-benefit study gives monetary values to benefits. In acute pain perspective, how should the valuation of “no pain” be done? Because of the use of survey, the amount patients will pay will be dependent on previous experience of pain, cultural, anxiety, and other factors.13 C O N C LU S I O N

As pain management specialist, you can no longer ignore the pressure of cost control that the hospital must respond to to succeed. In fact, changing perspective to a more system thinking approach will allow you to argue that not only is pain management an added-value for the hospital, but the hospital should spend more resources toward pain control! Further, if you are not involved in the process of evaluating and determining where resources will be spent, some one else, including someone who is not a physician, may end up making decisions that affect how you will practice.

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REFERENCES 1. Phillips DM. JCAHO pain management standards are unveiled. JAMA. 2000;284:428–429. 2. Pham DC, Gautheron E, Guilley J, et al. The value of adding sciatic block to continuous femoral block for analgesia after total knee replacement. Reg Anesth Pain Med. 2005;30:128–133. 3. Beaussier M, Weickmans H, Parc Y, et al. Postoperative analgesia and recovery course after major colorectal surgery in elderly patients: a randomized comparison between intrathecal morphine and intravenous PCA morphine. Reg Anesth Pain Med. 2006;31:531–538. 4. Williams BA, Kentor ML, Vogt MT, et al. Economics of nerve block pain management after anterior cruciate ligament reconstruction: potential hospital cost savings via associated postanesthesia care unit bypass and same-day discharge. Anesthesiology. 2004;100:697–706. 5. Ilfeld BM, Mariano ER, Williams BA, Woodard JN, Macario A. Hospitalization costs of total knee arthroplasty with a continuous femoral nerve block provided only in the hospital versus on an ambulatory basis: a retrospective, case-control, cost-minimization analysis. Reg Anesth Pain Med. 2007;32:46–54. 6. Williams BA. For outpatients, does regional anesthesia truly shorten the hospital stay, and how should we define postanesthesia care unit bypass eligibility. Anesthesiology. 2004;101:3–6. 7. Macario A, Vitez TS, Dunn B, McDonald T. Where are the costs in perioperative care? Analysis of hospital costs and charges for inpatient surgical care. Anesthesiology. 1995:83:1138–1144. 8. Watcha MF, White PF. Economics of anesthetic practice. Anesthesiology. 1997:86:1170–1196. 9. Sperry RJ. Principles of economic analysis. Anesthesiology. 1997:86:1197–1205. 10. Abouleish AE, Prough DS, Whitten CW, Zornow MH. The effects of surgical case duration and type of surgery on hourly clinical productivity of anesthesiologists. Anesth Analg. 2003;97:833– 838. 11. Rivero-Arias O, Campbell H, Gray A, Fairbank J, Frost H, WilsonMacDonald J. Surgical stabilisation of the spine compared with a programme of intensive rehabilitation for the management of patients with chronic low back pain: cost utility analysis based on a randomised controlled trial. BMJ. 2005;330:1239– 1245. 12. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery: a review of predictive factors. Anesthesiology. 2000;93:1123–1133. 13. Macario A, Fleisher LA. Is there a value in obtaining a patient’s willingess to pay for a particular anesthetic intervention. Anesthesiology. 2006;104:906–909.

40 Evidence-Based Medicine Tee Yong Tan and Stephan A. Schug

the results of research, other forms of scientific evidence, pathophysiologic reasoning, clinician’s experience, and patients’ preferences when making health care decisions.5,6 Clinical practice guidelines can be defined as “systematically developed statements to assist in clinicians’ and patients’ decisions about appropriate healthcare for specific clinical circumstances.”7 Thereby, evidence-based medicine provides both clinicians and patients with a structured process to guide them in making decision to achieve the outcome they desire.5

T H E G R OW I N G E M P H A S I S O N E V I D E N C E I N AC U T E PA I N M A NAG E M E N T

The pharmacology of and techniques in managing acute postoperative pain have improved dramatically since the late 1990s. But despite these advances, acute postoperative pain is still poorly managed, with 29.7% of postoperative patients having moderate-severe pain and 10.9% of postoperative patients having severe pain.1 In parallel, since the late 1990s, there has been an increased awareness of the suffering associated with acute postoperative pain and the importance of perceiving pain relief as a basic human right. This concept has received widespread endorsement from various international bodies such as the International Association for the Study of Pain (IASP) and the World Health Organization (WHO).2 The Australian and New Zealand College of Anaesthetists (ANZCA), in the year 2001, published its statement on patients’ rights to pain management.3 The statement explicitly points out the patients’ right of access to appropriate and effective pain management strategies, thus making the link between treatment strategies and supporting data. To further highlight the importance of evidence in the practice of acute postoperative pain management, The Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine produced the second edition of the book Acute Pain Management: Scientific Evidence.4 This document helps to guide clinicians in their practice of evidence-based medicine (EBM) in the arena of acute postoperative pain management; it will be discussed in more detail later in the chapter. Thus the understanding of the various principles, methodology, and limitations of EBM is critical to the successful translation of the scientific developments in the area of acute pain medicine into routine clinical care.

D I S T I N G U I S H I N G F E AT U R E S O F E B M

In the analysis of evidence, EBM emphasizes the importance of ensuring that any recommendation provided is comprehensive, critical, and explicit.8 ■

■

■

Comprehensiveness ensures that all available evidence is examined rather than that of a particular point of view, tradition, or belief. Critical appraisal looks into the quality of each of the evidence, its strengths and weaknesses, and its validity in the context of the clinical question. Last, explicitness ensures that the process of EBM is transparent and open to scrutiny by both peers and the public.

In the application of EBM, there are two major principles that guide decision-making. First, it is important to realize that pure evidence on its own is often inadequate in the multitude of differing clinical scenarios, and, second, there is always a hierarchy of evidence and no two statements of evidence are equal.9 Contrary to common beliefs and fears, EBM does not attempt to convert clinical practice into “cookbook” medicine.8 Clinicians have to be acutely aware that evidence alone cannot be the sole guide to our clinical practice. There is a need to synthesize the available evidence with a multitude of other factors that will influence the clinicians’ decision-making process. Such factors include the strength of the evidence, the potential

W H AT I S E V I D E N C E - B A S E D M E D I C I N E ?

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benefit and associated risk from the intervention, differing values among fellow clinicians, and the patient’s expectation and belief systems.9 An example would be the heightened concerns among surgeons with regard to the stimulating effects of epidural analgesia on bowel activity perioperatively and its potential risk of anastomotic leakage although there may not be evidence to support these claims.10 Such beliefs would directly influence the anesthetist’s practice with regard to the use of epidural analgesia for bowel surgery. In supporting decisions, EBM involves in addition to best current evidence the needs of the population and their value system. The needs of a population are influenced by disease patterns in this particular population and the resources available.11 In situations where resources are scarce, the implication is that any resource spent has an opportunity cost attached to it. Thus, improving acute pain management could diminish resources made available to other aspect of medicine. Furthermore, the value system of the population, represented frequently by the politicians of the country, will support decisions that best suit the interest of the population – which may not be evidence based but value based.11 An example would be the availability of opioids in many third-world countries. Although there is wide ranging evidence supporting the use of opioid in acute postoperative pain and cancer pain management, opioids for medical use are still not readily available in a large number of countries. In an attempt to correct this, the WHO, in collaboration with the IASP and the International Narcotics Control Boards, is working on approaches to make decisions on the national availability of opioids more rational and less driven by “opiophobia.”2 In the formulation of evidence-based guidelines, it is important to understand that there is frequently a lack of available evidence to provide a substantial recommendation.7 Available evidence may range from poor-quality evidence with limited internal or external validity to well-performed randomized controlled trials. Moreover, grading the quality of the evidence is critical, as is clearly stating or reporting the quality of evidence available. This practice allows clinicians to have a better idea of the presence or absence and level of evidence relevant to their practice. A hierarchy of available evidence will allow clinicians to formulate a clear course of action for the patient.9 EVIDENCE-BASED AND E X P E RT- B A S E D O P I N I O N

Evidence-based medicine has the potential of answering questions in situations where our clinical impression can actually cause more harm than good. Thus evidence-based medicine can provide clinicians with the necessary data to help overrule theoretically logical or belief-based, but potentially harmful, decisions.5 An example would involve the practice of adding a background infusion to intravenous patient-controlled analgesia (PCA) in an attempt to improve pain control and sleep in patients after a major surgical procedure. An examination of this practice using evidence-based techniques reveals that it does not improve pain relief or sleep or reduce the number of PCA demands (RCT based, ie, level II evidence), but increases the risk of respiratory depression (case series based, ie, level IV).4

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In addition, evidence-based medicine aids medical professional bodies in becoming more transparent in their practices by establishing standards and guidelines. Such changes have proved to be timely in the current global trend of increasing professional accountability.5 However, expert opinion will always remain an essential component in all evidence-based guidelines. Such expert input includes the subjective assessment of strength and generalizability of evidence and, when evidence is not available, providing recommendations based on opinion. Often such expert opinions are also needed to fill gaps that result either from areas of medical practice not yet scrutinized by randomized controlled trials or from areas where such evidence will never be obtainable (eg, for ethical concerns or because of the size of RCTs required to identify statistically rare benefits or adverse effects of a therapeutic intervention). The EBM document of ANZCA quoted above has therefore introduced a class of statements described as “Clinical practice points: Recommended best practice based on clinical experience and expert opinion.”4 A typical example of such a statement would be: “Self-reporting of pain should be used whenever appropriate as pain is by definition a subjective experience.” Expert opinion on the other hand is subject to a series of problems on its own. These include the bias, which arises from personal experience, and bias, selective use of evidence and external influence (eg, medicolegal concerns, patient’s pressure and business interest).8 D E V E LO P I N G E V I D E N C E - B A S E D P R AC T I C E GUIDELINES

Systematic reviews and meta-analyses have become a widely used technique to aid clinicians in summarizing and expanding their existing medical knowledge. Systematic review is defined as a formal process of identifying, appraising, and evaluating primary studies and other relevant research to draw conclusions to a specific issue.12 A systematic review becomes a meta-analysis when statistical technique is applied to synthesize the data collected from the numerous trials to generate a pooled estimate of the treatment effect or other end points.13,14 In systematic reviews and meta-analyses, as more than one trial is being examined for a particular intervention, the summation of the result should provide the best available evidence.14 To allow clinicians to practice with confidence, it is important for the clinician to know the processes by which recommendations are generated. These involve 4 main steps, namely5 : ■ ■ ■ ■

asking the right question searching the literature (both published and unpublished) for source of data appraising and evaluating the data collected answering the question posed using the collected data

SYNTHESIZING MEDICAL EVIDENCE

Evidence-based medicine is facilitated by converting information obtained from thousands of individual studies into userfriendly risk estimates.5 One useful tool that clinicians can readily understand and apply for weighing the benefits and risks of

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Tee Yong Tan, Stephan A. Schug

various treatments is the concept of number needed to treat/harm (NNT/NNH), respectively. The NNT is the number of people who need to be treated for 1 to achieve a specified level of benefit in comparison to placebo treatment. This number can be easily calculated from either raw data or from statistical estimates and applied to various end points.15 Furthermore, such numbers allow easy comparison between various analgesic agents with a common outcome (at least 50% pain relief compared with placebo). NNT can then be used as a yardstick whereby an alternative therapy can be measure. But it is also important for users to remember that NNT is always relative to the comparator and applies only to a specified clinical outcome.16 Further concerns regarding the pooling of data from various different pain models in an attempt to base NNT calculations on the largest possible numbers are discussed later in this chapter. Another limitation in the usage of NNT is that it can be applied only to data that are dichotomous. This means that the question must be answerable with either a yes or no. In the realm of pain relief, gradual analgesic effects cannot be considered and setting a cutoff at 50% pain relief compared to placebo may at times make this a difficult target to achieve. Thus, if an analgesic is capable of producing 30% pain relief in a patient, which might be a clinically relevant effect, then it will be deemed to be ineffective without due consideration of the clinical circumstances.16 Q UA L I T Y A N D VA L I D I T Y I S S U E S

Although each step used in performance of the meta-analysis appears relatively straightforward, users have to be aware of the possible pitfalls in its application. Some of the problems a clinician could face are as follows14,17 : ■

■

■

■ ■ ■ ■

Regression during analysis is often nonlinear, but estimates of effect size can be meaningful only when regressions are linear. The effect studied may often have a multivariate relationship rather than a univariate relationship to the intervention. For example, analyzing the effect of an analgesic on postoperative nausea and vomiting is difficult, as it is only one of multiple causes of postoperative nausea and vomiting. The clinical relevance of the studies analyzed can be limited by the exclusion criteria that were prespecified in the study design. Bad- or poor-quality studies are included in a meta-analysis. Data summarized are not homogenous. Grouping of different causal factors leads to meaningless estimates of effects. Theory-directed approaches in meta-analysis may obscure any discrepancies that existed in the data. Although clarifying the discrepancies is more important than estimating effect sizes, what typically clinicians are more interested in the latter.

To help clinician in deciding the quality of the meta-analysis that is performed, it is possible for the clinician to utilize the 18 items checklist and flow diagram that is suggested by the QUOROM (quality of reporting of meta-analysis) statement (available at: http://www.consort-statement.org/QUOROM.pdf).18,19

This practice will help clinicians better identify good-quality meta-analyses from those that are poorly done. Similarly, the CONSORT (consolidated standards of reporting trials) statement has provided clinicians with a framework to analyze randomized controlled trials to differentiate the quality of work and thus to see that only valid results are used in clinical practice (available at http://www.consort-statement. org/Downloads/Checklist.doc or http://www.consortstatement.org/Downloads/checklist.pdf).18,20 C H A L L E N G E S TO T H E P R AC T I T I O N E R O F EVIDENCE-BASED MEDICINE

There are two important issues to ensure the successful implementation of evidence-based medicine. First, there is a need to ensure that the available evidences in the area of practice have been adequately reviewed, with evidence-based practice guidelines and recommendations laid out for clinicians. Second, strategies have to be in place for the successful translation of guidelines and recommendations into practice. This would include a paradigm shift in clinical practice and the willingness of clinicians to adopt the recommendations.9 Knowledge of current best evidence together with willingness to discard outdated practice ideas is needed to ensure that clinicians are armed with the latest state-of-the-art medical care capabilities.21 Evidence-based guidelines or recommendations can provide a specific direction to guideline clinical practice. But for changes to be effective, they have to be preceded by learning. This is then followed by incorporating this new information using experience and wisdom.22 In a systematic review, it was found that evidence-based guidelines can work and are capable of improving patients’ care but often do not achieve this goal.23 The review further attempts to delineate the common features of guidelines, which achieved successful implementation. ■ ■ ■ ■ ■

guidelines covered an area with large variation in clinical practice evidence base is fairly secure indication for use of the guidelines is common among the clinicians clinician is aware of the knowledge gaps in area covered by guidelines benefit of implementation is huge

Thus, even with the availability of evidence-based guidelines, it can be seen only as a road map for clinical care. What is more important to a clinician is the intellectual wisdom to apply this road map to patient care. Thus the outcome cannot be based only on its clinical benefit or its biomedical good but also on its ability to translate the practices for the personal good of the patient, in the light of the patient’s circumstances and his or her choices. As such, a clinician can no longer be a just mere executor of these evidence-based guidelines; he or she must also be armed with the wisdom to be able to exercise the moral responsibilities endowed on them for the “good” of the practice.22 On a much broader view, evidence-based medicine that stimulates much discussion among practicing clinicians regarding how to best gather and assimilate data and translate it into

Evidence-Based Medicine

guidelines, and how to implement this evidence for the wellbeing of the patients, has within the medical community become a positive force in moving health care toward a better future.24 L I M I TAT I O N S O F E V I D E N C E - B A S E D MEDICINE

With the exponential growth in the amount of clinical researches and systematic reviews, it is hopeful that the number of “gray zones” in clinical practice would be reduced. Also notable is the fact that there are obvious limitations in the practice of evidencebased medicine that make practicing it imperfect in many ways. First, there is a lack of evidence in many areas of clinical practice and only a small proportion of medical practice has been tested in well-designed trials.7 Furthermore, there are areas where study is not feasible. The recommendation that the appropriate treatment of acute neuropathic pain might prevent chronic pain is currently based on expert opinion.4 Performing a randomized controlled trial in this area will require patients with acute neuropathic pain to be treated with placebo and such a trial may be deemed unethical. Another area of limitation involves mainly publication bias. It is common that compared to negative trials, trials with positive or statistically significant results get published in medical journals. In addition, certain data are used in multiple articles, resulting in duplication of data. Also, there is an obvious bias against articles that are not published in English language, as these trials tend to be missed in searches.12 In addition, there is a lack of a unified definition in many of the trials, which results in many difficulties in trying to compare “apples to apples.” The use of sedation as a marker of impending respiratory depression in patients on patient-controlled analgesia (PCA) produced an incidence of between 0% and 25.7%. This relatively wide range demonstrated the importance of a standardized definition to make data collection in clinical trials meaningful.25 For the outcome of any systematic reviews or meta-analysis can only be as accurate or reliable as the original studies.12 Furthermore, the recommendations provided by the author depends largely on the author’s interpretation of the results at hand. In two different systematic reviews published in the same year (2003) by two different authors on the same topic (the effects of nonsteroidal anti-inflammatory drugs [NSAIDs] and the risk of operative site bleeding after tonsillectomy), the conclusions were drastically different. One author concluded that the use of NSAIDs increases the risk of reoperation for hemostasis and thus the drug should not be used.26 By contrast, the other author felt that the evidence of increased bleeding remains ambiguous and, compared to opioids, NSAIDs seem to be equianalgesic with decreased risk of postoperative nausea and vomiting. On the balance of things, the second author concluded that NSAIDs can be used cautiously in tonsillectomy.27 This difference in recommendation on the level of a meta-analysis (level I) could well create confusion among practicing clinicians. To add to the confusion, different guidelines use different scales to assign different weightings to the various evidences. Thus similar practices may have different levels of recommendations depending on the source of the guideline.7 Two different recommendations are outlined below.

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The following levels of evidence are adapted from the National Health and Medical Research Council (NHMRC) of Australia for interventional studies4,28 : Level of Evidence

Study Design

I

Evidence obtained from a systematic review of all relevant randomized controlled trials.

II

Evidence obtained from at least one properly designed randomized controlled trial.

III – 1

Evidence obtained from well-designed pseudorandomized controlled trials (alternate allocation or some other method).

III – 2

Evidence obtained from comparative studies (including systematic reviews of such studies) with concurrent controls and allocation not randomized (cohort studies), case control studies, or interrupted time series with a control group.

III – 3

Evidence obtained from comparative studies with historical control, two or more arm studies, or interrupted time series without parallel control group.

IV

Evidence obtained from case series, either posttest or pretest and posttest.

Consensus

In the absence of scientific evidence and where the executive committee, steering committee, and review groups are in agreement, the term consensus has been applied.

In comparison, the Scottish Intercollegiate Guidelines use a set of evidence recommendations originating from the US Agency for Health Care Policy and Research, which differs from those above. Their guideline is set out in the following table.29 Level of Evidence

Study Design

Ia

Evidence obtained from meta-analysis of randomized controlled trials.

Ib

Evidence obtained from at least one randomized controlled trial.

II a

Evidence obtained from at least one well-designed controlled study without randomization.

II b

Evidence obtained from at least one other type of well-designed quasi-experimental study.

III

Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies. and case studies.

IV

Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.

Comparing the above 2 tables, it is not difficult to understand how confusion can result when 2 different forms of classification are being utilized.

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Tee Yong Tan, Stephan A. Schug

E V I D E N C E - B A S E D M E D I C I N E I N AC U T E PA I N M A NAG E M E N T

The most widely internationally endorsed EBM document on acute pain management is Acute Pain Management: Scientific Evidence, which was published in an initial version by the National Health and Medical Research Council of Australia (NHMRC) in 1999. This document has been updated by the Australian and New Zealand College of Anaesthetists and its Faculty of Pain Medicine and was then published in 2005 in the form of a paperback book4 and a PDF file on a Web site (http://www.anzca.edu.au/publications/acutepain.htm). It has been endorsed not only by the NHMRC but also by the Australian Pain Society, the Royal College of Anaesthetists, and the International Association for the Study of Pain and is recommended by the American Academy of Pain Medicine. It has also been the topic of editorials in a number of journals, including the British Journal of Anaesthesia.30–32 It presents the highest ranked, highest quality evidence on all aspects of acute pain management. The aim of the document is to combine the best available evidence in this area with current clinical and expert practice and to present the substantial amount of evidence currently available for the management of acute pain in a concise and easily readable form. It covers all aspects of acute pain, far beyond postoperative pain, and includes evidence-based statements on pain associated with nonsurgical conditions such as spinal cord injury, burns, cancer, acute zoster, neurological diseases, hematological disorders (eg, sickle cell disease), and HIV/AIDS, as well as abdominal (eg, renal and biliary colic), cardiac, musculoskeletal, and orofacial pain and headache. The main information is summarized in key messages based on highest levels of evidence available. The progress in the area can be shown by the fact that the 1999 document had 34 levels I, II, and III key statements, whereas the edition in 2005 has 108 level I recommendations alone. A consumer document has been developed from this document and is available from the same Web site as well as a version updated to December 2007. The revision of the document was organized and coordinated by a working party, which also prepared the final version of the document. A panel of contributors was selected to draft sections of the document and a large multidisciplinary consultative committee (including medical, nursing, and allied health and complementary medicine clinicians in addition to consumers) was appointed to review the early drafts of the document and contribute more broadly as required to ensure general applicability and inclusiveness. Although such guidelines can influence clinical decisionmaking in a positive way, they generalize the evidence and present no data on specific procedures. However, there is now good evidence that different surgical procedures may result in different types of pain, different intensities of pain, and different locations of pain. These procedural differences lead to different risk-benefit ratios for different analgesic techniques in the different settings. Examples of such differences are the different efficacy of, for example, paracetamol in different pain models.33 By pooling studies from disparate procedures the confidence intervals for numbers needed to treat from different agents overlap, providing little evidence for their real benefit in a specific procedure.34 Thereby NNT league tables ignore specific effects of analgesics in different pain models and lead

to extrapolations of efficacy that are inappropriate for a specific procedure.35 Therefore, generalized evidence-based guidelines for postoperative pain treatment may often be insufficient because available evidence does not suggest that different pain models are truly comparable and the efficacy of different agents may vary between procedures. In response to these issues, another avenue to summarize evidence on acute pain management has been taken by the members of the PROSPECT group.36 This approach recognizes that different surgical procedures may result in different types of pain, different intensities of pain, and different locations of pain. It is quite obvious that such differences lead to different risk/benefit ratios for different analgesic techniques in the various postoperative settings. This recognition has led to the concept of developing procedure-specific guidelines for postoperative pain management. The PROSPECT approach has followed this guidance and aims to provide health care professionals with procedure-specific information that is up to date and evidence based.37 The recommendations are presented on a Web site (www.postoppain.org) and provide recommendations for best practice accessible to everybody on this Web site with a user-friendly interface. The development of the PROSPECT recommendations is based on a systematic literature review of procedure-specific data which are then supplemented by evidence from studies of other procedures believed to have a similar pain profile as the procedure under review and by information from clinical practice as far as relevant. The overall information is assessed at a consensus meeting of the PROSPECT Working Group and procedure-specific recommendations for the management of pain after specific procedures are developed. The methodology underlying the PROSPECT recommendations is published in the peer-reviewed literature.38 In brief summary, the development of PROSPECT recommendations is based on a systematic literature review. This literature review includes studies that have a definable group of patients undergoing the procedure under review; are randomized trials of an analgesic, anesthetic, or surgical technique aimed at influencing postoperative pain; are appropriately randomized and blinded and where pain scores are reported on a linear pain scale. Such selected procedure-specific data are analyzed qualitatively and pooled where possible for quantitative meta-analysis. Specific outcomes analyzed are VAS scores, supplementary analgesic requirements, the time to first analgesic request, and incidence or severity of postoperative nausea and vomiting. The procedurespecific data thus assembled are supplemented by evidence from studies of other procedures believed to have a similar pain profile as the procedure under review.39 In addition, information from clinical practice, for example, with regard to aspects of practicality and risk benefit, are also taken into consideration when assessing the data. The overall information condensed in this way is assessed at a consensus meeting of the PROSPECT working group and procedure-specific recommendations for the management of the specific postoperative pain are developed. These recommendations are then formulated in a way that facilitates clinical decision-making and are provided in a Webbased interface with quick and easy access to the relevant information. This Web site presents the evidence in a tree structure. The evidence and the recommendation for each procedure are contained in folders representing each step in the perioperative care pathway; operative techniques, anesthetic techniques, and

Evidence-Based Medicine

analgesic strategies are reviewed. Information is then summarized in an overall set of recommendations for each procedure, which shows a pathway for the continuity of the pre-, intra-, and postoperative pain management. For each step, procedurespecific evidence, transferable evidence from other procedures and clinical practice recommendations are listed, as well as the concluding PROSPECT recommendations. The user is also able to see the original references for each of these recommendations. The user can access the qualitative analysis, the quantitative meta-analysis in a classical graph if available and the details of the underlying references, including their abstracts. The final recommendations for a procedure are presented in the form of a flow diagram. Currently online are the following surgical procedures: laparoscopic cholecystectomy,40 primary total hip arthroplasty,41 abdominal hysterectomy, colonic resection, herniorraphy, thoracotomy, total knee arthroplasty, and mastectomy. Overall, this approach offers a robust foundation for the development of clinical decision support by the use of the Cochrane Collaboration methodology and the inclusion of transferable evidence and clinical practice. C O N C LU S I O N

As medical science develops, the future promises an expansion of research information. Practicing clinicians will find it more and more difficult to incorporate all new findings into their everyday clinical decision-making because of a lack of time and resources.42 Systematic reviews have in recent years aided clinicians in keeping abreast of medical literature by summarizing the huge body of information available and addressing the differences that arise from the various studies.43 Armed with this new knowledge, clinicians now have the tools to discharge outdated practices and assimilate new guidelines and recommendations into their daily practice.

REFERENCES 1. Dolin SJ, Cashman JN, Bland JM. Effectiveness of postoperative pain management: I. Evidence from published data. Br J Anaesth. 2002;89(3):409–423. 2. Brennan F, Cousins MJ. Pain relief as a human right. IASP Pain Clinical Updates 2004;XII(5). 3. Australian and New Zealand College of Anaesthetists Professional Document. Statement on Patients’ Rights to Pain Management. PS45 (2001). www.anzca.edu.au/publications/profdocs/ profstandards/index.htm. 4. Australian and New Zealand College of Anaesthetists, Faculty of Pain Medicine. Acute Pain Management: Scientific Evidence. Melbourne: Australian and New Zealand College of Anaesthetists; 2005. 5. Donald A. Evidence-based medicine: Key concepts. MedGenMed. 2002;4(2). Available at: http://www.medscape.com/viewarticle/ 430709. 6. Cook DJ, Levy MM. Evidence-based medicine: a tool for enhancing critical care practice. Crit Care Clin. 1998;14(3):353–358. 7. Swinglehurst D. Evidence-based guidelines: the theory and the practice. Evidence-Based Healthcare Public Health. 2005;9:308– 314.

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8. Woolf SH. Evidence-based medicine and practice guidelines – an overview. Cancer Control. 2000;7(4):362–367. 9. Guyatt G, Rennie D. User’s Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice. Washington, DC: AMA Press; 2002. 10. Holte K, Kehlet H. Epidural analgesia and risk of anastomotic leakage. Reg Anesth Pain Med. 2001;26:111–117. 11. Muir Gray JA. Evidence-based and value-based healthcare. Evidence-Based Healthcare Public Health. 2005;9:317–318. [Editorial] 12. Columb MO, Lalkhen A-G. Systematic reviews and meta-analyses. Curr Anaesth Crit Care. 2005;6:391–394. 13. Barker FG, Carter BS. Synthesizing medical evidence: systematic reviews and meta-analyses. Neurosurg Focus. 2005;19(4). Available at http://www.medscape.com/viewarticle/515632 14. Herbert RD, Bø K. Analysis of quality of interventions in systematic reviews. BMJ. 2005;331:507–509. 15. Oulos J, Kam PCA. “Number needed to treat”: a tool for summarizing treatment effect, and its application in anaesthesia and pain management. Curr Anaesth Crit Care. 2005;16:173–179. 16. Holdcroft A, Jaggar S. Core Topics in Pain. Cambridge, UK; Cambridge University Press; 2005. 17. Eysenck HJ. Meta-analysis and its problems. BMJ. 1994;309:789– 792. 18. Needleman I. Editorial: Is this good research? Look for CONSORT and QUORUM. Evid Based Dent. 2000;2:61–62. 19. Moher D, Cook D J, Eastwood S, Olkin I, Rennie D, Stroup D. Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM statement. Lancet. 1999;354:1896–1900. 20. Moher D, Schulz KF, Altman DG for the CONSORT group. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Lancet. 2001;357:1191–1194. 21. Linklater D R, Pemberton L, Taylor S, Zeger W. Painful dilemmas: an evidence-based look at challenging clinical scenarios. Emerg Med Clin N Am. 2005;23:367–392. 22. Giordano J. Techniques, technology and tekne: the ethical use of guidelines in the practice of interventional pain management. Pain Physician. 2007;10:1–5. 23. Bazian Ltd. Do evidence-based guidelines improve the quality of care? Evidence-Based Healthcare Public Health. 2005;9:270– 275. 24. Cronje RJ, Freeman JR, Williamson OD, Gutsch CJ. Evidencebased medicine: recognising and managing clinical uncertainty. Lab Med. 2004;35(12):724–731. 25. Tan TY, Schug SA. Safety aspects of postoperative pain management. Rev Analg. 2006;9:45–53. 26. Marret E, Flahault A, Samama C M, Bonnet F. Effects of postoperative, nonsteroidal, anti-inflammatory drugs on bleeding risk after tonsillectomy. Anesthesiology. 2003;V98:1497–1502. 27. Møiniche S, Rømsing J, Dahl JB, Tram`er MR. Nonsteroidal antiinflammatory drugs and the risk of operative site bleeding after tonsillectomy: a quantitative systematic review. Anesth Analg. 2003;96:68–77. 28. Australian Acute Musculoskeletal Pain Guidelines Group. Evidence-based management of acute musculoskeletal pain: a guide for clinicians. Bowen Hills, Queensland: Australian Academic Press; 2004. 29. Scottish Intercollegiate Guidelines Network. Control of Pain in Patients with Cancer: A National Clinical Guideline. Edinburgh, UK: SIGN Publication; 2000. 30. Macintyre PE, Walker S, Power I, Schug SA. Acute pain management: scientific evidence revisited. Br J Anaesth. 2006;96(1):1–4.

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31. Macintyre PE, Schug SA, Scott DA. Acute pain management: the evidence grows. An Australian document now has an important role in acute pain management worldwide. Med J Aust. 2006;184(3):101–102. 32. Schug SA, Macintyre P, Power I, Scott D, Visser E, Walker S. The scientific evidence in acute pain management. Acute Pain. 2005;7(4):161–165. 33. Barden J, Edwards JE, McQuay HJ, Moore AR. Pain and analgesic response after third molar extraction and other postsurgical pain. Pain. 2004;107(1–2):86–90. 34. McQuay HJ, Moore RA. An Evidence-Based Resource for Pain Relief. Oxford, UK: Oxford University Press; 1998. 35. Gray A, Kehlet H, Bonnet F, Rawal N. Predicting postoperative analgesia outcomes: NNT league tables or procedure-specific evidence? Br J Anaesth. 2005;94(6):710–714. 36. Schug SA, Kehlet H, Bonnet F, et al. Procedure specific pain management after surgery – “PROSPECT.” Acute Pain. 2007;9(2):55– 57. 37. Kehlet H, Wilkinson RC, Fischer HB, Camu F. PROSPECT: evidence-based, procedure-specific postoperative pain management. Best Pract Res Clin Anaesthesiol. 2007;21(1):149–159.

38. Neugebauer EA, Wilkinson RC, Kehlet H, Schug SA. PROSPECT: a practical method for formulating evidence-based expert recommendations for the management of postoperative pain. Surg Endosc. 2007;21(7):1047–1053. 39. Neugebauer E, Wilkinson R, Kehlet H, on behalf of the PROSPECT Working Group. Transferable evidence in support of reaching a consensus. Z a¨ rztl Fortbild Qual Gesundh. 2007;101:103– 107. 40. Kehlet H, Gray A, Bonnet F, et al. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following laparoscopic cholecystectomy. Surg Endosc. 2005;19(10):1396–1415. 41. Fischer HB, Simanski CJ. A procedure-specific systematic review and consensus recommendations for analgesia after total hip replacement. Anaesthesia. 2005;60(12):1189–1202. 42. Mulrow CD, Cook DJ, Davidoff F. Systematic reviews: critical links in the great chain of evidence. Ann Intern Med. 1997;126(5):389– 391. [Editorial] 43. Cook DJ, Mulrow CD, Haynes RB. Systematic reviews: synthesis of best evidence for clinical decisions. Ann Intern Med. 1997;126(5):376–380.

41 Effect of Epidural Analgesia on Postoperative Outcomes Marie N. Hanna, Spencer S. Liu, and Christopher L. Wu

Epidural analgesia is a widely accepted analgesic technique for the treatment of postoperative pain. Compared to parenteral opioids, epidural analgesia in general will provide superior analgesia and may confer certain physiologic benefits, including attenuation of perioperative pathophysiologies, which may ultimately contribute to a decrease in perioperative morbidity or even mortality. High-risk surgical patients, such as those who are elderly, have decreased physiologic reserve or, undergoing certain procedures, may especially benefit from postoperative epidural analgesia. However, postoperative epidural management must be optimized to achieve any improvement in postoperative outcomes. Despite the potential benefits of postoperative epidural analgesia, the superiority of epidural analgesia compared to parenteral opioids is somewhat uncertain, which may be related to conflicting results of relatively small randomized controlled trials (RCTs) and other methodological issues. However, we limit our focus to larger RCTs, meta-analyses of RCTs, and large databases in an attempt to elucidate the benefits of postoperative epidural analgesia on conventional outcomes (eg, mortality, major morbidity) and patient-reported outcomes (eg, satisfaction, quality of recovery, and analgesia).

from 2% to 1% would require approximately 4600 patients, which is 3 to 4 times more subjects than the largest available RCT on this topic. In addition, there are other limitations of an RCT in examining the effect of epidural analgesia on mortality.3 Thus, use of meta-analyses and database analysis may facilitate assessment of the effect of epidural analgesia on postoperative mortality. The largest meta-analysis of RCTs (Collaborative Overview of Randomised Trials of Regional Anaesthesia, CORTRA) comparing neuraxial anesthesia, including epidural anesthesia and analgesia) to general anesthesia included 141 RCTs with 9559 patients undergoing a variety of surgical procedures.4 The results of this meta-analysis suggested that perioperative neuraxial anesthesia and analgesia (versus general anesthesia) was associated with a reduction in mortality (1.9% vs 2.8%; odds ratio [OR] = 0.7 with 95% confidence intervals [CI] = 0.54 to 0.90) that was attributed to a reduction of major morbidity in various multiple organ systems. A subset of approximately 5000 patients (66 RCTs) utilized epidural anesthesia and analgesia. Other smaller subsequent meta-analyses, however, have shown no benefit for the use of epidural analgesia in decreasing mortality. A meta-analysis examined 11 RCTs (1173 subjects) that used postoperative epidural analgesia for 24 hours or more after surgery demonstrated no difference in the incidence of mortality between those who received epidural analgesia or systemic opioids (3.1% vs 4.4%, P = .30).5 Other meta-analyses have also noted no difference in death although the authors of many of these meta-analyses acknowledged that it would be difficult to assess a relatively rare outcome such as mortality because of the small numbers of patients studied. A meta-analysis (13 RCTs, 1224 subjects) examining patients undergoing open abdominal aortic surgery compared patients randomized to epidural analgesia or systemic opioid but found similar mortality rates (3.5% vs 4.3%).6 Another meta-analysis (15 RCTs, 1178 subjects) for patients undergoing coronary artery bypass grafting did not note a reduction in mortality with use of epidural anesthesia (0.7% vs 0.3%).7 Other meta-analyses on RCTs examining epidural analgesia versus systemic opioids for postoperative analgesia after abdominal surgery (711 subjects)8 and hip/knee replacement

M O RTA L I T Y

The overall advances in anesthesia care have significantly decreased the incidence of mortality since the late 1960s, as reflected in the Institute of Medicine report on medical errors (ie, “anesthesiology has successfully reduced anesthesia mortality rates from two deaths per 10,000 anesthetics administered, to one death per 200,000–300,000 anesthetics administered”).1 Although the incidence of postoperative death is fortunately relatively infrequent, the low incidence is problematic in determining whether an intervention such as perioperative epidural anesthesia and analgesia might be associated with a decrease in perioperative mortality. For instance, data from Medicare surgical patients indicated a 30-day mortality rate of approximately 2.5%.2 An RCT designed to detect a 50% reduction in incidence 637

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Table 41.1: Summary of Meta-Analyses and Large Randomized Controlled Trials: Mortality Author

No. of No. of Type of Mortality in Mortality in RCTs Patients surgery NA Group (%) GA Group (%)

Odds Ratio (95% CI)

P Value

Rodgers et al (2000)4

141

9559

MIX

1.9%

2.8%

0.70 (0.54–0.90) P = .0006

Beattie et al (2001)5

11

1173

MIX

3.1%

4.4%

0.74 (0.40–1.37) P = .3

Nishimori et al (2006)6

13

1224

ABD

3.5%

4.3%

0.86 (0.48–1.55) P = .6

Liu et al (2004)7

15

1178

CABG

0.7%

0.3%

1.56 (0.35–6.91) P = .56

Park et al (2001)10

1

1021

ABD

4%

3.4%

n/c

P = .74

Rigg et al (2002)11

1

915

ABD

5.1%

4.3%

n/c

P = .67

Abbreviations: ABD = abdominal (including aortic) surgery; CABG = coronary artery bypass surgery; CI = confidence interval; GA = general anesthesia; MIX = mixed surgical procedures; NA = neuraxial analgesia; n/c: not calculated.

surgery (555 subjects)9 indicated that there was insufficient evidence for a benefit of postoperative epidural analgesia in decreasing perioperative mortality (Table 41.1). There have been at least two large multicenter RCTs comparing epidural analgesia to systemic opioids since the publication of the CORTRA meta-analysis with both of these RCTs showing no difference in mortality between the two forms of analgesia. The Veterans Affairs Cooperative Studies Program (VACS) randomized approximately 1000 patients undergoing aortic, gastric, biliary, or colon surgery to combined general/epidural anesthesia followed by epidural morphine or general anesthesia followed by systemic opioids.10 Overall mortality rates were similar between groups (4% for epidural opioid versus 3.4% for systemic opioids). Another relatively large RCT, the Multicentre Australian Study of Epidural Anesthesia (MASTER), enrolled 915 highrisk patients who underwent abdominal surgical procedures and were randomized to combined general/epidural anesthesia followed by 72 hours of postoperative epidural analgesia with local anesthetic/opioids or general anesthesia followed by systemic opioids.11 The overall mortality rates were similar between the groups (5.1% for epidural versus 4.3% for systemic opioids); however, there was poor protocol compliance, as only 225 of 447 patients fully adhered to the epidural analgesia protocol. Although both RCTs did not demonstrate a difference in mortality between epidural analgesia and systemic opioids, the studies were not adequately sized to assess a relatively mortality. In an attempt to circumvent the issue of inadequate sample size, a group of investigators used a 5% random sample of the Medicare claims database to examine patients undergoing a variety of surgical procedures and stratified them according to the presence (n = 12 780 subjects) or absence (n = 55 943) of postoperative epidural analgesia (Table 41.2).2 Regression analysis revealed that the presence of postoperative epidural analgesia was associated with a significantly lower risk for both 7-day (0.5% vs 0.8%, OR = 0.52 with 95% CI = 0.38 to 0.73) and 30-day (2.1% vs 2.5%, OR = 0.74; 95% = CI 0.63 to 0.89) mortality. However, the benefit of epidural analgesia in possibly decreasing mortality was limited to patients undergoing higher-risk (eg, thoracotomy) rather than lower-risk (eg, joint replacement) surgery. The lack of benefit for epidural analgesia for lower-risk surgery is reflected in a separate Medicare claims analysis in patients undergoing total hip replacement where there was no significant difference in mortality between those who did or did not receive epidural analgesia (0.2% vs 0.4%; OR = 0.6; 95% CI = 0.2 to 1.5).12

Thus, the definitive evidence for reduction of perioperative mortality with postoperative epidural analgesia compared to systemic opioids is lacking. Although, the largest sets of data (CORTRA meta-analysis and Medicare claims dataset) suggest a benefit for epidural anesthesia and analgesia in decreasing postoperative mortality, there are limitations to each type of analyses.3 Procedure specific meta-analyses and individual RCTs have noted no benefit for epidural analgesia in reducing postoperative mortality; however, these studies lack sufficient sample size to assess relatively rare outcomes such as death. MAJOR MORBIDITY

The perioperative pathophysiologies (eg, neuroendocrine stress response) that result from surgery will affect all organ systems. Use of epidural analgesia may confer many analgesic and physiologic benefits that may theoretically translate into improved patient outcomes postoperatively. Furthermore, because the incidences of complications and major morbidities (eg, cardiovascular, pulmonary, gastrointestinal, coagulation) are generally higher than that seen for mortality in the perioperative period, any benefits for epidural analgesia may be more apparent for these higher frequency events. Many meta-analyses have been conducted examining the efficacy of postoperative epidural analgesia on various patient outcomes. C A R D I OVA S C U L A R M O R B I D I T Y

Approximately 100 million adults worldwide undergo noncardiac surgery annually, and nearly half of the patients are estimated to have cardiac risk factors.13 It has been estimated that 5% of these patients will develop some type of perioperative cardiac complication or morbidity.14 Although the reported incidences of perioperative cardiovascular morbidity varies depending on surgical and patient factors, high-risk patients (eg, elderly, preexisting comorbidities) or procedures (eg, emergency or cardiac surgery) carry the highest risk of developing cardiovascular morbidity postoperatively. For instance, the incidence of myocardial infarction is higher for emergency surgery in the elderly (approximately 19% vs 0.2% for myocardial infarction)2,15 and those undergoing major vascular surgery (5%–10% incidence).7,16 Postoperative pain control is important in attenuating the perioperative pathophysiology (eg, activation of the sympathetic nervous system, surgical stress response, and coagulation

Effect of Epidural Analgesia on Postoperative Outcomes

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Table 41.2: Summary of Databases (Medicare) Analyses: Mortality Author

Procedure

Wu et al (2004)2 12

Wu et al (2003)

Mixed Hip replacement

Mortality in GA (%)

Mortality in NA (%)

Odds Ratio (95% CI)

P Value

7 days: 0.8%

7 days: 0.5%

0.52 (0.38–0.73)

P = .0001

30 days: 2.5%

30 days: 2.1%

0.74 (0.63–0.89)

P = .0005

7 days: 0.2%

0.6 (0.24–1.48)

P = 0.27

30 days: 0.6%

0.63 (0.35–1.11)

P = 0.11

7 days: 0.39% 30 days: 0.9%

Abbreviations: CI = confidence interval; GA = general anesthesia; MIX = mixed surgical procedures; NA = neuraxial analgesia.

cascade) that can contribute to cardiovascular morbidity by increasing myocardial oxygen demand (via increases in heart rate, blood pressure, and contractility) or decreasing myocardial oxygen supply (via enhanced perioperative hypercoagulability, coronary thrombosis, or vasospasm).17,18 Animal data suggest that use of thoracic epidural anesthesia and analgesia with local anesthetics may confer physiologic benefits by reducing sympathetic activation and providing a favorable balance of myocardial oxygen.19 Clinical data also suggest a physiologic benefit of thoracic epidural analgesia with local anesthetics in patients with multivessel ischemic heart disease.17,20 It is important to note that lumbar epidural anesthesia may not provide the same physiologic benefits as thoracic epidural anesthesia as there is a compensatory increase in sympathetic activity above the level of blockade for lumbar epidural analgesia,21 which may be associated with an increased incidence of left ventricular wall dysfunction (compared to thoracic epidural anesthesia).17 Nevertheless, use of lumbar epidural analgesia may still be preferable to systemic opioids as a small study noted a marked reduction in cardiovascular events (0% vs 19%) in patients with hip fractures randomized to preoperative lumbar epidural analgesia versus systemic analgesia.15 There are at least 5 meta-analyses that have examined the efficacy of postoperative epidural analgesia on cardiovascular morbidity either as a primary or secondary outcome (Table 41.3).5–9 Three meta-analyses that specifically examined the efficacy of postoperative epidural analgesia on cardiovascular morbidity indicated a benefit for thoracic epidural analgesia in decreasing cardiovascular morbidity. The first meta-analysis (9 RCTs, 632 patients) evaluated subjects undergoing a variety of surgical procedures but where epidural analgesia was extended for at least 24 hours postoperatively.5 The use of thoracic epidural (OR = 0.43; 95% CI = 0.19 to 0.97) but not lumbar epidural (OR = 0.77; 95% CI = 0.31 to 1.92) analgesia provided a significant reduction in the rate of myocardial infarction (3.6% vs 8.5%, rate difference = −5.3% with 95% CI of −9.9% to −0.7%). Another similar but more procedure specific meta-analysis in patients undergoing open abdominal aortic surgery (13 RCTs, 1224 patients) also suggested a significant reduction in risk of cardiovascular complications (relative risk [RR] = 0.74; 95% CI = 0.56 to 0.97) and myocardial infarction (RR = 0.52; 95% CI 0.29 to 0.93) with epidural analgesia compared to that for systemic analgesia.6 The third procedure specific meta-analysis (15 RCTs, 1178) examined patients undergoing coronary artery bypass surgery7 and found a significant reduction in the incidence of dysrhythmias with thoracic epidural analgesia (17.8% vs 30%, OR = 0.52; 95% CI = 0.29 to 0.93) compared to systemic opioids. Finally, two other procedure-specific meta-analyses examining effects of

epidural analgesia on abdominal and hip and knee replacement surgery found no benefit for epidural analgesia in decreasing cardiovascular morbidity; however, the authors concluded that there was insufficient evidence in these meta-analyses to analyze cardiovascular complications.8,9 The two previously described RCTs (VACS and MASTER trials) did not consistently demonstrate a benefit of epidural analgesia in decreasing postoperative cardiovascular complications. Although the VACS trial overall did not note a significant reduction in cardiovascular complications with use of epidural morphine, the abdominal aortic surgery subgroup had a significantly lower incidence of cardiovascular complications (9.8% vs 17.9%, P = .03) primarily due to reduction in myocardial infarction (2.7% vs 7.9%, P = .05).10 The MASTER trial observed no benefit for epidural analgesia in decreasing cardiovascular morbidity (2.6% vs 2.4%) and there were no significant differences in cardiovascular complications in a subgroup analysis of patients undergoing abdominal aortic surgery (4.5% vs 4.7%).22 Several analyses of the Medicare claims data did not demonstrate a differences in cardiovascular complications between patients with and without postoperative epidural analgesia for a variety of surgical procedures; however, the accuracy of these databases in capturing major morbidity is uncertain as the overall cardiovascular complication rates were quite low (0.8%–4%).2,12 Thus, there is consistent evidence that thoracic epidural analgesia may reduce the risk of cardiovascular complications, such as myocardial infarction, in high-risk patients, including those undergoing major vascular surgery. The benefit for thoracic epidural analgesia reflects experimental data demonstrating physiologic benefits of this technique and may also reflect the higher underlying rate of cardiovascular complications for highrisk surgical population (4%–18%). However, there is minimal evidence that epidural analgesia reduces cardiovascular complications in the general (more healthy) surgical population. P U L M O NA RY M O R B I D I T Y

Postoperative pulmonary complications (PPC) remain a significant problem and may occur at a higher frequency than cardiac morbidity in patients undergoing elective abdominal procedures.23,24 Like that seen in other systems, the pathophysiology of postoperative pulmonary dysfunction is multifactorial and may include disruption of normal respiratory muscle activity, reflex inhibition of phrenic nerve activity and subsequent decrease in diaphragmatic function, and uncontrolled postoperative pain leading to deceased lung volumes.24 Use of epidural analgesia, particularly if placed in the thoracic region and

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Table 41.3: Summary of Meta-Analyses and Large Randomized Controlled Trials: Cardiovascular Author Beattie et al (2001)5 Nishimori et al (2006)6 Liu et al (2004)7 Park et al (2001)10

Peyton et al (2003)22

No. of RCT

No. of Patient

Type of Surgery

9

632

MIX

13

1224

Rate of CV Events: Epidural

Rate of CV Events: Control

Outcomes Assessment

Odds Ratio (95% CI)

P Value

T: 0.43 (0.19–0.97)

T: P = .04

L: 0.77 (0.31–1.92)

L: P = .06

ABD: 0.74 (0.56–0.97)

ABD: P = .03

AAA: 32/851

Overall complications, MI

AAA: 0.52 (0.29–0.93)

AAA: P = .03

T: 7/196

T: 17/201

L: 8/328

L; 12/351

ABD

ABD: 65/611

ABD: 85/611

AAA

AAA: 16/851

Overall complications

15

1178

CABG

17.8%

30%

Dysrythmias

0.52 (0.29–0.93)

P = 0.03

1

1021

ABD

ABD: 23/317 (7.3%) AAA: 34/190 (17.9%)

Overall complications,

n/c

ABD: P = .88

AAA

ABD: 26/330 (7.9%) AAA: 18/184 (9.8%)

MI

n/c

AAA: P = .03

ABD

ABD: 2.6%

ABD: 2.4%

Overall complications

ABD: 1.09 (0.81–1.48)

ABD: P = .56

AAA

AAA: 4.5%

AAA: 4.7%

AAA: 0.92 (0.50–1.70)

AAA: P = .79

1

915

Abbreviations: AAA = abdominal aortic aneurysm procedure; ABD = abdominal (non-aortic) procedure; CABG = coronary artery bypass graft; CI = confidence interval; L = lumbar epidural analgesia; MI = myocardial infarction; MIX = mixed surgical procedures; n/c = not calculated; T = thoracic epidural analgesia.

incorporating a local anesthetic-based solution, will confer superior analgesia (vs systemic opioids) and other physiologic benefits, which ultimately may result in improved voluntary pulmonary function.25 Although the physiologic effects of epidural analgesia on respiratory muscle function are complex,24 some data indicate that thoracic epidural analgesia with bupivacaine (0.25%) does not impair ventilatory mechanics, inspiratory respiratory muscle strength, or airway flow, even in patients with severe chronic obstructive pulmonary disease.26,27 There are at least 4 meta-analyses that examine the effects of epidural analgesia on PPC (Table 41.4). Although the CORTRA meta-analysis did not specifically examine postoperative epidural analgesia, a large percentage of subjects did receive epidural anesthesia and analgesia, and use of neuraxial block for a variety of surgical procedures was associated with significantly decreased risk of pneumonia (3.1% vs 6%, OR = 0.61; 95% CI = 0.48 to 0.76) with thoracic epidural analgesia demonstrating strong efficacy (OR = 0.48; 95% CI = 0.35 to 0.67) compared to spinals or lumbar epidurals (OR = 0.76; 95% CI = 0.55 to 1.04).4 One of the first meta-analyses (18 RCTs, 1016 patients) examined the effect of analgesia on PPC noted a reduced risk of overall pulmonary complications (RR = 0.58; 95% CI = 0.42 to 0.80) and infections (RR = 0.35; 95% CI = 0.21 to 0.65) with epidural regimens compared to systemic or epidural opioids.28 Other procedure-specific meta-analyses also indicated that use of thoracic epidural analgesia (vs systemic opioids) is associated with a significantly decreased risk of respiratory failure (RR = 0.63; 95% CI = 0.51 to 0.79) for open abdominal aortic surgery6 and PPC (17.2% vs 30.3%, OR = 0.41; 95% CI = 0.27 to 0.60) for coronary artery bypass surgery.7 Meta-analyses examining use of epidural analgesia in abdominal surgery and total hip-knee replacement surgery concluded there were insufficient subjects to perform analysis on PPCs.8,9 For RCTs, the VACS study noted a nonsignificant reduction in respiratory failure for all patients (9.9% for epidural vs 14% systemic analgesics); however, subgroup analysis of

patients undergoing abdominal aortic surgery revealed a significant reduction in respiratory failure with use of epidural analgesia (14% vs 28%, P < .01).10 Similarly, the MASTER study noted a lower incidence of respiratory failure for patients randomized to receive epidural analgesia (23% vs 30%, P = .02).11 Analyses of the Medicare claims data revealed no benefit for postoperative epidural analgesia in decreasing the risk of pneumonia or respiratory failure in patients undergoing a variety of surgical procedures although again the authors noted significant limitations of the Medicare database in assessing complications such as PPC.2,12 Thus, there is consistent evidence from meta-analyses and large RCTs that use of thoracic epidural analgesia with local anesthetics (compared to systemic opioids) is associated with a significantly reduced risk of PPC, particularly in high-risk surgical patients such as those undergoing open abdominal aortic surgery or coronary artery bypass. These benefits are not apparent with use of epidural opioids compared to systemic opioids. G A S T R O I N T E S T I NA L M O R B I D I T Y

Postoperative ileus is a common complication, particularly after abdominal surgery, and may result in an increase in resource use and length of stay.29 Like that seen with other systems, the pathophysiology of postoperative ileus and decreased gastrointestinal (GI) motility is multifactorial. Possible etiologies include neurogenic (spinal, supraspinal adrenergic pathways), inflammatory (ie, local inflammatory responses instigate neurogenic inhibitory pathways), and pharmacologic mechanisms.30 Use of epidural analgesia with local anesthetics may attenuate several of the mechanisms of postoperative ileus. By decreasing both the degree of postoperative pain (compared to systemic opioids) and amount of systemic opioids used,25 epidural analgesia may facilitate return of GI function postoperatively. In addition, sympathetic block from epidural local anesthetics may attenuate postoperative reflex inhibition of GI motility, and the

Effect of Epidural Analgesia on Postoperative Outcomes

641

Table 41.4: Summary of Meta-Analyses and Large Randomized Controlled Trials: Pulmonary

Author Rodgers et al 20004

Ballantyne et al 199828

Nishimori et al 20066

Liu et al 20047 Park et al 200110

Rate of Pulmonary Events: Control

No. of RCT

No. of Patients

Type of Surgery

141

9559

MIX

3.1%

6%

Pneumonia

T: 0.61(0.48–0.76) L: 0.48 (0.35–0.67) I: 0.76 (0.55–1.04)

n/c

18

1016

MIX

n/c

n/c

Overall complications, pneumonia

RR: 0.58 (0.42–0.80)

n/c

Respiratory failure, pneumonia

RR: 0.63 (0.51–0.79)

ABD: P = .00004

RR: 0.64 (0.38–1.05)

AAA: P = .08

0.41 (0.27–0.60)

P < .00001

13

1224

ABD

19.8%

30,6%

AAA

4.8%

7.8%

Outcomes Assessment

15

1178

CABG

17.2%

30.3%

Overall complications

1

1021

ABD

25/330 (7.6%) 26/184 (14.1%)

18/317 (5.7%) 55/190 (28.9%)

Overall complications

23%

30%

Respiratory failure

AAA Rigg et al 200211

Rate of Pulmonary Events: Epidural

1

915

ABD

Odds Ratio (95% CI)

P Value

RR: 0.35 (0.21–0.65)

ABD: P = .35 n/c AAA: P = .0006 n/c

P = .02

Abbreviations: AAA = abdominal aortic aneurysm procedure; ABD = abdominal (nonaortic) procedure; CABG = coronary artery bypass graft; CI = confidence interval; I = intrathecal opioids; L = lumbar epidural analgesia; MI = myocardial infarction; MIX = mixed surgical procedures; n/c = not calculated; RR = relative risk; T = thoracic epidural analgesia.

suppression of the surgical stress response and systemic absorption of epidural local anesthetics may reduce the inflammatory response to attenuate postoperative ileus.29,30 Experimental data consistently indicate that epidural analgesia with local anesthetics shortens time of intestinal paralysis without impairing anastomotic healing or increasing risk of anastomotic leakage.31 There have been numerous RCTs examining the efficacy of epidural analgesia on the return of GI function and many of these were included in a Cochrane Library meta-analysis (22 RCTs with 1023 patients) that examined patients undergoing abdominal surgery.32 Similarly to that seen in experimental studies, this meta-analysis indicates that epidural analgesia with local anesthetics consistently showed reduced time to return of gastrointestinal function compared to systemic opioids (mean of −37 hours) or epidural opioids (mean of −24 hours). Thus, it appears that epidural analgesia with local anesthetics hastens return of postoperative GI function after abdominal surgery by 24 to 37 hours. C OAG U L AT I O N - R E L AT E D M O R B I D I T Y

It is widely recognized that a general state of hypercoagulability occurs following surgical procedures that may increase the risk of coagulation-related complications such as deep venous thrombosis (DVT) or pulmonary embolism (PE). Following surgery, there is a tendency toward thrombosis as the normal process of coagulation becomes unbalanced with increases in levels of tissue factor, tissue plasminogen activator, plasminogen activator inhibitor-1, and von Willebrand factor, all of which contribute to

a hypercoagulable and hypofibrinolytic state postoperatively.33 Despite the presence of modern practices of thromboprophylaxis, coagulation-related events are still an important cause of perioperative morbidity and mortality. Intra-operative neuraxial (spinal and epidural) anesthesia with local anesthetic regimens can attenuate perioperative hypercoagulability and may confer physiologic benefits, including increased arterial and venous blood flow, attenuation of perioperative increases in coagulation proteins and platelet activity, and preservation of fibrinolytic activity.19 In addition, systemic absorption of epidural local anesthetics may confer beneficial rheologic properties, including reduction in platelet aggregation, inhibition of thrombus formation, and reduction in blood viscosity.34 Thus, use of intraoperative neuraxial anesthesia may prevent some of these coagulation-related complications. However, it is not certain whether these potential benefits can be extended into the postoperative period with use of epidural analgesia as some experimental data suggest that postoperative epidural analgesia using common local analgesic concentrations (≤0.125% bupivacaine) does provides no significant increase in blood flow or decrease in postoperative hypercoagulability.35 The large numbers of subjects examined in the CORTRA metaanalysis allowed the authors to perform subgroup analyses that revealed that use of neuraxial block was associated with a significant reduction in risk of DVT (2.9% vs 4.7%) and PE (0.6% vs 1.4%) (Table 41.5).4 However, it may be difficult to apply these data to individual patients as there were a mix of surgical procedures and intraoperative neuraxial anesthesia. Subsequently performed procedure-specific meta-analyses for open aortic surgery, abdominal surgery, and total hip and knee

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Table 41.5: Summary of Meta-Analyses and Large Randomized Controlled Trials: Coagulation

Author Rodgers et al (2000)4 Christopherson et al (1993)36 37

Tuman et al (1991)

Rate of Coagulation Events: Epidural

Rate of Coagulation Events: Control

MIX

2.9% 0.6%

4.7% 1.4%

DVT PE

100

LER

4%

22%

80

LER

2.5%

20%

No. of RCT

No. of Patients

Type of Surgery

141

9559

1 1

Outcomes Assessment

Odds Ratio (95% CI)

P Value

0.56 (0.43–0.72) 0.45 (0.29–0.69)

n/c

Graft failure

n/c

P < .01

Graft failure

n/c

P = .013

Abbreviations: CI = confidence interval; DVT = deep venous thrombosis; LER = lower extremities revascularization; MIX = mixed surgical procedure; n/c = not calculated; PE = pulmonary embolism.

replacement were unrevealing as there were insufficient subjects for analysis.6,8,9 It also must be noted that many of the metaanalyses did not comment on use of thromboprophylaxis, which is important as many of the underlying RCTs were performed prior to the release of currently popular thromboprophylactic agents (ie, only 38 of 141 RCTs were published >1990).4 Several RCTs have also noted that use of perioperative epidural anesthesia and analgesia may be associated with a lower risk of graft failure in patients undergoing vascular surgical procedures.36,37 Thus, although intraoperative neuraxial anesthesia appears to be associated with a reduced risk of coagulation-related events such as DVT, PE, and graft failure, there is minimal evidence that postoperative epidural analgesia affects risk of DVT and PE. A confounding factor is that very few studies have addressed this question with use of current methods of effective thromboprophylaxis. OT H E R O U TC O M E S

Chronic Pain Chronic pain following surgery can be a significant postoperative complication with the incidence as high as 30%–81% after limb amputation, 22%–67% after thoracotomy, 17%–57% after breast surgery, and 4%–37% after hernia repair.38,39 The etiology of chronic postoperative pain is most likely multifactorial and may include peripheral and central sensitization. Although the severity of acute postoperative pain is a recognized risk factor for development of chronic postoperative pain38 and use of epidural analgesia would theoretically confer superior postoperative analgesia that possibly may result in a lower incidence of chronic postsurgical pain, the causality of this relationship is uncertain and the degree of hyperalgesia may be important is determining the extent of chronic postsurgical pain.40

Cognitive Decline and Delirium Postoperative cognitive decline is common, particularly in older patients, with rates of postoperative cognitive decline reported as high as 7%–26% and delirium as high as 10%–60% after certain procedures.41 Although the etiology of postoperative cognitive decline and delirium is uncertain, it most likely is multifactorial and certain factors, such as the severity of postoperative pain and use of opioids, have been identified as possible risk factors for the development of postoperative delirium in the elderly.41,42 Despite the theoretical advantages of regional anesthesia and

analgesia, no meta-analyses or systematic reviews show a benefit for this technique in decreasing postoperative cognitive decline and delirium. Also refer to Chapter 31 (Acute Pain Management for Elderly High-risk and Cognitively Impaired Patients: Rationale for Regional Analgesia).

Infectious and Immune Complications Following major surgical procedures, there is an early hyperinflammatory response (eg, release of proinflammatory tumor necrosis factor-␣ [TNF-␣], interleukins, and cytokines) with subsequent cell-mediated immunosuppression.43 Although use of epidural analgesia with local anesthetics has been shown to reduce lymphocyte suppression, attenuate proinflammatory cytokines, and increase surgical wound oxygen tension,44,45 no large-scale data exist to demonstrate a translation of these benefits clinically into a decrease rate of infection per se.46 The CORTRA meta-analysis noted low incidences of wound infections (0.05% vs 0.07%) without differences between those who received neuraxial or general anesthesia.4 Interestingly, however, there are some experimental studies showing that use of regional anesthesia and analgesia can preserve perioperative immune function that may be of benefit in those undergoing cancer surgery.47 PAT I E N T- R E P O RT E D O U TC O M E S

Despite the number of studies examining the effect of postoperative epidural analgesia on patient outcomes, only a few have examined the effect on patient-reported outcomes such as quality of life, postoperative quality of recovery, and patient satisfaction. Patient-reported outcomes are recognized as valid and important end points that are assessed from the patient’s perspective. These outcomes, like other common low-morbidity events (ie, medication-related side effects), may become more relevant as the incidence of anesthesiology-related mortality and major morbidity has decreasedsince the late 1960s.1 Different analgesic agents and techniques (eg, epidural local anesthetic vs systemic opioids) would be expected to result in different levels of analgesia and incidences of side effects. In general, peripheral and epidural regional analgesic techniques are expected to provide superior analgesia compared to systemic opioids.48–50 These difference in analgesia may influence patientreported outcomes as higher levels of postoperative pain may be associated with an overall decrease in mental and psychological function,51,52 higher levels of postoperative fatigue,53,54 and

Effect of Epidural Analgesia on Postoperative Outcomes

disturbances in sleep.55 Furthermore, the presence of side effects may be an important input into the patient-reported outcomes of health-related quality of life (HQRL), postoperative quality of recovery (QOR), and patient satisfaction. Thus, it is possible that different analgesic agents or techniques may result in different levels of HRQL, QOR, or patient satisfaction in the immediate postoperative period.

Health-Related Quality of Life Health-related quality of life can be considered as the comprehensive assessment of the medical care received by a patient. This assessment conceptually incorporates the domains of physical functioning, mental health, cognitive functioning, symptoms (eg, pain), role and social functioning, general health perceptions, sleep, and energy. There are many validated HRQL instruments, some of which are generic and others specific. A recent systematic review56 found 5 RCTs that examined the effect of postoperative analgesia on HRQL but found that only 1 of 5 demonstrated any difference in HRQL between analgesic techniques. The 1 study that showed a difference examined patients undergoing elective colon surgery who were randomized to receive perioperative epidural analgesia vs IV PCA opioids.57 Those who received epidural analgesia had significantly preserved quality of life (SF-36) at up to 6 weeks after surgery. Despite the presence of this study, no definitive conclusions can be made regarding the effect of the type of analgesic technique, degree of analgesia, and presence of side effects on HRQL.

Postoperative Quality of Recovery Postoperative QOR specifically assesses postoperative recovery on a daily basis58 and in some sense may be considered a subset of HRQL in part because of some of the common domains assessed. In fact, changes in postoperative QOR may correlate with long-term changes in HRQL.59 A recent systematic review56 found 4 RCTs that examined the effect of postoperative analgesia on QOR; however, none showed any difference in postoperative QOR using different analgesic regimens. There were methodologic issues with these studies and as such, it is not clear whether the type of analgesic technique, degree of analgesia, and presence of side effects may influence postoperative QOR.

Patient Satisfaction The measurement of patient satisfaction is quite complex and very few studies have examined the effect of postoperative analgesia on satisfaction as a primary outcome. Although there may not be a direct correlation between levels of postoperative pain and satisfaction as there are many inputs into satisfaction, the level of pain may be one of the more important inputs60 and poor control of postoperative pain (along with the presence of analgesic-related side effects) generally correlates with decreased patient satisfaction.61,62 A recent systematic review56 found 95 RCTs assessing satisfaction with different analgesic techniques but only 2 RCTs used a validated instrument to assess patient satisfaction. Approximately half of the RCTs (47 of 95) noted an improvement in satisfaction with one analgesic technique or regimen over another but no definitive conclusions can be made because of the methodologic issues in assessing satisfaction.

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E C O N O M I C O U TC O M E S

Very few studies have incorporated economic assessments in their evaluation of the efficacy of epidural analgesia (versus systemic opioids) on outcomes. Many studies that do incorporate economic assessments, however, generally are not comprehensive in their inputs for costs. Nevertheless, there are some data that can be summarized in the areas of length of stay and a multimodal approach to patient convalescence.

Length of Stay There are at least 16 RCTs that have examined the effect of postoperative epidural analgesia on length of stay.56,62 Only a minority used prospectively defined discharge criteria for assessment of length of stay. None of the 5 RCTs that used a multimodal approach to patient convalescence (see Multimodal Approach to Patient Recovery below) showed any difference in length of stay. Thus, the quality of the available data is inconsistent and no definitive conclusion can be made regarding the effect of analgesia on length of stay.

Multimodal Approach to Patient Recovery Although individual interventions (eg, epidural analgesia, antibiotics, thromboembolism prophylaxis) may be efficacious in reducing some morbidities, a multimodal intervention or approach to patient recovery (“fast track” or accelerated recovery programs) may decrease perioperative morbidity and decrease length of stay.63 One of the key components of this approach is use of regional anesthetic-analgesic techniques that may provide superior analgesia compared to systemic opioids48–50 and physiologic benefits that may facilitate convalescence. Other aspects of a multimodal approach to patient recovery include early enteral nutrition, improved perioperative education, and maintenance of oxygen delivery and normothermia.63 Several RCTs have compared multimodal to conventional care and the vast majority of studies used epidural analgesia with a local anestheticbased solution as part of the multimodal approach to patient recovery. Although some RCTs demonstrated earlier return of gastrointestinal function and improvement in patient-oriented outcomes with use of a multimodal recovery program, there were no differences between those who received an accelerated with regard to mortality or major pulmonary or cardiovascular morbidity.54,56 Thus, use of a multimodal or accelerated recovery program, which typically includes epidural analgesia with a local anesthetic-based solution, may be associated with lower pain scores, increased mobilization, and decreased length of stay when compared to conventional care. There also may be an earlier return of gastrointestinal function, although no difference in other major morbidity or mortality has been found. However, the number and size of available RCTs is relatively small and limited to evaluation in a few surgical procedures and additional studies are needed to provide a definitive answer. S U M M A RY

There are many benefits for the perioperative use of epidural analgesia for the treatment of postoperative pain. Compared to systemic opioids, epidural analgesia provides superior analgesia

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Marie N. Hanna, Spencer S. Liu, and Christopher L. Wu

and certain physiologic benefits. The attenuation of perioperative pathophysiology with perioperative epidural analgesia may result in a decrease in perioperative cardiovascular, pulmonary and gastrointestinal morbidity although any benefit in decreasing coagulation-related morbidity or mortality is uncertain. Although epidural analgesia is associated with lower pain scores, it is unclear whether this benefit may result in any improvement in patient-reported outcomes such as satisfaction, quality of life, and quality of recovery. Further development of instruments assessing patient-reported outcomes in the postoperative period is needed. Finally, the effect of perioperative epidural analgesia on length of stay is uncertain.

REFERENCES 1. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000. 2. Wu CL, Hurley RW, Anderson GF, Herbert R, Rowlingson AJ, Fleisher LA. Effect of postoperative epidural analgesia on morbidity and mortality following surgery in Medicare patients. Reg Anesth Pain Med. 2004;29:525–533. 3. Wu CL, Fleisher LA. Outcomes research in regional anesthesia and analgesia. Anesth Analg. 2000;91:1232–242. 4. Rodgers A, Walker N, Schug S, McKee A, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ. 2000;321:1493. 5. Beattie WS, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: a meta-analysis. Anesth Analg. 2001;93:853–858. 6. Nishimori M, Ballantnye JC, Low JHS. Epidural pain relief versus systemic opioid based pain relief for abdominal aortic surgery. Cochrane Database Syst Rev. 2006;3:CD005059. 7. Liu SS, Block BM, Wu CL. Effects of perioperative central neuraxial analgesia on outcome after coronary artery bypass surgery: a meta-analysis. Anesthesiology 2004;101:153–161. 8. Werawatganon T, Charuluxanun S. Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database Syst Rev. 2005:CD004088. 9. Choi PT, Bhandari M, Scott J, Douketis J. Epidural analgesia for pain relief following hip or knee replacement. Cochrane Database Syst Rev. 2003:CD003071. 10. Park WY, Thompson JS, Lee KK. Effect of epidural anesthesia and analgesia on perioperative outcome: a randomized, controlled Veterans Affairs cooperative study. Ann Surg. 2001;234:560–569. 11. Rigg JR, Jamrozik K, Myles PS, et al. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet. 2002;359:1276–1282. 12. Wu CL, Anderson GF, Herbert R, Lietman SA, Fleisher LA. Effect of postoperative epidural analgesia on morbidity and mortality after total hip replacement surgery in Medicare patients. Reg Anesth Pain Med. 2003;28:271–278. 13. Devereaux PJ, Goldman L, Cook DJ, Gilbert K, Leslie K, Guyatt GH. Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and methods to estimate and communicate risk. Can Med Assoc J. 2005;173:627–634. 14. Mangano DT. Assessment of the patient with cardiac disease: an anesthesiologist’s paradigm. Anesthesiology. 1999;91:1521–1526.

15. Matot I, Oppenheim-Eden A, Ratrot R, et al. Preoperative cardiac events in elderly patients with hip fracture randomized to epidural or conventional analgesia. Anesthesiology. 2003;98:156–163. 16. Mackey WC, Fleisher LA, Haider S, et al. Perioperative myocardial ischemic injury in high-risk vascular surgery patients: incidence and clinical significance in a prospective clinical trial. J Vasc Surg. 2006;43:533–538. 17. Meissner A, Rolf N, Van Aken H. Thoracic epidural anesthesia and the patient with heart disease: benefits, risks, and controversies. Anesth Analg. 1997;85:517–528. 18. Warltier DC, Pagel PS, Kersten JR. Approaches to the prevention of perioperative myocardial ischemia. Anesthesiology. 2000;92:253– 259. 19. Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Their role in postoperative outcome. Anesthesiology. 1995; 82:1474–1506. 20. Nygard E, Kofoed KF, Freiberg J, et al. Effects of high thoracic epidural analgesia on myocardial blood flow in patients with ischemic heart disease. Circulation. 2005;111:2165–2170. 21. Taniguchi M, Kasaba T, Takasaki M. Epidural anesthesia enhances sympathetic nerve activity in the unanesthetized segments in cats. Anesth Analg. 1997;84:391–397. 22. Peyton PJ, Myles PS, Silbert BS, Rigg JA, Jamrozik K, Parsons R. Perioperative epidural analgesia and outcome after major abdominal surgery in high-risk patients. Anesth Analg. 2003;96:548– 554. 23. Qaseem A, Snow V, Fitterman N, et al. Risk assessment for and strategies to reduce perioperative pulmonary complications for patients undergoing noncardiothoracic surgery: a guideline from the American College of Physicians. Ann Intern Med. 2006;144:575–580. 24. Warner DO. Preventing postoperative pulmonary complications: the role of the anesthesiologist. Anesthesiology. 2000;92:1467– 1472. 25. Wu CL, Cohen SR, Richman JM, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology. 2005;103:1079–1088. 26. Gruber EM, Tschernko EM, Kritzinger M, et al. The effects of thoracic epidural analgesia with bupivacaine 0.25% on ventilatory mechanics in patients with severe chronic obstructive pulmonary disease. Anesth Analg. 2001;92:1015–1019. 27. Groeben H, Schafer B, Pavlakovic G, Silvanus MT, Peters J. Lung function under high thoracic segmental epidural anesthesia with ropivacaine or bupivacaine in patients with severe obstructive pulmonary disease undergoing breast surgery. Anesthesiology. 2002;96:536–541. 28. Ballantyne JC, Carr DB, de Ferranti S, et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesth Analg. 1998;86:598–612. 29. Mythen MG. Postoperative gastrointestinal tract dysfunction. Anesth Analg. 2005;100:196–204. 30. Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus. Neurogastroenterol Motil. 2004;16(uppl 2):54–60. 31. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006;367(9522):1618–1625. 32. Jorgensen H, Wetterslev J, Moiniche S, Dahl JB. Epidural local anaesthetics versus opioid-based analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after abdominal surgery. Cochrane Database Syst Rev. 2000:CD001893. 33. Bombeli T, Spahn DR. Updates in perioperative coagulation: physiology and management of thromboembolism and haemorrhage. Br J Anaesth. 2004;93:275–287.

Effect of Epidural Analgesia on Postoperative Outcomes 34. Moraca RJ, Sheldon DG, Thirlby RC. The role of epidural anesthesia and analgesia in surgical practice. Ann Surg. 2003;238:663– 673. 35. Bew SA, Bryant AE, Desborough JP, Hall GM. Epidural analgesia and arterial reconstructive surgery to the leg: effects on fibrinolysis and platelet degranulation. Br J Anaesth. 2001;86:230–235. 36. Christopherson R, Beattie C, Frank SM, et al. Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery. Perioperative Ischemia Randomized Anesthesia Trial Study Group. Anesthesiology. 1993;79: 422–434. 37. Tuman KJ, McCarthy RJ, March RJ, DeLaria GA, Patel RV, Ivankovich AD. Effects of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg. 1991;73:696–704. 38. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000;93:1123–1133. 39. Macrae WA. Chronic pain after surgery. Br J Anaesth. 2001;87:88– 98. 40. Lavand’homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery. Anesthesiology. 2005;103:813–820. 41. Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients: a systematic review. Anesth Analg. 2006;102:1255–1266. 42. Vaurio LE, Sands LP, Wang Y, Mullen EA, Leung JM. Postoperative delirium: the importance of pain and pain management. Anesth Analg. 2006;102:1267–1273. 43. Sido B, Teklote JR, Hartel M, Friess H, Buchler MW. Inflammatory response after abdominal surgery. Best Pract Res Clin Anaesthesiol. 2004;18:439–454. 44. Buggy DJ, Doherty WL, Hart EM, Pallett EJ. Postoperative wound oxygen tension with epidural or intravenous analgesia: a prospective, randomized, single-blind clinical trial. Anesthesiology. 2002;97:952–958. 45. Beilin B, Shavit Y, Trabekin E, et al. The effects of postoperative pain management on immune response to surgery. Anesth Analg. 2003;97:822–827. 46. Yokoyama M, Itano Y, Katayama H, et al. The effects of continuous epidural anesthesia and analgesia on stress response and immune function in patients undergoing radical esophagectomy. Anesth Analg. 2005;101:1521–1527. 47. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006;105:660–664. 48. Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA Jr, Wu CL. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA. 2003;290:2455–2463.

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49. Wu CL, Cohen SR, Richman JM, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology. 2005;103:1079–1088. 50. Richman JM, Liu SS, Courpas G, et al. Does continuous peripheral nerve block provide superior pain control to opioids? A metaanalysis. Anesth Analg. 2006;102:248–257. 51. Wu CL, Naqibuddin M, Rowlingson AJ, Lietman SA, Jermyn RM, Fleisher LA. The effect of postoperative analgesia on quality-of-life measurements. Anesth Analg. 2003;97:1078–1085. 52. Royse C, Royse A, Soeding P, Blake D, Pang J. Prospective randomized trial of high thoracic epidural analgesia for coronary artery bypass surgery. Ann Thorac Surg. 2003;75:93–100. 53. DeCherney AH, Bachmann G, Isaacson K, Gall S. Postoperative fatigue negatively impacts the daily lives of patients recovering from hysterectomy. Obstet Gynecol. 2002;99:51–57. 54. Anderson AD, McNaught CE, MacFie J, Tring I, Barker P, Mitchell CJ. Randomized clinical trial of multimodal optimization and standard perioperative surgical care. Br J Surg. 2003;90:1497– 504. 55. Cronin AJ, Keifer JC, Davies MF, King TS, Bixler EO. Postoperative sleep disturbance: influences of opioids and pain in humans. Sleep. 2001;24:39–44. 56. Liu SS, Wu CL. Effect of postoperative analgesia on major postoperative complications: a systematic update of the evidence. Anesth Analg. 2007;104:689–702. 57. Carli F, Mayo N, Klubien K, Schricker T, Trudel J, Belliveau P. Epidural analgesia enhances functional exercise capacity and health-related quality of life after colonic surgery: results of a randomized trial. Anesthesiology. 2002;97:540–549. 58. Myles PS, Hunt JO, Nightingale CE, et al. Development and pyschometric testing of a quality of life recovery score after general anesthesia and surgery in adults. Anesth Analg. 1999;88:83–90. 59. Leslie K, Troedel S, Irwin K, et al. Quality of recovery from anesthesia in neurosurgical patients. Anesthesiology. 2003;99:1158– 1165. 60. Sauaia A, Min SJ, Leber C, Erbacher K, Abrams F, Fink R. Postoperative pain management in elderly patients: correlation between adherence to treatment guidelines and patient satisfaction. J Am Geriatr Soc. 2005;53:274–282. 61. Myles PS, Williams DL, Hendrata M, Anderson H, Weeks AM. Patient satisfaction after anaesthesia and surgery: results of a prospective survey of 10811 patients. Br J Anaesth. 2000;84:6– 10. 62. Jamison RN, Ross MJ, Hoopman P, et al. Assessment of postoperative pain management: patient satisfaction and perceived helpfulness. Clin J Pain. 1997;13:229–236. 63. Kehlet H, Dahl JB. Anaesthesia, surgery, and challenges in postoperative recovery. Lancet. 2003;362:1921–1928.

42 Research in Acute Pain Management Craig T. Hartrick and Garen Manvelian

The current revision of this textbook is a testament to the ongoing evolution of new techniques, agents, and devices specifically for the management of acute pain. Medical practice generally has concurrently evolved to a state where clinical practices are increasingly guided by thoughtful review of the best available evidence. Consequently, the ability to judge the evidence from clinical trials, no longer the exclusive province of editors and academics, is now of primary importance to all clinicians. Clinical analgesic trials serve two masters. Regulatory agencies require evidence of safety and efficacy. Practitioners require clinically relevant evidence to establish or modify best practices in caring for their patients. The resultant jargon, acronyms, and procedural peculiarities that accompany the merger of these two purposes can present a challenge to clinicians not familiar with research methods as they attempt to judge the quality and practical applicability of this evidence. Similarly, the terminology used to provide the rationale behind the clinical trial process can seem like a language unto itself. The purpose of this chapter is to briefly translate some of the more common terms, explain the rationale behind their use and misuse, and point out frequently encountered pitfalls in trial design. Our intention in this brief introduction to the interpretation of clinical trials is to assist the research na¨ıve clinician to better evaluate the quality of published analgesic studies.

the Declaration of Helsinki and the Guidelines for Good Clinical Practice (GCP) of the International Conference of Harmonization (ICH). Even though basic principles of these regulations, such as “ . . . ethical and scientific quality standard for designing, conducting, recording and reporting trials . . . ”1 are applicable to all clinical trials, they are specifically aimed for trials to be submitted to regulatory authorities for marketing approval of new products. These clinical trials are commonly classified as phase 1, 2, 3, or 4, with the understanding that the drug/device product progresses through these phases gradually. Sometimes it is difficult to classify a clinical trial into 1 phase or another, but general study phase objectives are outlined below. Phase 1 clinical trials are usually performed in healthy male volunteers (not patients) in a specialized clinic providing around-the-clock observation. These trials are designed to determine pharmacologic actions of a drug with specific emphasis on clinical pharmacology related to absorption, distribution, metabolism, and elimination (ADME). Also, phase 1 trials may evaluate drug exposure with respect to certain subpopulations (eg, gender, age, subjects with impaired hepatic or renal function) and food effect. Further, phase 1 clinical trials may evaluate effect of certain concomitant medications on metabolism of a drug or effect of a drug on selected concomitant medications. Another important goal of a phase 1 trial can be to establish tolerability to a drug product at dose levels higher than the projected clinical dose. Phase 2 clinical trials are conducted in patients and usually are controlled and blinded. They are designed to begin the evaluation of the effectiveness of the drug for a particular indication and to determine short-term side effects and risks associated with the drug. Importantly, the goal of these trials is to estimate safe and effective doses and explore relevant study methodologies for future phase 3 studies. After establishing the initial pharmacokinetics and understanding basic safety and efficacy, phase 3 studies commence with selected doses. Phase 3 trials, also usually controlled and blinded, are conducted in patients under “real-life” conditions. They are designed to confirm the efficacy and safety profiles in a specific target population. Phase 4 clinical trials, which typically take place after marketing approval, further refine safety

W H AT I S T H E P U R P O S E O F A C L I N I C A L T R I A L ?

A clinical trial is a prospective research study to evaluate effects of intervention, pharmacologic, or biological product(s) or use of a device in human volunteers. A clinical trial can be initiated by various public or private organizations, government agencies, universities, and/or individual investigators. The clinical trials vary significantly based on goals they are set to pursue. When designed and executed appropriately, the clinical trials generate valid data, which in turn play a very important (if not the most important) role in evidence-based medicine. There are international and country-specific regulations governing the conduct of clinical trials in human subjects, such as 646

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and efficacy in the general population and, in additional subpopulations, address dose recommendations in specific clinical situations, identify less common adverse effects, and evaluate new end points (eg, pharmacoeconomics). H OW D O W E K N OW T H E T R I A L WA S C O N D U C T E D A P P RO P R I AT E LY ?

All clinical trials must adhere to high ethical standards. It is seldom that all subjects/patients participating in a clinical trial benefit from it directly because of the fact that the currently accepted standard for clinical trials employs randomization with the consequent chance of being assigned to a placebo treatment arm or to inadequate treatment due to dose evaluation. As a result, every clinical protocol must have built-in criteria for adequate rescue medications or intervention or patient withdrawal on demand from the trial. When there is a conflict between the needs of the particular clinical trial and the needs of the subject/patient, the best interest of the subject should always prevail. To ensure that procedures employed by the protocol are consistent with sound research methodology, and to evaluate the risk/benefit ratio to subjects, each protocol must be evaluated by an Institution Review Board (IRB). Responsibilities of the IRB do not end with the initial approval. IRB must continue evaluating the clinical trial at intervals appropriate to the degree of risk associated with the trial but not less that once per year. In addition to the protocol review and approval, the IRB must ensure that the informed consent presented to the subject adequately describes the clinical trial at a language level (eighth grade) understandable to the subject or the representative. With rare exception, no subject can be involved in a clinical trial without obtaining effective informed consent of the subject or the subject’s legally authorized representative. This consent needs to be obtained under circumstances that provide the prospective subject or representative sufficient opportunity to consider whether to participate while minimizing the possibility of coercion or undue influence. In light of the above, administration of the consent to the subject the morning of surgery for a clinical trial evaluating a pre-, intra- or postoperative investigational product may be viewed as inadequate unless additional efforts are made to ensure ample time is given to the subject to evaluate his/her participation in the trial (eg, presentation and discussion of the protocol by study personnel in advance by phone or during earlier visit or by simply mailing the consent form to the subject). The pharmaceutical industry has been long criticized as biased by publishing and promoting only positive trial results. In a response to this critique, the Pharmaceutical Research and Manufacturers of America (PhRMA) announced their commitment for timely communication of meaningful results of controlled clinical trials of marketed or investigational products that are approved for marketing, regardless of outcome. This initiative is voluntary and is not guaranteed.2 Further, in addressing this issue the International Committee of Medical Journal Editors (ICMJE) member journals require authors to register their trial in a registry that meets several criteria. The registry must be accessible to the public at no charge. It must be open to all prospective registrants and managed by a not-for-profit organization. There must be a mechanism to ensure the validity of the registration data and the registry should be electronically searchable. An acceptable registry must include at minimum the

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data elements in the following table (Table 42.1). Trial registration with missing fields or fields that contain uninformative terminology is inadequate.3 One such database meeting these requirements was established by the U.S. National Institutes of Health (NIH), through its National Library of Medicine (NLM). This database (ClinicalTrials.gov)4 was developed in collaboration with the Food and Drug Administration (FDA) as a result of the FDA Modernization Act, which was passed into law in November 1997. In May 2007, ClinicalTrials.gov contained over 36 000 clinical studies sponsored by the National Institutes of Health, other federal agencies, and private industry. Finally, all participants in the peer review and publication process must disclose all relationships that could be viewed as presenting a potential conflict of interest.5 In addition, FDA requires sponsors to collect and file with a new drug application financial disclosure of investigators participating in pivotal registration trials. As a rule, pharmaceutical companies check the debarment list published by FDA for firms or persons debarred from assisting or performing clinical investigation.5

D I D T H E AU T H O R S E S TA B L I S H A T E S TA B L E , C L I N I C A L LY R E L E VA N T S T U DY Q U E S T I O N ?

The trial objectives, both primary and secondary, must be clearly stated a priori. The subsequent trial design and its end points must establish the framework as to how these objectives are to be assessed and define the patient population on which the clinical trial is to be conducted. The objectives of the trial must be very specific, such as “to evaluate pharmacokinetic profile of . . . ,” “to compare efficacy of medicine X vs. Y,” or “to assess dose response of . . . ,” and so on. It is important to keep in mind that if many objectives are built into a single clinical trial, the subsequent data analyses may be cumbersome or impossible (not adequate patient representation) and it may impact statistical power of the study. Noncritical, secondary objectives may be presented in the trial for exploratory purposes only, which in turn may help to design subsequent trial(s). When primary objectives fall short, the tendency to seek positive findings through multiple comparisons, subgroup analyses, and other data chasing maneuvers reduces the clinical impact accordingly, even when statistically significant. The nature of the compound under evaluation (eg, nonsteroidal anti-inflammatory drugs [NSAIDs] vs opioids) will determine the appropriate patient population and choice of the comparator or control. As the following sections will show, the ideal study question should be feasible, novel, ethical, and relevant.6 Pitfalls related to each of these factors are possible.

H OW WA S T H E P R I M A RY E F F I C AC Y VA R I A B L E D E F I N E D ?

After the establishment of the study question, there is perhaps no more important feature of a clinical report than a clearly defined primary efficacy variable. The reader should at once be able to see that the measure selected accurately captures the most salient efficacy information and that this information will answer the study question. Feasibility then relates to the ability of the primary outcome variable to be directly measured. It is paramount

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Table 42.1: Minimal Registration Data Set.a Item

Comment

1.

Unique trial number

The unique trial number will be established be the primary registering entity (the registry)

2.

Trial registration date

The date of registration will be established by the primary registering entity

3.

Secondary IDs

May be assigned by sponsors or other interested parties (there may be none)

4.

Funding source(s)

Name of the organization(s) that provided funding for the study

5.

Primary sponsor

The main entity responsible for performing the research

6.

Secondary sponsor(s)

The secondary entities, if any, responsible for performing the research

7.

Responsible contact person

Public contact person for the trial, for patients interested in participating

8.

Research contact person

Person to contact for scientific inquiries about the trial

9.

Title of the study

Brief title chosen by the research group (can be omitted if the researchers wish)

10.

Official scientific title of the study

This title must include the name of the intervention, the condition being studied, and the outcome (eg, The International Study of Digoxin and Death from Congestive Heart Failure)

11.

Research ethics review

Has the study at the time of registration received appropriate ethics committee approval (yes/no)? (It is assumed that all registered trials will be approved by an ethics board before commencing.)

12.

Condition

The medical condition being studied (eg, asthma, myocardial infarction, depression)

13.

Intervention(s)

A description of the study and comparison/control intervention(s) (for a drug or other product registered for public sale anywhere in the world, this is the generic name; for an unregistered drug, the generic name or company serial number is acceptable). The duration of the intervention(s) must be specified.

14.

Key inclusion and exclusion criteria

Key patient characteristics that determine eligibility for participation in the study.

15.

Study type

Database should provide drop-down lists for selection. This would include choices for randomized versus nonrandomized, type of masking (eg, double-blinded, single-blinded), type of controls (eg, placebo, active), and group assignment, (eg, parallel, crossover, factorial)

16.

Anticipated trial start date

Estimated enrollment date of the first participant

17.

Target sample size

The total number of subjects the investigators plan to enroll before closing the trial to new participants.

18.

Recruitment status

Is this information available (yes/no) (If yes, link to information).

19.

Primary outcome

The primary outcome that the study was designed to evaluate Description should include the time at which the outcome is measured (e.g., blood pressure at 12 months)

20.

Key secondary outcomes

The secondary outcomes specified in the protocol. Description should include time of measurement (e.g., creatinine clearance at 6 months).

a

The data fields were specified at a meeting convened by the WHO in April 2005; the explanatory comments are largely from the ICMJE.

that the primary efficacy variable be defined in advance of the conduct of the study as it is the key to the design of the entire study. Consequently, the validity of the result is severely compromised when failure to firmly establish the primary efficacy variable turns the study into a fishing expedition. Making objective assumptions about a subjective pain experience is the Achilles’ heel of analgesic clinical trials. Although positron emission tomography, functional magnetic resonance imaging, and other technologies may allow us to quantitatively

measure sensory and affective elements of analgesic trials independently,7 the patients’ interpretation of the overall integrated pain experience is best reflected by their response. A number of scales have been validated as a means of assessing pain levels at a given point in time. Other scales assess alternative dimensions of the pain experience such as pain relief or impressions of change and require subjects to remember their previous pain state and then make the appropriate judgments. Self-reports of pain, relief of pain, and global assessments of pain

Research in Acute Pain Management

relief remain the best, although imperfect, measures by which analgesics are judged.

Pain Measurement Pain measurements can be nominal (yes or no), categorical (often arranged as Likert scales with increasing degrees of pain), or continuous measures that may have ratio characteristics. Previously referred to as the gold standard for self-reported pain in analgesic studies, the visual analog scale (VAS) is an example of the latter. Typically the VAS for pain is a 10-cm horizontal line anchored at the left with the number 0 and the comment no pain and anchored on the right with the number 10 and the comment worst pain possible. The subject is asked to place a single vertical mark on the line at the point that corresponds to their present pain intensity. The resultant score determined by measuring the distance from the left-hand anchor (0) to the point where the vertical line crosses the horizontal. Because subjects are free to choose any point along the line, a continuous range of choices is available and in most circumstances the VAS is considered a ratio measure.8 Continuous ratio variables may be manipulated arithmetically, which is a major advantage. The numeric rating scale (NRS) has certain similarities to the VAS. Here the subject verbally reports a score on an 11-point scale, from 0 to 10, again where 0 represents no pain and 10 represents the worst pain possible. Clearly NRS scores should never be intermingled with VAS scores: the VAS is continuous; the NRS uses 11 discrete, ranked, whole number responses. Still, the NRS has often been considered a ratio measure and thus a suitable substitute for VAS.9 Caution must be advised, however, as this ratiolike relationship does not apply in all circumstances.10 Unless the NRS has been demonstrated to be a ratio measure in the specific study situation, it would be arguably better treated with nonparametric statistical methods, thus avoiding assumptions regarding the population distribution. Ordered categorical pain measurement instruments commonly used include assessment of present pain intensity using the 4-point verbal rating scale (VRS: none = 0; mild = 1; moderate = 2; severe = 3), and for evaluating change in pain intensity the 5-point pain relief scale (no relief = 0; a little = 1; moderate = 2; a lot = 3; complete = 4), and a 7-point patient global impression of change scale (PGIC). The assignment of numerical values is arbitrary: arithmetic operations involving these values should be limited. Continuous and categorical pain measurement scales are presented in Chapter 11, Qualitative and Quantitative Assessment of Pain.

Significant Pain Reduction To study pain, some pain must be present. How much pain needs to be present to ensure studies performed are sufficiently sensitive to evaluate analgesics remains a significant issue. A clinically analogous dilemma arises when one considers how much pain should be present before an intervention is offered. The VAS is often used to determine the point at which pain intervention may be required. Just as some trial designs may require moderate pain or a VAS pain score of “4 cm” prior to subject randomization, institutional credentialing bodies may determine that pain scores at or above “4 cm” ethically require intervention. This breakpoint is commonly considered the division between “mild” and “moderate” pain. The pathophysiology underlying this, however, may relate to the nature of the nociceptors themselves or to

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psychometric peculiarities wherein subjects are unconsciously relaying additional embedded satisfaction information. Consequently, an exponential rise in response may occur once a certain stimulus threshold is reached. There is no reason to assume that any simple arithmetic relationship holds up, for example, in the transition from “moderate” to “severe” pain, as once the threshold is crossed the rise in reported pain might not be linear with increasing stimulus intensity.11 This highlights the need to avoid the common mistake of treating values artificially assigned to ordinal measures with simple arithmetic manipulations. Fortunately, when used to make individual patient comparisons of pain relief, a remarkably linear response does seem to apply. Bernstein et al12 reported that when simultaneously using the VAS and the 5-point pain relief scale the difference between no relief and mild relief, mild relief and moderate relief, and moderate relief and a lot of relief was 2.2, 1.8, and 1.8 cm on the VAS, respectively. This finding has other practical implications in trial design. The minimally clinically meaningful change in pain is commonly defined as 2 cm,13 which correlates nicely with movement from one pain relief category to another. Additionally, PGIC categories of much improved and very much improved have been used to determine the minimally significant change in NRS.14 A 30% reduction in NRS was needed regardless of the initial pain level. Therefore higher baseline pain levels required larger reductions making the NRS, as previously noted, nonlinear.10 Still, there is a long history of assigning numerical scores to categorical measures for pain and then manipulating these scores arithmetically as if they were ratio measures.15 The justification has been that good correlations have been observed between these Likert scales for pain (perhaps even more so for pain relief scales) and continuous measures. In analyzing individual patient data from 11 postoperative pain trials, including in excess of 1000 subjects, Collins et al16 reported the VAS (100-mm scale) for moderate pain was 49±17 mm (mean±SD) and for severe pain was 75±18 mm. Nevertheless, despite seemingly good correlation at these two specific points (moderate and severe), intermediate points on the Likert scales were not examined. Therefore one should not necessarily assume a linear relationship from 0 to 100 mm. Other possibilities exist, such as a sigmoidshaped curve with an inflection point at 50 mm. It should therefore be borne in mind that categorical variables with arbitrarily assigned numerical values for pain, although frequently manipulated as if they were continuous variables, are not ratio measures. This becomes of further practical significance when we go on to add, subtract, divide, and otherwise manipulate these arbitrary values; the more the values are remanufactured, the greater the disparities between computed and actual results may become. Although self-report is by far the preferred method of assessment, observational methods are needed when subjects have cognitive impairment, are under the influence of sedatives or anesthetic agents, or have not yet reached the developmental age required for abstract reasoning needed to understand of the concept of proportions. In contrast to the limited number of observational pain scales for cognitively impaired adults, a number of age-specific observational scales are used in pediatrics. There is also evidence that some scales may be preferred in distinguishing painful from nonpainful (related to anesthetic emergence, separation-anxiety, etc.) postoperative situations.17 Importantly, regardless of how they are scored, observational pain scores must be treated as ordinal measures.

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Figure 42.1: In this example, the curve represents the theoretical analgesic effect of a treatment. Intermittent pain measurements taken at 30 minutes, 1 hour, and 2 and 3 hours following administration resulted in decreases in VAS for pain from the baseline measurement (at time = 0) of 16, 36, 52, and 18 mm, respectively. The product of the elapsed time since the last measurement and the change in VAS represent TOTPAR (total pain relief; shaded area), which approximates the area under the curve (AUC).

Summary Measures Thus far the pain measures discussed have been derived from snapshots in time. Although differences in pain scores following specific interventions are calculated, no understanding of the total amount of suffering, or at any time points between the measurements can be inferred. Attempts to quantify a total “amount” of pain could theoretically be derived by continuously measuring a ratio measure of pain over a period of time and then using calculus to integrate the curve, thus establishing a “total quantity” of pain suffered (area under the curve, AUC) over the entire study. Aside from the fact that near-continuous assessments are impractical, they also would affect the outcome, thus confounding the measurements. However, regularly spaced assessments are used in this fashion as a crude approximation to better capture the overall pain experience. One must be mindful of the fact that the spacing of the assessments can unwittingly skew the results, especially when the measurement intervals are unequal, even when properly weighted. Additional philosophical questions also arise with practical clinical relevance: is a prolonged period with a VAS of 5 worse than a brief period at 10? One commonly used summary measure is total pain relief (TOTPAR). When reductions in pain intensity (ie, pain relief), as measured ideally using the VAS (or other validated ratio measure), are measured over time, the time-weighted resultant summation value (approximating the AUC) is termed TOTPAR (Figure 42.1). The related measure, summed pain intensity difference (SPID), considers differences in baseline pain intensity. SPID is calculated in an analogous fashion to TOTPAR, but instead of using pain relief scores, SPID uses PID (pain intensity difference scores). PID scores are derived by subtracting each subsequent score from the baseline value. Positive PID scores are also a measure of “pain relief.” Various other mathematical manipulations are commonly used, such as %SPID, where SPID is divided by the maximum possible SPID that would be obtained if the subject were pain free throughout the entire observation

period. The justification for this further manipulation is a correction to account for the potentially much larger reduction in pain in subjects starting with higher initial pain scores. The concept of a percentage of subjects experiencing the maximum analgesic effect (%maxTOTPAR) has been used to compare analgesics and as a means of combining data to perform meta-analyses.18 It can also be used to calculate number needed to treat (NNT) values. The number of patients you would need to treat to have one patient with at least 50% pain relief is one definition of NNT that on the surface would appear to have clear clinical implications. The addition of 95% confidence interval (95%CI; if repeated, 19 of 20 confidence intervals on average would contain the population mean) places the NNT data in perspective. Yet direct extrapolation of NNT data from a given study to other pain models remains clinically suspect.19 Agents with differing modes of action might behave differently in various clinical circumstances, making direct comparisons only valid for similar settings. For example, an agent with strong anti-inflammatory properties may work better than a strong opioid in inflammatory pain settings but less well in the absence of inflammation. The commonly accepted use of pooled TOTPAR values derived from categorical measures, instead of continuous measures, might also contribute to the difficulties in generalization. The odds ratio (OR) represents an alternative method for analgesic efficacy comparisons. The odds of a given event occurring (such as the odds of experiencing at least 50% relief), divided by the odds of an alternative event (the placebo or comparator analgesic producing at least 50% relief) defines the OR. As with the NNT, OR analysis lends itself to the analysis of dichotomous adverse events, such as the presence or absence of nausea. For example, if treatment A resulted in 4 of 10 subjects becoming nauseated (6 subjects not nauseated; odds of nausea 4/6 or 0.67), and treatment B resulted in nausea in 6 of 10 subjects (odds of nausea 6/4 or 1.5), then the OR is 0.44 (0.67 divided by 1.5). An odds ratio of 1 represents even money, equal odds. An odds ratio of less than 1 means the event is less likely in the first group; conversely an odds ratio of greater than 1 means the event is more likely in the first group. Once again the confidence interval provides needed perspective. Not only does the CI reflect a dichotomous (yes or no) judgment regarding the statistical significance, the magnitude of its range provides a sense of precision, potentially affecting the clinical significance. A narrow range, as may be seen in large studies with many subjects, suggests greater credibility. Again, if the 95%CI includes the value 1, then the chance of “even money” (ie, no significant difference between groups) falls within that range of probability. Relative risk (RR), defined as the ratio of probabilities (example above: 4/10 divided by 6/10), is perhaps more intuitive but not always easily determined because we often arbitrarily assign subjects into equal groups, thus distorting true incidence (and probability) information. Odds, rather than probabilities, are the basis for a number of statistical approaches. Moreover, the reciprocal relationship between the odds in favor and the odds against an event are additional mathematical benefits. These mathematical advantages often translate into greater utility in the clinical setting. In an attempt to evaluate the performance of investigational drugs in clinical trial settings, Silverman et al20 proposed an integrated assessment of the pain scores and rescue morphine used during the same evaluation period. Each parameter is expressed as a percent difference from the mean rank for that variable in

Research in Acute Pain Management

the overall study population. The percentage differences for each parameter are summated on a per-subject basis. The data can be analyzed comparing the treatment groups with standard statistical tests. Although unpublished, we have successfully utilized this method in several clinical trials. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group recommended the adoption of 6 core outcomes in chronic pain analgesic studies (pain, physical functioning, emotional functioning, ratings of improvement and satisfaction with treatment, symptoms and adverse effects, and subject disposition).21 Health-related quality of life (HRQoL), functional outcomes, time to discharge, ease of care, and pharmacoecomomic measures are increasingly frequent secondary outcomes in acute pain analgesic trials. HRQoL share certain characteristics with global indices wherein they rely on the subjects’ memory for pain and other health-related measures. Although memory for pain has long been regarded with skepticism, recent evidence supports its use in the design and implementation of pain assessment instruments.22 H OW D O E S T H E S T U DY D E S I G N A F F E C T I N T E R P R E TAT I O N ?

Ethical considerations require that all subjects be afforded access to analgesics in the presence of conditions that are expected to be painful. The analgesic-sparing or morphine-sparing design is common. With this approach subjects in each group may be afforded equal opportunity for analgesia in which theoretically may result in equivalent pain scores. In this case, comparisons are made with respect to the amount of additional rescue analgesic required (or spared) to achieve adequate pain control. As a result, various end points can be defined with respect to the lower bound of the CI corresponding to inferiority, equivalence, or superiority. These designs can be used with active comparator agents, yet do not preclude the use of placebo, as a sham/placebo group also has access to rescue analgesia. Interpretation of trial results based on this endpoint from the clinician’s standpoint is difficult, because “clinically meaningful” opioid-sparing effect is not defined. Further, regulatory agencies are reluctant to accept this as a primary end point. Randomized controlled trials (RCT), especially when double blinded and placebo controlled, are considered to provide the highest level of evidence in the establishment of best practice. This gold standard has recently come into question, especially as it relates to the study of invasive analgesic techniques.23 Double-blind, double-dummy designs generally have two treatment groups. One group receives active treatment A and sham treatment B, whereas the other group receives active treatment B and sham treatment A. Double-blind, double-dummy designs, although cumbersome, offer the advantage of canceling out the “novelty” factor associated with new technology. Additional ethical considerations involving the use of placebo in clinical trial design are discussed elsewhere.24 The a priori determination of how missing data (inevitable in longitudinal studies) will be handled is critical to study design. The proper handling of missing data is not only important because of a loss of power (fewer observations), but data missing “not at random” can introduce bias that complicates interpretation of the study results. For example, subjects may withdraw because of factors related to an outcome measure. Whether missing data values will be ignored or imputed, either based on data

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points before and after the missing point or by carrying forward the last recorded value, can have significant effects of summated measures. The choice of one approach over another should be dictated by the clinical relevance and will vary depending on the variable being measured. Although there can be many definitions, commonly the intention-to-treat (ITT) analysis considers all subjects randomized, regardless of whether they follow or complete the protocol. With this definition the pendulum has swung to the extreme. In an attempt to guard against bias introduced when dropout is related to outcome, subjects are included in the treatment group who may not have actually been exposed to the treatment if that is where they were originally assigned. At worst this process can confuse the interpretation of the results and at best it dilutes the results if one assumes that dropouts, because of events unrelated to the outcome, will occur in equal frequencies in all groups. The addition of a Consolidated Standards of Reporting Trials (CONSORT diagram) is of significant benefit in interpreting RCT trials and is required by many journal editors.25 The progress of subjects through a trial and the reasons for discontinuation are clarified using the CONSORT diagram, thus aiding interpretation and clinical application (Figure 42.2). Bias control for confounding effects extends beyond randomization and the use of placebo and sham. The observers may affect the subjects’ response in ways that might not be readily apparent. For example, both the gender and professional status of the observer can affect subjects’ pain score.26 In an experimental pain setting, subjects tolerated pain longer when they were tested by an observer of the opposite sex and when the observer was considered a professional. Further, higher pain intensities were reported when tested by females. Other subtle cues can bias responses, making specific scripting when questioning subjects ideal. Finally, crossover trials are sometimes used to control for bias introduced by interindividual differences in subjects. Instead of matching subjects in different groups for comparison, each subject serves as his/her own control by sequentially receiving both treatments. Inherent in the design is the assumption that the order of treatment has no bearing on the results. This assumption can be valid only if there is no carryover effect from the initial treatment that might contaminate the results of the subsequent treatment. Typically a “washout” period is defined in an attempt to reduce carryover effects. The clinical relevance of this interval must be carefully assessed as other motivations in the design of the trial may be at play to shorten this period. The ethical need to limit periods without treatment and to reduce dropout of subjects due to reduced satisfaction when the trial periods are drawn out are practical design considerations. Moreover, although the crossover design lends itself well to the comparison of 2 alternative treatments, analysis and interpretation are somewhat more complicated when 3 or more groups are studied, such as in dose-finding trials or combination therapy trials. As in the examples previously mentioned, assuring that the appropriate nonparametric tests are used for categorical measures that account for period effects, when necessary, is critical to the believability of the results. A R E T H E R E S U LT S B E L I E VA B L E ?

Unfortunately, published reports where the authors have statistically treated categorical measurements as if it were normally

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Figure 42.2: Consolidated Standards of Reporting Trials (CONSORT) diagram.22

distributed continuous values is not a rare occurrence. Although one expects the peer review process and editorial oversight to identify these errors before publication, vigilance in carefully dissecting clinical reports cannot be overemphasized. Yet believability goes beyond recognition of whether the correct statistical tests are selected for the type of data being analyzed. The results must be viewed within a clinically relevant context. Confidence intervals are aptly named and as previously mentioned help add perspective. But exactly what is the chance that the results presented in a clinical trial are spurious? This assessment requires consideration of several factors. Most readers are familiar with type I errors, false positives, where a difference between groups is falsely declared. The risk of making this type of error is defined by the P value. A P value of .05 is most common, where the risk of a type I error (␣) is 5% (ie, a 1 in 20 risk that the difference between groups is at least as large as that observed if the null hypothesis were true, no difference between groups). Although the statistical significance level is often set at 0.05, it too is arbitrary.27 Clinically significant differences may well be accepted at other levels depending on the alternative risks. However, one might expect these significance levels to be defined prior to the onset of the trial and not raised later using terms such as trend to describe results that fail to meet predefined expectations. Another approach is to consider the introduction of prior experience to guide the analysis. This could potentially be especially helpful for trials involving invasive techniques, as the approach might allow researchers to limit unnecessary exposure to sham procedures.28 Bayesian statistical methods use this

common sense approach based on prior experience but are infrequently used as researchers and editors often lack familiarity.29 In this approach a “prior probability” (often based on previous clinical experience) is assigned and then modified after considering the study results to derive a “posterior probability.” The probability that a given treatment is at least as good as another, although having no meaning when constrained by frequentist statistical analysis (testing against a null hypothesis), it is quite meaningful in Bayesian analysis. Type II errors, false negatives, occur when a true difference exists between groups that goes undetected. This relates directly to the sample size because very small studies may not produce statistically significant results unless the difference between groups is very large. The risk of making this type of error (␤) is commonly set at 0.20, meaning 2 times of 10 a true difference will be missed. Obviously this may be unacceptable in some circumstances. Clinically, if the risk of making this error is considered grievous, then the value can be appropriately adjusted, at the expense of exposing a greater number of subjects to the study. The power of a study is 1 − ␤, often set at 80%. However, by way of example, if the risk of having a false negative result is set at 0.1, then the power is 0.9 or 90%. These values should be set prospectively and are used, along with assumptions as to the variability of the data (eg, standard deviations in the primary efficacy measure), to determine sample size. Failure to perform a power analysis before the study begins compromises the results, especially when negative findings are reported. Secondary end points, unless the study was powered to evaluate these outcomes should be, as the term secondary implies, viewed as lower tier

Research in Acute Pain Management

findings. Suppose 20 different outcomes are examined: A P value of .05 would presume that perhaps 1 outcome would demonstrate a significant difference between groups purely by chance. The simplest method, although by no means the only way of dealing with multiple simultaneous comparisons, is the Bonferroni correction, where the ␣ value is divided (for the entire set of comparisons) by the number of comparisons. This is arguably the most conservative approach to avoiding spurious conclusions. The type of data and the nature of the comparisons to be made between groups dictate the appropriate statistical treatments. As mentioned previously, data can be nominal (dichotomous: yes or no), categorical (no relief, mild or a little relief, moderate relief, lots of relief, complete relief), or continuous (where a range of possible values exist: weight, blood pressure, VAS, etc). Further, the types of tests selected depend on whether the data set fits a normal (bell-shaped curve) or other well-defined distribution. Finally, repeated measures over time require special handling. The most commonly used test for the comparison of two means is the t test. The validity of this approach depends on the equality of the standard deviations of each population. When the standard deviations for the 2 groups are very different and the sample size is small, alternative methods of analysis should be used. When the data consist of pairs of measurements, as in matched case-control studies, or when the same subject is exposed to 2 different treatments, paired t tests may be appropriate. When a well-characterized distribution of outcomes cannot be expected, such as when categorical variables are measured, nonparametric methods based on ranks must be used. In this sense, the Wilcoxon signed rank test is the nonparametric counterpart to the paired t test. Examining differences between multiple groups requires alternative methods such as the 1-way analysis of variance (ANOVA) or the nonparametric Kruskal-Wallis 2-way ANOVA. Correlations are similarly handled with parametric (correlation coefficient) or nonparametric (Spearman’s rank correlation) approaches. Time to event measures are commonly assessed using Kaplan-Meier survival curves. Although many alternative methods are used, the distinction between parametric methods and nonparametric methods is of paramount importance. Critically, the aforementioned tests, although demonstrating relationships, do not assure causality. Common sense must always be the final check. Assessing the relevance and, thus, the importance to everyday clinical practice likewise requires a pragmatic approach. The quality of individual published reports is greatly dependent on an impartial peer review process. Yet how specific reports then affect the larger body of work in an area of study speaks to the study’s impact. Regardless of how impact is measured, conceptually a high-impact study is one that affects the clinicians’ decision-making process. Redefining clinical pathways based on such evidence often requires synthesis of many, often conflicting, reports. The most commonly applied tool to facilitate this process is termed meta-analysis. Meta-analyses attempting to assimilate quality data from many studies are themselves, however, prone to possible bias. Sampling bias can result from publication bias as well as bias introduced by indexing and search strategies. Selection bias as result of inclusion criteria should be clearly defined, whereas selector bias (when study results are considered as nonstated inclusion criteria) may be more difficult to detect. Bias introduced in the analysis itself may also affect the clinical applicabil-

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ity of the conclusions. Quality score bias is very possible unless the scoring system is strictly defined and the method of resolving disagreements between observers is defined. Length of followup is also difficult to control for, leading to time-dependent differences in conclusions drawn. C O N C LU S I O N

As is often the case, more questions have been raised than answers provided. One may rightly wonder that if a sham procedure produces a beneficial effect by virtue of both expectation and reward,30 is it ethical to perform clinical trials that eliminate these effects? If so, are the results obtained, depriving the subjects of this added “placebo” benefit, clinically relevant because the clinical treatment of patients by its nature always comes with a certain context that may itself have meaning?31 One might also question whether RCTs are in fact a gold standard, whether categorical pain assessments may be more clinically relevant that VAS scores, or whether P values actually have any value at all. The design of clinical trials is beyond the scope of this discussion. Certainly future study designs that address these complex issues will emerge. The use of a “cumulative proportion of responders analysis” as a method to make clinical trial data more clinically relevant has recently been proposed and may represent one such advance.32 Instead we have attempted to provide the reader with some insight into what to look for when reading the published report of a clinical trial, how to identify weaknesses or strengths that may decrease or bolster enthusiasm for the findings, and how to assess the clinically applicability of the results.

REFERENCES 1. ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice, E6(R1). International Conference on Harmonisation. 1996. Available at: http://www.ich.org/LOB/media/MEDIA482. pdf. Accessed September 2, 2008. 2. Pharmaceutical Research and Manufacturers of America. Mission Statement. PhRMA: New Medicines, New Hope. 2008. Available at: http://www.phrma.org/mission statement/. Accessed September 2, 2008. 3. International Committee of Medical Journal Editors. Obligation to Register Clinical Trials. Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication. 2007. Available at: http://www.icmje.org/ #clin trials. Accessed September 2, 2008. 4. United States National Institutes of Health. Protocol Registration System. ClinicalTrials.gov. 2008. Available at: http://prsinfo. clinicaltrials.gov/. Accessed September 2, 2008. 5. Food and Drug Administration. Code of Federal Regulations: Title 21 – Food and Drugs; 21CFR1404.800. 2008. Available at: http://frwebgate4.access.gpo.gov/cgi-bin/waisgate.cgi? WAISdocID=37473784732+37+0+0&WAISaction=retrieve. Accessed September 2, 2008. 6. Cummings SR, Browner WS, Hulley SB. Conceiving the research question. In: Hulley SB, Cummings SR, eds. Designing Clinical Research: An Epidemiologic Approach. Baltimore, MD: Williams & Wilkins; 1988;12–17. 7. Geha PY, Baliki MN, Chialvo DR, Harden RN, Paice JA, Apkarian AV. Brain activity for spontaneous pain of postherpetic neuralgia

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Craig T. Hartrick and Garen Manvelian and its modulation by lidocaine patch therapy. Pain. 2007;128:88– 100. Price, DD, McGrath, PA, Rafii, A, Buckingham, B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain. 1983;17:45–56. Breivik, EK, Bjornsson, GA, Skovlund, E. A comparison of pain rating scales by sampling from clinical trial data. Clin J Pain. 2000;16:22–28. Hartrick CT, Kovan JP, Shapiro S. The numeric rating scale for clinical pain measurement: a ratio measure? Pain Pract. 2003;3:310–316. Price, DD, Bush, FM, Long, S, Harkins, SW. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain. 1994;56:217–226. Bernstein SL, Chang A, Esses D, Gallagher EJ. Relationship between intensity and relief in patients with acute, severe pain. Acad Emerg Med. 2005;12:158–159. Farrar JT, Portenoy RK, Berlin JA, Kinman JL, Strom BL. Defining the clinically important difference in pain outcome measures. Pain. 2000;88:287–294. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2002;96:410–411. McQuay HJ, Moore RA. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review. Health Technol Assessment. 1998;2:17–21. Collins SL, Moore A, McQuay HJ. The visual analogue pain intensity scale: what is moderate pain in millimeters? Pain. 1997;72:95– 97. Hartrick CT, Kovan JP. Pain assessment following general anesthesia using the Toddler Preschooler Postoperative Pain Scale: a comparative study. J Clin Anesth. 2002;14:411–415. Moore A, Moore O, McQuay H, Gavaghan D. Deriving dichotomous outcome measures from continuous data in randomised controlled trials of analgesics: use of pain intensity and visual analogue scales. Pain. 1997;69:311–315. Gray A, Kehlet H, Bonnet F, Rawal N. Predicting postoperative analgesia outcomes: NNT league tables or procedure-specific evidence? Br J Anaesth. 2005;94:710–714.

20. Silverman DG, O’Connor TZ, Brull SJ. Integrated assessment of pain scores and rescue morphine use during studies of analgesic efficacy. Anesth Analg. 1993;77:168–170. 21. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113:9–19. 22. Jamison RN, Raymond SA, Slawsby EA, McHugo GJ, Baird JC. Pain assessment in patients with low back pain: comparison of weekly recall and momentary electronic data. J Pain. 2006;7:192– 199. 23. Cahana A. Ethical and epistemological problems when applying evidence-based medicine to pain management. Pain Pract. 2005;5:298–302. 24. Koshi EB, Short CA. Placebo theory and its implications for research and clinical practice: a review of the recent literature. Pain Pract. 2007;7:4–20. 25. Moher D, Schulz KF, Altman D. The CONSORT Statement: revised recommendations for improving the quality of reporting for parallel-group randomized trials. JAMA. 2001;285:1987– 1991. 26. Kallai I, Barke A, Voss U. The effects of experimenter characteristics on pain reports in women and men. Pain. 2004;112:142– 147. 27. Goodman SN. Toward evidence-based medical statistics. 1. The P value fallacy. Ann Intern Med. 1999;130: 995–1004. 28. Hartrick CT. Low back pain: best evidence – best tools. Pain Pract. 2005;5:151–152. 29. Goodman SN. Toward evidence-based medical statistics. 2. The Bayes factor. Ann Intern Med. 1999;130:1005–1013. 30. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci. 1999;19: 484–494. 31. Moerman, Daniel E. The meaning response: thinking about placebos. Pain Pract. 2006:6:233–236. 32. Farrar JT, Dworkin RH, Max MB. Use of the cumulative proportion of responders analysis graph to present pain data over a range of cut-off points: making clinical trial data more understandable. J Pain Symptom Manage. 2006;31:369–377.

43 Quality Improvement Approaches in Acute Pain Management Christine Miaskowski

right way, for the right person – and having the best results.6 These definitions need to guide the development of all quality improvement initiatives.7,8 Initial systematic efforts to evaluate quality came from industry’s efforts to develop quality control standards for manufactured products. In the early 1980s, Deming recognized that the quality of a product was the primary driver for industrial success and introduced systematic measures to evaluate the quality of a variety of products to Japanese engineers and executives. The strategic application of these quality measures produced considerable growth, particularly in the Japanese automobile industry, and led to subsequent worldwide recognition of the importance of quality in the manufacturing of goods and services.9,10

Rapid advances in scientific knowledge and technology mandate that all clinicians actively engage in processes that evaluate the quality of care that they provide to patients and their family caregivers. Nearly a decade ago, the Institute of Medicine released two landmark reports on health care safety and quality, namely To Err is Human and Crossing the Quality Chasm.1,2 These reports mobilized the health care system, as well as the public to demand changes in health care delivery when they noted that medical errors cause 44,000 to 98,000 deaths annually in the United States. In addition, differences in what should be done for patients and what actually is done accounts for more than $9 billion per year in lost productivity and nearly $2 billion per year in health care costs.1,3 Although these two Institute of Medicine reports helped to articulate a broad agenda for quality improvement in health care, progress in improving the quality of care has been relatively slow.4 What appears to be slow progress is somewhat understandable because several recent reviews have acknowledged that the creation of reliable and sustained quality improvement approaches in acute care pose numerous challenges for clinicians.3,5 Quality improvement efforts often require clinicians to change the structures and processes surrounding the delivery of patient care. However, clinicians may not have received education and training in how to develop and implement quality improvement initiatives. The purposes of this chapter include providing an overview of the basics of quality improvement, highlighting the major methodologies that can be used in quality improvement initiatives, and describing guidelines for and approaches to improve the quality of acute pain management.

M E A S U R E M E N T O F Q UA L I T Y I N H E A LT H C A R E

Avedis Donabedian is considered to be the father of quality measurement in health care. In a recent review,11 he described and evaluated the current methods for evaluating the quality of health care. He acknowledged that the measurement of quality in health care rests on a conceptual and operationalized definition of what “quality of health care” means. In addition, he noted that there will never be a single comprehensive criterion by which to measure the quality of patient care. Donabedian championed the idea that quality measurement involved an evaluation of the structures, processes, and outcomes of care. Structural measures assess the availability and quality of resources, management systems, policies, guidelines, and organizational approaches to the provision of care. Structural measures are critical to sustaining processes of care over time. Process measures use the actual processes of health care delivery as an indicator of the quality of care. Usually, process measures examine what clinicians do or analyze the activities of clinicians to determine whether patient care is practiced according to specific standards or guidelines. Outcome indicators measure the end results of care. They depend not only on the results of patient care but also on genetic, environmental, and behavioral factors.

D E F I N I T I O N O F Q UA L I T Y

Quality of health care was defined by the Institute of Medicine as care that is safe, timely, efficient, effective, equitable, and patient centered.2 These terms are defined in Table 43.1. In addition, the Agency for Healthcare Research and Quality defined quality health care as doing the right thing, at the right time, in the 655

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Table 43.1: Institute of Medicine’s Definitions of the Elements of Quality Health Care Aim

Definition

Safe

Freedom from accidental injury. To improve patient safety, health care organizations and professionals must establish and improve systems to minimize the likelihood of errors that do occur, and prevent or mitigate harm from errors that reach the patient.

Effective

The disciplined use of systematically-acquired knowledge to provide services that are likely to benefit patients and refrain from providing services not likely to benefit patients.

Patient centered

Health care that respects and honors patients’ individual wants, needs, and preferences, and that assures that individual patients’ values guide all decisions.

Timely

The flow of care, free of undesired waits and delays for both those who receive care and those who give care. The process flows smoothly and waiting times are continually reduced for both patients and those who give care.

Efficient

The continual reduction of waste in health care, especially waste stemming from errors and overuse of ineffective tests, medications, procedures, technologies, and other interventions. Waste includes any resource use that fails to help meet patients’ needs including materials, supplies, time, forms, measurements, reports, motion, duplicated efforts, ideas not used and information that is lost.

Equitable

The care of populations and individuals. At a population level, the goal of a health care system is to improve health status for all Americans and to do so in a manner that reduces disparities among particular subgroups. For individuals, the provision of health care services should be based on individual needs and not on personal characteristics unrelated to their health condition. In particular, the quality of care should not differ solely because of such characteristics as sex, race, ethnicity, income, education, disability, sexual orientation, or location of residence.

Adapted from: Committee on Quality Health Care in America, Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC, National Academy Press; 2001.

In many quality of care studies, outcome indicators are presented based on an evaluation of a group of patients rather than as individual cases.3,5,11 A list of the strengths and limitations of structure, process, and outcome indicators, as well as examples of each type of indicator relative to acute pain management, are presented in Table 43.2. Q UA L I T Y I M P ROV E M E N T M E T H O D O LO G I E S

A shift has occurred in the evaluation of the quality of care from quality assurance to continuous quality improvement.12–15 Continuous quality improvement promotes the principle that an opportunity for improvement exists in every process of care and on every occasion. Unlike the old quality assurance initiatives,

continuous quality improvement initiatives focus on the development of strategies to improve the quality of patient care and not on the identification of individuals who did not perform to some standard of care. The implementation of continuous quality improvement initiatives requires that a health care organization makes a commitment to constantly improve operations, processes, and activities to meet patient care needs in an efficient, consistent, and cost-effective manner. The continuous quality improvement model emphasizes the view of health care as a process and focuses on the system rather than on the individual when considering how to improve the delivery of patient care.3,12 The process of continuous quality improvement provides organizations with the ability to collect benchmark data, determine the effectiveness of various processes of care, and evaluate whether systematic changes in processes of care improve the quality of care that patients receive.16,17 To achieve the goal of continuous quality improvement in health care, specific methodologies need to be considered and used depending on the goal of the quality improvement initiative. The three most commonly used quality improvement methodologies in health care are plan-do-study-act (PDSA), six sigma, and lean strategies. The choice of a particular methodology depends on the nature of the quality improvement project and on the training of individuals within an organization in a particular methodology. Most of the methodologies use similar techniques. In addition, most of the methodologies include iterative testing of ideas and redesigns of a process of care based on the lessons learned from the quality improvement evaluation.3 Each of these methodologies is summarized below.

PDSA Cycle The PDSA cycle is the most common quality improvement methodology used to date. As illustrated in Figure 43.1, it involves a sequence of four repetitive steps (ie, plan, do, study, act) that is carried out repeatedly in a series of small cycles and eventually leads to exponential improvements. The planning part of the PDSA cycle involves the development of the objectives for the quality improvement study and the development of an action plan to carry out the study. In this phase of the PDSA cycle, the most critical step is the determination of which measures will be used to evaluate a specific structure, process, and/or outcome indicator. In the do phase of the cycle, the evaluation study is done and initial analysis of the study findings occur. As part of the study phase of the PDSA cycle, the study findings are reviewed and evaluated in the context of the outcome indicators. In the act phase, the study findings are presented to clinicians. During this phase, the findings are discussed, an action plan is developed with input from all of the relevant clinicians and stakeholders, and the action plan is implemented. Those individuals involved in the quality improvement initiative will determine when the next PDSA cycle will be repeated to evaluate the magnitude of the improvements that occurred as a result of the action plan. More specific details on implementing the PDSA approach within the context of a continuous quality improvement initiative for acute pain management are provided in subsequent sections of this chapter.

Selection of Quality Measures As mentioned, one of the most difficult tasks within the PDSA cycle is the selection of quality measures based on the quality indicators chosen for a particular project. Quality indicators

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Table 43.2: Strengths and Limitations of Structure, Process, and Outcome Quality Indicators and Examples of Acute Pain Management Indicators Example of an Acute Pain Management Indicator

Indicator

Strengths

Limitations

Structure

Deals with concrete information and accessible information

The relationship between structure, process, and outcome measures are not well established

Patient controlled analgesia pumps are available on all surgical units

Process

Emphasis is placed on whether or not what is known to be “good patient care” was applied Requires that attention be given to specifying the relevant dimensions, values, and standards to be used in the assessment

The estimates of quality may be less stable and less final than those that derive from outcome measures

Pain intensity is documented at frequent intervals

Outcome

Frequently used indicator Validity of the outcome measure is not questioned Outcome measures tend to be concrete measures important to patients

Is it the most relevant measure to evaluate the quality of patient care (eg, survival in the context of palliative care) Many factors other than patient care can influence or confound an outcome measure Some outcomes (e.g., patient satisfaction) are difficult to measure

Acute pain is prevented and controlled to a degree that facilitates function and quality of life

can be classified as structure, process, or outcome indicators that require different types of quality measures. The specific features that define a good quality measure are listed in Table 43.3.18,19 Although members of the team that will evaluate the quality of acute pain management do not need to test the validity, reliability, and responsiveness of every quality measure, they need to ascertain that the specific measures they choose to use as part of a quality improvement project have all of these features. Specific

IV. ACT Determine what changes are to be made Implement the changes

III. STUDY Summarize the findings from the evaluation

quality measures for acute pain management are discussed later in this chapter.

Six Sigma A recent methodology to promote and enhance quality that has caught the attention of the health care field is six sigma. This approach was developed by Motorola and refined over the past

I. PLAN Develop clear objectives Develop a plan to carry out the test cycle

II. DO Carry out the evaluation Begin data analysis

Figure 43.1: The PCSA cycle in quality improvement.

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Table 43.3: Features of a Good Quality Measure Feature

Description

Important

For outcome indicators High prevalence outcomes Outcomes associated with significant consequences (e.g., morbidity, mortality) For structure and process indicators: Measure must be linked to clinically important outcomes Individuals involved in the quality improvement project need to consider the quality measure important Different measures may need to be selected to meet the need of various constituencies (e.g., patients, family members, clinicians, administrators)

Valid

A valid measure refers to the extent to which a measure reflects what it is supposed to measure.

Reliable

A reliable measure refers to the extent to which a measure yields the same result when assessed by a different rater (interrater reliability) or the extent to which repeated measurement provides the same result when the factor being measured has not changed (intrarater reliability).

Responsive

A responsive measure refers to the extent to which a measure is sensitive to change introduced by the quality improvement process. Needs to be room for improvement in the measure chosen Measure chosen needs to be able to detect the improvement

Interpretable

An interpretable measure is easily understood by the target audience.

Feasible

A feasible measure is useful because it is relatively easy to obtain and be collected with available resources.

10 years by top corporations like General Electric, Sony, and Allied Signal.3,20–23 Sigma is the Greek letter used to designate a standard variation in a process. The higher the sigma, the fewer are the number of errors or defects. One sigma equals 690 000 defects per million opportunities and two sigma equates with 308 537 defects per million. However, six sigma equals just 3.4 defects per million opportunities or as close to perfection as one can get in the everyday world.21 In an excellent review article,20 Chassin summarized how the use of six sigma, as a quality improvement methodology, could be applied to health care. As shown in Table 43.4, he summarized the level of defects per million that correspond to different sigma levels and gave examples of health care quality studies that documented the incidence of specific problems. In this review, he noted that one health care specialty that reduced serious defects to rates that are close to 3.4 per million is surgical anesthesia. In the 1970s and 1980s, anesthesia-related death rates ranged from 1 in 10 000 to 20 000 or 25 to 50 per million.24 Through a variety of initiatives, current estimates of anesthesiarelated deaths are at about 5 per million cases.25,26

Six sigma is a process improvement methodology that uses data and statistical analyses to identify and fix problems. Theoretically, once defects per million opportunities is calculated, sigma values can be looked up in tables in common statistics books. Quality improvement teams can then identify the level of intended magnitude of improvement. Over the past 10 years, the use of the six sigma methodology has delivered a variety of sustainable benefits to companies from many industries. Some of these benefits have included reduced costs, increased revenues, strengthened customer relationships, increased processing speed, and introduction of more efficient production processes.23 The six sigma methodology differs from more traditional continuous quality improvement approaches like PDSA in that six sigma is more of a business tool, in which a control phase is built in to focus on sustaining improvements. In contrast, total quality management approaches like PDSA are focused primarily on quality initiatives.23 Six sigma is achieved through a series of steps that are outlined in Table 43.5 and abbreviated as DMAIC. The first step (define) entails the creation of a project charter. This charter defines the customers’ needs, scope of the project, goals of the project, success criteria, team members, and project deadlines. In the second step (measurement), a data collection plan for the process is developed and data are collected from several sources to determine the depth of the defects or errors (ie, defects per million opportunities) in the system. Control charts are created to study the process further. In the third step (analyze), data analysis occurs, deviations from standards are identified, key drivers that lead to the current process performance are identified, and the target for the improved performance is identified. In the fourth step (improve), created solutions and implementation plans are developed. Finally, in the sixth step (control), the process is controlled by implementing policies, guidelines, and error-proofing strategies to make reverting to the old process impossible. Quality controls are developed to monitor the new process and prevent backsliding.3,23

Lean Methodology Lean methodology was developed by Taiichi Ohno, a Toyota Motor Corporation engineer. Lean methodology is driven by the identified needs of the customer and aims to improve processes by removing non-value-added activities. These nonvalue-added activities, also referred to as waste, do not add to the business margin or to the customer’s experience and customers are not willing to pay for them. Seven different types of waste have been identified, including overproduction or underproduction; wasted inventory, reworks, or rejects (ie, mistakes in assembly); wasted motion (eg, poor work area ergonomics); waste associated with waiting (eg, patients waiting to be seen for appointments); waste associated with processing (eg, outdated policies and procedures); and waste from transport or handling (eg, transporting patients when it is not necessary). Lean tools maximize value-added steps in the best possible sequence to deliver continuous flow. Services and products are delivered when the customer needs them and how the customer requests them.3,27 Although the PDSA methodology has been used for a number of years to improve the quality of patient care, six sigma21–23,28 and lean methodology27,29 have only recently been used in health care. To date, neither of these two methodologies has been used to improve the quality of acute pain management.

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Table 43.4: Selected Health Care Quality Problems Viewed as Defects per Million Compared with Quality Performance in Selected Industries Sigma Level 6

Defects per Million Opportunities

Selected Health Care Examples

Selected Industrial Examples

3.4

–

5.4

Deaths caused by anesthesia during surgery –

Allied Signal: 3 model factories Publishing: one misspelling in all of the books in a small library –

10–16

Two Siebe plants in Italy and the United Kingdom that make temperature controls for refrigerators

5

230

–

Airline fatalities

4

6210

–

Airline baggage handling Restaurant errors –

3

10 000

1% of hospitalized patients injured by negligence

66 800

–

210 000 2

308 000 580 000

1

690 000 790 000

21% of ambulatory antibiotics for colds – 58% of patients with depression not detected or treated adequately – 79% of eligible heart attack survivors fail to receive beta blockers

Publishing: 7.6 misspelled words per page in a book – – – – –

Adapted from: Chassin MR. Is health care ready for Six Sigma quality? Milbank Q. 1998;76(4): 565–591, 510.

A N H I S TO R I C A L P E R S P E C T I V E O N Q UA L I T Y I M P ROV E M E N T I N I T I AT I V E S I N AC U T E PA I N M A NAG E M E N T

In the late 1980s, the first guidelines to be used to evaluate the quality of acute pain management were published by the American Pain Society.30 Since that time, these guidelines were revised twice.31,32 The impetus for the development of these quality improvement guidelines was the overwhelming evidence that postoperative pain33–35 is not well managed and that the under treatment of pain results in deleterious consequences36,37 and may lead to the development of chronic pain.38 In fact, these early studies of the undertreatment of acute pain provided the impetus for the Agency for Health Care Policy and Research to publish a clinical practice guideline on the management of acute postoperative pain.39 One of the recommendations in this guideline was that after its implementation, the quality of acute pain management should be evaluated. Another impetus for the development of quality improvement initiatives in acute pain management was the publication of pain standards by the Joint Commission for the Accreditation of Health Care Organizations. These pain standards, published in 2001, represented a landmark initiative by the Joint Commission.40–42 In addition, they represented a rare and important opportunity for widespread and sustainable improvements in how pain is to be managed in the United States. The

requirements contained within the Joint Commission’s pain standards are enumerated in Table 43.6. Based on the need to meet the final pain standard listed in Table 43.6, many health care organizations have developed quality improvement committees that focus on an evaluation of the quality of acute pain management. In addition, many of these pain standards have become structure, process, and outcome indicators for various quality initiatives related to acute pain management. For example, many health care organizations have developed a policy that all clinicians (ie, physicians, nurses, allied health professionals) must receive education about pain management. In addition, most hospitals who are accredited by the Joint Commission have policies and procedures that govern universal screening for pain as well as the initial and ongoing assessment of pain. Ongoing quality improvement programs within health care organizations focus on evaluating whether these types of initiatives improve the quality of acute pain management. D E V E LO P M E N T, I M P L E M E N TAT I O N , A N D M A I N T E NA N C E O F A C O N T I N U O U S Q UA L I T Y I M P R OV E M E N T P R O G R A M F O R AC U T E PA I N M A NAG E M E N T

As noted, to change the quality of patient care, health care organizations must implement the process of continuous quality improvement. The continuous quality improvement process

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Table 43.5: Five Phases of Six Sigma

Table 43.6: Pain Standards from the Joint Commission for the Accreditation of Health Care Organizations

Phase

Deliverables

Define

Identify process customers and their requirements Identify the boundaries of the project using high-level process map Complete an approved project-charting document

Recognize the right of patients to appropriate assessment and management of their pain

Develop an accurate system for measuring the process result Develop a detailed drill down on the process flow Report the current process performance for the targeted customer requirement

Record the results of the assessment in a way that facilitates regular assessment and follow-up

Measure

Analyze

Improve

Control

Compare the current process performance with customer requirements Identify key drivers that lead to the current process performance Identify target for the improved performance Determine the statistical relationship between the key process drivers and the process outcome Propose and pilot potential solutions Determine operating ranges for the process drivers Ensure accurate measurement of the improved key process drivers Confirm that improved drivers are delivering the targeted process results in actual practice Develop a tracking and rapid reaction plan to detect and correct any process backsliding to ensure that gains are sustained

Adapted from: Elberfeld A, Bennis S, et al. The innovative use of Six Sigma in home care. Home Healthc Nurse. 2007;25(1):25–33.

provides organizations with the ability to collect benchmark data on various aspects of acute pain management; determine the effectiveness of various acute pain management practices or processes of care, and evaluate whether systematic changes in the processes and practices surrounding acute pain management improve the quality of care that patients with acute pain receive. Individuals who work to develop and maintain a continuous quality improvement program in pain management need to remember that continuous quality improvement is a process. The emphasis on the term process underscores the fact that continuous quality improvement efforts take time and perseverance. Although it is easy to become frustrated with an apparent lack of progress on the part of administrators or clinicians, the quality improvement committee for acute pain management needs to have a long-term vision, clear goals and objectives, and a flexible timeline to complete their quality improvement plan.16,17 The steps to develop, implement, and maintain a continuous quality improvement program for acute pain management are outlined in Table 43.7. Following the publication of the pain standards by the Joint Commission for the Accreditation of Health Care Organizations, most health care organizations established quality improvement programs in acute pain management. These quality improvement programs were often mandated by hospital administrators to help facilitate the organization’s adherence with the new pain standards.

Identify patients with pain in an initial screening assessment Perform a more comprehensive assessment if pain is identified

Educate relevant providers in pain assessment and management Determine and assure staff competency in pain assessment and management Address pain assessment and management in the orientation of all new staff Establish policies and procedures that support appropriate prescription or ordering of effective pain medications Ensure that pain does not interfere with the process of rehabilitation Educate patients and families about the importance of effective pain management Address patient needs for symptom management in the discharge planning process Collect data to monitor the appropriateness and effectiveness of pain management

Development of a Continuous Quality Improvement Program for Acute Pain Management The development of a continuous quality improvement program for acute pain management requires an enormous commitment from the health care organization, as well as from the members of the quality improvement committee. The initial development of the quality improvement program usually begins with one or more individuals who have already made a commitment to improving pain management within the health care organization. The establishment of a formal quality improvement program in acute pain management allows these individuals an opportunity to develop a more structured approach to achieve specific programmatic goals. Initial development of the quality improvement program needs to center on enlisting the support of key administrators within the organization. Without this level of administrative support, the initiative will not be successful. Once administrative support is secured, a multidisciplinary committee needs to be constituted to begin to develop the quality improvement program for acute pain management. At a minimum, the committee membership should include physicians, nurses, pharmacists, and administrators. Careful consideration should be given to who serves as chair of the committee. In some cases, it may be advantageous to have cochairs who represent key constituencies within the organization. In addition, in some cases, it may be advantageous to invite the participation of individuals who might be most resistant to change their acute pain management practices. An additional area that warrants consideration, in terms of committee membership, is that all of the key areas in the hospital and all of the key job titles are represented on the committee. Some quality improvement committees have included patients and family caregivers as members to insure that these

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Table 43.7: Steps to Develop, Implement, and Maintain a Continuous Quality Improvement Program for Acute Pain Management Development of a Continuous Quality Improvement Program Do background work on acute pain management structures, processes of care, and patient and system outcomes Enlist the aid and support of key opinion leaders and stakeholders Enlist the aid and support of key administrators within the organization and various departments who play critical roles in acute pain management (eg, chief executive officer, chief nursing officer) Constitute a multidisciplinary committee to develop the continuous quality improvement program for acute pain management Identify the key stake-holders in acute pain management and establish their support for the program and the continuous quality improvement plan Develop a multidisciplinary committee that should include at a minimum – physicians, nurses, pharmacists, and administrators Consider carefully who should chair or co-chair the committee Consider the mix of job titles needed to do the work of the committee (eg, senior level administrators, middle management, staff) when developing the list of committee members Consider the areas of the hospital and specialty areas that need to be represented on the committee (eg, nursing units, radiology, pediatrics, post anesthesia care unit) Invite the participation of individuals who might be most resistant to change their acute pain management practices Include patient and family member participation when appropriate Perform an initial analysis of acute pain management practices within the organization Identify areas for improvement in acute pain management based on brainstorming sessions with the continuous quality improvement committee Collect some initial data and analyze the data to verify the need for improvement in a variety of pain management practices Evidence of areas for improvement in acute pain management facilitates the buy-in of key opinion leaders and administration for the establishment of a quality improvement program Develop an initial continuous quality improvement plan for acute pain management Establish the overall goals of the quality improvement program Prioritize potential projects and choose the initial projects High-volume problems High-risk problems High-cost problems Develop a timeline for completion of initial projects Do an environmental scan to understand the current climate within the organization relative to a specific quality improvement project Potential barriers Potential opportunities Potential resources for the project Develop the specific approaches needed to complete the initial quality improvement project(s) Create and test the data collection tools and systems Create and test the data analysis methods Create and test the methods that will be used to report findings and obtain feedback from clinicians on the findings from the quality improvement project Implementation of a Continuous Quality Improvement Program Present findings from initial quality improvement projects to key stakeholders and opinion leaders Obtain a buy-in to move forward with a comprehensive quality improvement program for acute pain management Develop a comprehensive quality improvement program for acute pain management Develop a plan to “institutionalize” acute pain management Establish a timeline for completion of major goals and projects Determine which acute pain management policies and procedures need to be written, revised, and disseminated Pain assessment policies and procedures Use of pharmacologic interventions for acute pain management Use of nonpharmacologic interventions for acute pain management Use of technology for acute pain management Safety considerations with acute pain management (continued )

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Table 43.7 (continued ) Develop and obtain approval for a budget to implement and maintain the continuous quality improvement program Establish accountability for acute pain management within the health care organization Determine which staff and which administrators will be responsible for each aspect of the quality improvement program in acute pain management Incorporate effective pain management into the mission statement of the health care organization Develop competency based assessment tools to evaluate staff performance Integrate the principles of effective acute pain management and assign responsibility for pain management into policies, procedures, and job descriptions Provide education to all personnel involved in acute pain management Provide education on pain assessment Provide education on both pharmacologic and nonpharmacologic interventions for acute pain management Provide education on the use of new technologies for acute pain management Provide education on patient safety issues related to acute pain management Provide education on discharge planning considerations related to acute pain management Provide education to patients and family caregivers about acute pain management Provide education on admission of their right to prompt acute pain treatment Explain to patients and family caregivers why acute pain management is an important part of their care Teach patients and family caregivers how to report pain using established pain assessment tools Provide patients and family caregivers with discharge teaching about acute pain management Establish ongoing systems to collect and report data for ongoing quality improvement projects Develop approaches to change clinicians’ behaviors and to change organizational systems that will lead to improvements in acute pain management Maintenance of a Continuous Quality Improvement Program Determine if the quality improvement indicator is changing based ongoing evaluations Use different quality improvement methodologies (e.g., PDSA, six sigma) and tools (eg, medical record reviews, adherence with policies and procedures, competency evaluations of staff, patient interviews) to collect and analyze data Modify approaches to change clinicians’ behaviors and system issues on a regular basis Develop strategies to sustain the enthusiasm and collaboration among the members of the multidisciplinary quality improvement committee Maintain ongoing communication with and support from key stake holders, key opinion leaders, and hospital administration

perspectives are taken into account as the quality improvement plan develops. Taking the time to obtain the appropriate “mix” of committee members will help to insure that the findings and recommendations from the quality improvement committee are accepted by all of the relevant constituencies. Once the quality improvement committee is formed, its initial efforts need to focus on an analysis of acute pain management practices within the organization. One way to begin this process is to have committee members identify key areas for improvement. These brainstorming efforts can be used to build consensus among committee members on the key acute pain management issues that face the organization. Once a list of the key areas for improvement is identified, some initial data can be collected and analyzed to verify the need to a more detailed and comprehensive quality improvement initiative. This initial investigation provides preliminary data on opportunities for improvement that are specific to acute pain management. In addition, these data can be presented to key opinion leaders and administrators to facilitate their acceptance and buy-in for the quality improvement program. Once the initial evaluation of acute pain management practices is completed, the quality improvement committee in a sense has “the lay of the land” and can begin the development of the

initial continuous quality improvement plan for acute pain management. The first step is to establish the overall goals for the quality improvement program. As part of this step, the committee needs to determine the scope of their quality improvement program. Decisions need to be made about whether the committee will focus only on quality improvement studies or whether they will choose to have a larger scope that includes a variety of activities related to acute pain management (eg, development of policies and procedures for acute pain management, clinician education, patient and family caregiver education, development of competency-based performance evaluations). The choices that the committee makes about the scope of the program will influence the goals and objectives of the quality improvement program for acute pain management. Once the goals of the quality improvement program are established, the committee needs to determine the specific topics for the initial quality improvement project or projects. As mentioned previously, the choice of topic for a quality improvement study is often based on the identification of high-volume, high-risk, or high-cost problems. Additional considerations for the choice of topic for the initial project might include the interest level of clinicians in a particular topic, the availability of valid and reliable tools to measure the problem, the ease and

Quality Improvement Approaches

Step 1 – Determine those aspects of acute pain management that requires evaluation

663

Step 2 – Conduct an

evaluation study to obtain data on a specific aspect of acute management

Step 6 – Reevaluate the specific aspect of acute pain management after a designated period of time

Step 3 – Analyze the data from the evaluation study

Step 5 – Develop and implement a plan to improve a specific aspect of acute pain management

Step 4 – Determine which pain management processes require modification

Figure 43.2: The process of continuous quality improvement.

rapidity with which data can be collected, the potential impact that improvement in this area of practice would have on patient care, and the ease with which behavioral strategies to improve this area of practice could be implemented. Once the initial quality improvement projects are identified, the committee needs to develop and implement the project. This part of the process can be accomplished using the steps outlined in Figure 43.2. One of the critical steps in this part of the process is the development of the data collection tools. The types of tools that are developed often depend on the type of data that are going to be collected. For example, for a chart review, the tool will need to be developed based on the type of data that are available in the medical record. For a patient or staff member interview, the tool may contain more open-ended questions. All of these tools should be piloted tested before the larger quality improvement study is launched. Pilot testing of a tool provides the committee with an opportunity to refine the measure, as well as to refine the instructions that are given to the individuals who will collect the study data. Following data collection, the results of the study are analyzed and presented to the quality improvement committee. This initial presentation provides the committee with the opportunity to begin to interpret the study findings, as well as to consider additional analyses that may be needed to strengthen the interpretation of the study findings. Once the quality improvement committee is satisfied with the data analysis, they need to determine how the data will be presented to various key stake holders and clinicians. Feedback from clinicians needs to be obtained prior to the development of the quality improvement plan. In many cases, clinicians can identify specific aspects of care that can be modified to improve various aspects of acute pain management.

Once the data are presented and the specific aspects of acute pain management that require modification are determined, the quality improvement committee needs to develop and implement a plan to improve that aspect of acute pain management. The final step in the process of continuous quality improvement is to reevaluate that specific aspect of acute pain management after a designated period of time has elapsed. The quality improvement committee needs to establish the timeline for the reevaluation and how much improvement they expect to achieve following the implementation of their plan to change clinicians’ behaviors or systems of care.

Implementation of a Continuous Quality Improvement Program in Acute Pain Management As outlined in Table 43.7, the implementation of a continuous quality improvement program in acute pain management is a large undertaking that requires a substantial commitment of financial and personnel resources on the part of a health care organization. One of the major goals for this phase of the quality improvement program is the development of a plan and methodologies to institutionalize acute pain management practices. A variety of activities need to be accomplished to achieve this goal. In most health care organizations, quality improvement committees write, revise, and disseminate acute pain management policies and procedures. This activity is part of the scope of the quality improvement program because the members of the quality improvement committee are often the most knowledgeable clinicians within the organization about various aspects of acute pain management. In addition, these individuals have the knowledge to insure that the policies and procedures are in compliance with the mandates or requirements

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of various accreditation bodies (eg, State Health Department, Joint Commission for the Accreditation of Health Care Organizations). An important consideration to insure the success of a quality improvement program in acute pain management is the actual resources that are allocated to the program. The quality improvement committee needs to develop a realistic budget that reflects the scope and magnitude of the proposed program. Both financial and personnel resource allocation needs to be consider in terms of the time needed to plan the quality improvement studies, the time needed to collect and analyze the data, the time needed to present the data to various constituencies, and the resources needed to develop and implement the action plan. The quality improvement committee needs to consider which of its functions can be delegated to other groups within the organization (eg, staff development department to disseminate the findings from the quality improvement studies and educate clinicians on new pain management practices). A critical component of an effective quality improvement program is the establishment of accountability within an organization for acute pain management. The quality improvement committee often takes the lead in the determination of which staff and administrators are responsible for which aspects of acute pain management. In many health care organizations, the mission statement of the organization is revised to incorporate effective pain management as a stated goal of the organization. In addition, many health care organizations are including specific competencies regarding acute pain management (eg, pain assessment, use of pain management technologies) into staff members’ job descriptions and performance evaluations. These types of changes within an organization emphasize the importance of pain management within the organization and demonstrate an institutional commitment to acute pain management. Numerous studies have documented that one of the key factors that contributes to the undertreatment and inappropriate management of pain is lack of clinician,43–48 patient,49–51 and family caregiver52,53 education about pain management. Many quality improvement committees will establish as one of their goals to improve clinician, patient, and family caregiver education about acute pain management. This goal is in concert with the pain standards published by the Joint Commission for the Accreditation of Health Care Organizations. Again, the members of the quality improvement committee have the knowledge and expertise to achieve this goal. However, substantial personnel and financial resources need to be allocated to achieve this goal. Initial educational efforts often need to focus on clinicians. Successful quality improvement programs have incorporated clinician education on pain management into all orientation programs. In addition, the quality improvement committee often facilitates annual updates on pain management within the health care organization.

Maintenance of a Continuous Quality Improvement Program in Acute Pain Management One of the most challenging aspects of any quality improvement program is the maintenance of momentum and enthusiasm for the program. The major goal of the maintenance phase of the program is to determine if the indicator(s) that were selected for improvement have improved. The reevaluation component of the program, that needs to be done on an ongoing basis, is

the most challenging aspect of any quality improvement program. The quality improvement committee needs to be actively engaged in selecting the types of quality improvement methodologies (eg, PDSA, six sigma) that are employed within the health care organization. In addition, they need to be involved in the development of the tools and approaches that will be used to collect data on the various aspects of acute pain management. In many cases, the quality improvement committee can use a variety of tools to collect data. The choices of tools (eg, chart review, clinician interviews, patient interviews) that are used can enrich the breadth of the data that are obtained and provide new directions for quality improvement initiatives. The committee must engage in processes that maintain members’ enthusiasm for the projects and goals of the quality improvement program. In addition, they must think of methodologies to sustain multidisciplinary collaboration and maintain the growth and development of the program. Areas to consider in this regard include turnover of committee chairs, turnover of committee members, periodic retreats to evaluate accomplishments as well as redefine the long-term goals and objectives of the program, and solidification of the ongoing commitment of the institution to the quality improvement program. Q UA L I T Y I M P ROV E M E N T I N D I C ATO R S A N D M E A S U R E S I N AC U T E PA I N M A NAG E M E N T

Initial efforts to improve the quality of acute pain management came through the publication of a specific set of recommendations for monitoring the quality of acute pain management by the Agency for Health Care Policy and Research and the American Pain Society.30,39 These recommendations included a patient outcome questionnaire that could be used or adapted to evaluate the quality of acute or cancer pain management. Several studies were done with the original or modified versions of the patient outcome questionnaire.32,54–60 The major finding across all of these studies was that patients reported high levels of satisfaction with pain management despite significantly high levels of pain and long waiting times for pain medications. This paradox suggested that the evaluation of patient satisfaction was not a valid and reliable measure to use to judge the quality of acute pain management. In 1995, the American Pain Society’s Quality of Care Committee revised these quality improvement guidelines based on the published reports and clinical experience.31 This interdisciplinary committee concluded that efforts to improve the quality of acute pain management must move beyond the assessment of pain and documentation of pain assessments to implementation and evaluation of improvements in pain treatment that are timely, safe, evidenced based, and multimodal. As shown in Table 43.8, the American Pain Society’s Quality of Care Committee identified 5 key components that should guide the development of quality improvement programs in acute pain management. In addition, a revision of the patient outcome questionnaire was included in the article. The main revisions to the patient outcome questionnaire were the addition of 6 items on how pain interferes with function from the Brief Pain Inventory61 and 7 items from the Patient Barriers Questionnaire.62 In addition, emphasis was placed on the use of continuous quality improvement approaches to improve the quality of acute pain management within health care organizations.

Quality Improvement Approaches

Table 43.8: American Pain Society’s Key Components for a Quality Improvement Program in Acute Pain Management Assure that a report of unrelieved pan raised a “red flag” that attracted clinicians’ attention

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Table 43.9: Key Indicators and Measures Used in Initial Studies of the Quality of Acute Pain Management Quality Indicator

Quality Measure

Make information about analgesics convenient where orders are written

Outcome

Patient comfort (pain intensity)

Outcome

Impact of pain on function

Promise patients responsive analgesic care and urge them to communicate pain

Outcome

Patient and family satisfaction with pain management

Implement policies and safeguards for the use of modern analgesic technologies

Process

Documentation of pain assessments

Structure

Range and appropriateness of options available for acute pain management

Process and Outcome

Effectiveness of pain management options used to prevent and treat pain

Outcome

Prevalence and severity of side effects and complications associated with acute pain management

Structure and process

The quality of pain management across points of transition in the provision of services

Coordinate and assess implementation of these measures Adapted from: American Pain Society Quality of Care Committee. Quality improvement guidelines for the treatment of acute pain and cancer pain. JAMA. 1995;274(23):1874–1880.

Results of Studies That Evaluated the Quality of Acute Pain Management Using the Indicators and Measures Developed by the American Pain Society Over the next decade, a number of studies were published that used the revised patient outcome questionnaire to evaluate the quality of acute and cancer pain management.63–66 In addition, Gordon and colleagues summarized the findings from the majority of the quality improvement studies in acute pain management.60 The purpose of their extensive review was to determine which indicators were being used for quality improvement, compare findings across these studies, and develop specific recommendations to simplify and standardize future measurement of quality for hospital-based quality improvement initiatives in pain management. As part of this review,60 the results of 20 studies performed at 8 large hospitals in the United States were evaluated and compared. In the majority of these studies, convenience samples of patients who had pain were recruited. Patients and records were surveyed either within 3 days of surgery or admission to the hospital or in the 3 days before discharge. The purpose of each of the studies was to gather baseline data, discover targets for improvement, or monitor changes in pain management overtime as part of ongoing hospital-wide quality improvement initiatives. As listed in Table 43.9, the specific measures used in the patient surveys and medical record audits were derived from structure, process, and outcome indicators recommended for monitoring in the early 1990s.30,39 Measures included pain intensity, interference with function, patient satisfaction, patient beliefs, documentation of pain assessment, and the range and appropriateness of pain treatments. Analyses of the data across the 20 studies led to consensus on 6 quality indicators for hospital-based pain management programs. The authors of the review concluded that a comprehensive evaluation of the quality of pain management involves both practice patterns and patient outcomes. Although the use of the American Pain Society’s patient outcome questionnaire combined with a comprehensive medical record review tool represented more than 100 potentially distinct data points, more and different quality improvement indicators and measures needed to be investigated.60 For example, acts of omission and the identification of patient safety issues in pain management needed to be investigated in detail.34

Adapted from: Gordon DB, Pellino TA, et al. A 10-year review of quality improvement monitoring in pain management: recommendations for standardized outcome measures. Pain Manag Nurs. 2002;3(4):116– 130.60

American Pain Society Recommendations for Improving the Quality of Acute and Cancer Pain Management Based on the findings from this review, as well as clinician feedback, in 2005, the American Pain Society Quality of Care Task Force published a revision of their Recommendations for Improving the Quality of Acute and Cancer Pain Management.67 The differences between the 19953 and 2005 recommendations are summarized in Table 43.10. The American Pain Society recommendations specify that all care settings need to formulate structured multilevel systems’ approaches to ensure prompt recognition and treatment of pain, involvement of patients and family members in the pain management plan, improved treatment patterns, regular reassessments and adjustments of the pain management plan as needed, and measurement of the processes and outcomes of pain management. The main emphasis in this document is that efforts to improve the quality of pain management must move beyond the assessment and communication about pain to the implementation and evaluation of improvements in pain treatments that are timely, safe, evidenced based, and multimodal. Based on the work by Gordon and colleagues ,60 the American Pain Society Quality of Care Task Force recommended 6 new quality indicators and several measures that can be used to evaluate the quality of acute pain management. These indicators and measures are summarized in Table 43.11. Additional research is warranted to determine if these indicators and measures are useful tools to evaluate the quality of acute pain management.

Additional Considerations in the Development and Implementation of Quality Improvement Programs for Acute Pain Management Patient Safety As noted previously, the major impetus for the publication of pain standards by the Joint Commission for the Accreditation

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Table 43.10: Comparison of the 1995 American Pain Society (APS) Quality Improvement (QI) Guidelines and the 2005 APS Recommendations 1995 APS QI Guidelines

2005 APS Recommendations

Recognize and treat pain promptly Routine assessment of pain intensity

Recognize and treat pain promptly Emphasis on comprehensive pain assessment

Routine documentation of pain intensity Make information about analgesics readily available in places where clinicians write medication orders

Emphasis on the importance of the prevention of pain Emphasis on prompt recognition and treatment of pain Involve patients and families in the pain management plan Emphasis on the need to customize the pain management plan Emphasis on the importance of having the patient participate in the pain management plan

Promise patients attentive analgesic care Urge patients to report pain to clinicians

Improve treatment patterns Eliminate inappropriate practices Emphasis on the need to provide multimodal therapy

Develop explicit policies for analgesic technologies Patient controlled analgesia Spinal administration of opioids and anesthetics

Reassess and adjust pain management plan as needed Emphasis placed on the need to respond not only to pain intensity scores but to changes in patient’s functional status and side effects

Examine the processes and outcomes of pain management with the goal of continuous quality improvement

Monitor processes and outcomes of pain management Emphasis on new standardized QI indicators

Adapted from: Gordon DB, Dahl JL, et al. American Pain Society recommendations for improving the quality of acute and cancer pain management. Arch Int Med. 2005;165(14):1574–1580.67

of Health Care Organizations was the overwhelming evidence on the under treatment of acute33,35,68 and cancer pain.69–71 The need exists to continue these efforts to improve the management of acute and cancer pain because studies continue to document the undertreatment of acute and cancer pain in both inpatient and outpatient settings. However, recent studies completed after the publication of the pain standards by the Joint Commission for Accreditation of Health Care Organizations suggest that careful evaluation of pain management practices is required to insure quality care and patient safety. In one study,72 following the implementation of a routine numeric pain scoring system in the postanesthesia care unit, an overall increase in the average consumption of opioids was observed (ie, 10.5 ± 10.4 mg versus 6.5 ± 7.3 mg, P < .001). This increase in opioid use was not associated with an increased length of stay, an increase in the requirement for naloxone, or an increase in treatment for postoperative nausea and vomiting. The authors concluded that the increase in opioid use as a result of a quality improvement initiative was not associated with additional opioid-induced morbidity in the immediate postoperative period. In contrast, in another study that reported on a quality improvement initiative for acute pain management,73 the incidence of opioid-induced adverse events increased from 11 to 25 per 100 000 inpatient days at the medical center. Of note, the majority of the adverse drug reactions were preceded by a documented decrease in patient’s level of consciousness because of opioid-related sedation. Findings from these studies suggest that quality improvement initiatives related to acute pain management should be evaluated in terms of improvements in

the quality of acute pain management, as well as in terms of potential adverse effects. Within the context of patient safety, it should be noted that based on the findings from the Institute of Medicine’s study on medical errors,1 Congress passed and the President signed the Patient Safety and Quality Improvement Act in 2005. This act encourages the voluntary reporting of medical errors by providing legal protections to those who report the errors. The idea is to have these errors recorded in databases for subsequent analyses. These analyses should identify patterns in these errors and result in strategies to reduce errors.74 Of note, the Institute for Healthcare Improvement has noted that 58% of medication-related injuries are because of high-alert medications. The 4 high-alert medications most responsible for injuries are anticoagulants, sedatives, opioids, and insulin (see http://ihi.org/IHI/Programs/Campaign). Therefore, it behooves clinicians and administrators involved in quality improvement programs for acute pain management to include indicators that evaluate various aspects of patient safety associated with analgesic medications, as well as adverse events.

Quality Indicators and Measures in Day Surgery Settings In an excellent review, Shnaider and Chung75 summarized the results of published studies on the outcome measures that can be used to assess the quality of ambulatory surgery and anesthesia. In this review, they noted that postoperative pain is one of the most frequent adverse events that occurs following ambulatory surgery. It is associated with a longer postoperative stay and delays patients’ return to normal function. In

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Table 43.11: Quality Indicators and Measures for Acute Pain Management Quality Indicator

Measures

Intensity of pain is documented Numeric rating scale (ie, 0 to 10) Descriptive rating scale (ie, none, mild, moderate, or severe) Pain intensity is documented at frequent intervals

Is there any documentation of pain in the medical record? In charts with documentation of pain, was a pain rating scale used?

Pain is treated by a route other than intramuscular injection

Percentage of patients who received an intramuscular injection of an analgesic in the postoperative period

Pain is treated with regularly administered analgesics

Percentage of patients who received an analgesic on a regular schedule

How many pain intensity ratings were documented in a 24-hour period?

Percentage of patients who received meperidine Pain is treated, when possible, with multimodal approaches

Percentage of patients who received only a single analgesic modality Percentage of patients who received combinations of therapeutic approaches (nonopioid, opioid, local anesthetic, regional techniques) Percentage of patients who received both pharmacologic and nonpharmacologic approaches

Pain is prevented and controlled to a degree that facilitates function and quality of life

Measurement of worst pain in past 24 hours Amount of time the patient was in moderate to severe pain in the past 24 hours Level of pain’s interference with sleep, walking ability, mood (0 = does not interfere to 10 = completely interferes)

Patients are adequately informed and knowledgeable about pain management

Patient’s rating of the adequacy of information received about pain and pain management while in the hospital (1 = poor to 5 = excellent)

Adapted from: Gordon DB, Pellino TA, et al. A 10-year review of quality improvement monitoring in pain management: recommendations for standardized outcome measures. Pain Manag Nurs. 2002;3(4):116–130.60 Gordon DB, Dahl JL, et al. American Pain Society recommendations for improving the quality of acute and cancer pain management. Arch Int Med. 2005;165(14):1574–1580.67

addition, postoperative pain is one of the most common causes for unanticipated admission and readmission.76 Quality improvement projects need to be designed and implemented that focus on improving the management of acute pain in the ambulatory surgery setting.

E F F E C T I V E A P P ROAC H E S TO C H A N G E C L I N I C I A N S ’ B E H AV I O R S

The fundamental goal of all quality improvement programs is to improve the quality of patient care. In many cases, to achieve improvements in the quality of patient care, clinicians need to change their behaviors. However, even in the era of evidence-based practice, little is known about the most effective approaches to use to change clinicians’ behaviors in general and in relationship to pain management in particular. In one of the most comprehensive reviews published to date, Grimshaw and colleagues77 attempted to synthesize the evidence from systematic reviews of professional education or quality improvement

interventions that were designed to improve the quality of patient care. Forty-one reviews were identified that covered a wide range of approaches to behavior change. In general, the conclusion was that passive approaches (eg, continuing education programs) were ineffective and did not result in changes in clinicians’ behaviors. The most promising interventions were multifaceted and targeted different barriers to behavior change. Systematic investigations are warranted to determine the most appropriate interventions to change clinicians’ behaviors in terms of safe and effective pain management. S U M M A RY A N D C O N C LU S I O N S

The need to improve, on an ongoing basis, the quality of patient care is firmly established within the health care system. Caregivers who are involved in acute pain management need to evaluate the quality of acute pain management from multiple perspectives. Patients deserve the most effective and safest pain management that is possible within the context of their medical condition and the setting in which they receive their care.

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Christine Miaskowski

REFERENCES 1. Kohn LT, Corrigan JM, et al, eds. To Err Is Human: Building a Safer Health Care System. Washington, DC: National Academy Press; 2000. 2. Committee on Quality Health Care in America, Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy Press; 2001. 3. Varkey PM, Reller K, et al. Basics of quality improvement in health care. Mayo Clin Proc. 2007;82(6):735–739. 4. Berwick DM, Calkins DR, et al. The 100,000 lives campaign: setting a goal and a deadline for improving health care quality. JAMA. 2006;295(3):324–327. 5. Curtis JR, Cook DJ, et al. Intensive care unit quality improvement: a “how-to” guide for the interdisciplinary team. Crit Care Med. 2006;34(1):211–218. 6. Agency for Healthcare Research and Quality, United States Department of Health and Human Services. Your guide to choosing quality health care: a quick look at quality. Available at: www.ahrq.gov/consumer/qnt/qntqlook.htm. Accessed December 29, 2007. 7. Shine KI. Health care quality and how to achieve it. Acad Med. 2002;77(1):91–99. 8. McGlynn EA, Cassel CK, et al. Establishing national goals for quality improvement. Med Care. 2003;41(1 suppl): I16–I29. 9. Deming EW. Out of Crisis. Cambridge, MA: MIT Center for Advanced Engineering; 2002. 10. James, C. Manufacturing’s prescription for improving healthcare quality. Hosp Top. 2005;83(1):2–8. 11. Donabedian A. Evaluating the quality of medical care. Milbank Q. 2005;83(4):691–729. 12. Berwick DM. Continuous improvement as an ideal in health care. N Engl J Med. 1898;320(1):53–56. 13. Berwick DM. A primer on leading the improvement of systems. Br Med J. 1996;312(7031):619–622. 14. Berwick DM. Developing and testing changes in delivery of care. Ann Int Med. 1998;128(8): 651–656. 15. Berwick DM, James B, et al. Connections between quality measurement and improvement. Med Care. 2003;41(1 suppl):I30–I38. 16. Miaskowski C. Monitoring and improving pain management practices: a quality improvement approach. Crit Care Nurs Clin North Am. 2001;13(2):311–317. 17. Miaskowski C. New approaches for evaluating the quality of cancer pain management in the outpatient setting. Pain Manag Nurs. 2001;2(1):7–12. 18. McGlynn EA. Introduction and overview of the conceptual framework for a national quality measurement and reporting system. Med Care. 2003;41(1 suppl):I1–I7. 19. McGlynn EA. Selecting common measures of quality and system performance. Med Care. 2003 41(1 suppl):I39–I47. 20. Chassin MR. Is health care ready for Six Sigma quality? Milbank Q. 1998;76(4):565–591. 21. Simmons JC. Using Six Sigma to make a difference in health care quality. Qual Lett Healthc Lead. 2002;14(4):2–10. 22. Chan AL. Use of Six Sigma to improve pharmacist dispensing errors at an outpatient clinic. Am J Med Qual. 2004;19(3):128– 131. 23. Elberfeld A, Bennis S, et al. The innovative use of Six Sigma in home care. Home Healthc Nurse. 2007;25(1):25–33. 24. Ross AF, Tinker JH, eds. Anesthesia risk. In: Anesthesia. New York, NY: Churchill-Livingston; 1994. 25. Lunn JN, Devlin HB. Lessons from the confidential enquiry into perioperative deaths in three NHS regions. Lancet. 1987;2(8572):1384–1386.

26. Eichhorn JH. Prevention of intraoperative anesthesia accidents and related severe injury through safety monitoring. Anesthesiology. 1989;70(4):572–577. 27. Kim CS, Spahlinger DA, et al. Lean health care: what can hospitals learn from a world-class automaker? J. Hosp Med. 2006;1(3):191– 199. 28. Hagland M. Six sigma practices: a strategy based on data is perfect fit for healthcare. Healthc Inform. 2006;23(1):27–28, 30. 29. de Koning H, Verver JP, et al. Lean six sigma in healthcare. J Healthc Qual. 2006;28(2):4–11. 30. American Pain Society Committee on Quality Assurance. Quality assurance standards for relief of acute and cancer pain. In: Bond MR, Charlton JE, Woolf CJ, eds. Proceedings of the VI World Congress on Pain. Amsterdam: Elsevier; 1991. 31. American Pain Society Quality of Care Committee. Quality improvement guidelines for the treatment of acute pain and cancer pain. JAMA. 1995;274(23):1874–1880. 32. Dahl JL, Gordon D, et al. Institutionalizing pain management: the Post-Operative Pain Management Quality Improvement Project. J Pain. 2003;4(7):361–371. 33. Warfield CA, Kahn CA. Acute pain management: programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology. 1995;83(5):1090–1094. 34. McNeill JA, Sherwood GD, et al. Assessing clinical outcomes: patient satisfaction with pain management. J Pain Symptom Manage. 1998;16(1):29–40. 35. Apfelbaum JL, Chen C, et al. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97(2):534–540. 36. Breivik H. Postoperative pain management: why is it difficult to show that it improves outcome? Eur J Anaesthesiol. 1998;15(6):748–751. 37. Foss NB, Kristensen MT, et al. Effect of postoperative epidural analgesia on rehabilitation and pain after hip fracture surgery: a randomized, double-blind, placebo-controlled trial. Anesthesiology. 2005;102(6):1197–1204. 38. Perkins FM, Kehlet. Chronic pain as an outcome of surgery: a review of predictive factors. Anesthesiology. 2000;93(4):1123– 1133. 39. Acute Pain Management Guideline Panel. Acute pain management in adults: operative procedures. Quick reference guide for clinicians. Medsurg Nurs. 1994;3(2):99–107. 40. Berry PH, Dahl JL The new JCAHO pain standards: implications for pain management nurses. Pain Manag Nurs. 2000;1(1):3– 12. 41. Phillips DM. JCAHO pain management standards are unveiled. JAMA. 2000;284(4):428–429. 42. Berry PH. Getting ready for JCAHO – just meeting the standards or really improving pain management. Clin J Oncol Nurs. 2001;5(3):110–112. 43. Jacobsen R, Sjogren P, et al. Physician-related barriers to cancer pain management with opioid analgesics: a systematic review. J Opioid Manag. 2007;3(4):207–214. 44. Matthews E, Malcolm C. Nurses’ knowledge and attitudes in pain management practice. Br J Nurs. 2007;16(3):174–179. 45. Michaels TK, Hubbartt E, et al. Evaluating an educational approach to improve pain assessment in hospitalized patients. J Nurs Care Qual. 2007;22(3):260–265. 46. Sun VC, Borneman T, et al. Overcoming barriers to cancer pain management: an institutional change model. J Pain Symptom Manag. 2007;34(4):359–369. 47. Xue Y, Schulman-Green D, et al. Pain attitudes and knowledge among RNs, pharmacists, and physicians on an inpatient oncology service. Clin J Oncol Nurs. 2007;11(5):687–695.

Quality Improvement Approaches 48. Zanolin ME, Visentin M, et al. A questionnaire to evaluate the knowledge and attitudes of health care providers on pain. J Pain Symptom Manage. 2007;33(6):727–736. 49. Bender JL, Hohenadel J, et al. What patients with cancer want to know about pain: a qualitative study. J Pain Symptom Manage. 2008;35(2):177–187. 50. Ochroch EA, Troxel AB, et al. The influence of race and socioeconomic factors on patient acceptance of perioperative epidural analgesia. Anesth Analg. 2007;105(6):1787–1792. 51. Silver J, Mayer RS. Barriers to pain management in the rehabilitation of the surgical oncology patient. J Surg Oncol. 2007;95(5): 427–435. 52. Letizia M, Creech S, et al. Barriers to caregiver administration of pain medication in hospice care. J Pain Symptom Manage. 2004;27(2):114–124. 53. Lin CC, Chou PL, et al. Long-term effectiveness of a patient and family pain education program on overcoming barriers to management of cancer pain. Pain. 2006;122(3):271–281. 54. Miaskowski C, Nichols R, et al. Assessment of patient satisfaction utilizing the American Pain Society’s Quality Assurance Standards on acute and cancer-related pain. J Pain Symptom Manage. 1994;9(1):5–11. 55. Ward SE, Gordon. Application of the American Pain Society quality assurance standards. Pain. 1994;56(3):299–306. 56. Bookbinder M, Coyle N, et al. Implementing national standards for cancer pain management: program model and evaluation. J Pain Symptom Manage. 1996;12(6):334–347; discussion 331– 333. 57. Ward SE, Gordon DB. Patient satisfaction and pain severity as outcomes in pain management: a longitudinal view of one setting’s experience. J Pain Symptom Manage. 1996;11(4):242– 251. 58. Bostrom BM, Ramberg T, et al. Survey of post-operative patients’ pain management. J Nurs Manag. 1997;5(6):341–349. 59. Lin CC. Applying the American Pain Society’s QA standards to evaluate the quality of pain management among surgical, oncology, and hospice inpatients in Taiwan. Pain. 2000;87(1):43– 49. 60. Gordon DB, Pellino TA, et al. A 10-year review of quality improvement monitoring in pain management: recommendations for standardized outcome measures. Pain Manag Nurs. 2002;3(4):116–130. 61. Daut RL, Cleeland CS, et al. Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain. 1983;17(2):197–210. 62. Ward, SE, Goldberg N, et al. Patient-related barriers to management of cancer pain. Pain. 1993;52(3):319–324. 63. Mann C, Beziat C, et al. Quality assurance program for postoperative pain management: impact of the Consensus Conference of

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44 The Future of Acute Pain Management Brian Durkin and Peter S. A. Glass

The management of acute pain has come a long way since Roe asked, in his landmark 1963 article, “are postoperative narcotics necessary?”1 It would be difficult to imagine the past several decades without opioids in our arsenal for the treatment of postoperative pain, but what about the next several decades? Have we really improved in our management of postoperative pain and are too many patients still suffering? This book covers our present management of acute pain, and this chapter covers the future management of acute pain. Before we look into the future, we should reflect on and learn from the past. Figure 44.1: Cardiff palliator.

AC U T E PA I N M A NAG E M E N T I N T H E PA S T

tarian, in the cases of terminal cancer patients, to adequate pain control for discharge home from ambulatory surgery. The discovery of central nervous system opioid receptors in 1973 by Pert8 led to the discovery of neuraxial opioid analgesia in humans by Wang9 in 1979. The safe use of epidural anesthesia and analgesia in obstetrical patients made the conversion to epidural anesthesia and analgesia for postoperative pain rather easy. The 1980s were marked by the beginning of an abundance of literature on postoperative epidural analgesia with, first, intermittent bolus opioids10 and then combination opioid and local anesthetic infusions. The 1980s represented an exciting time for anesthesiologists interested in treating acute pain. Technology in the form of

From the mid-1960s and early 1970s, we saw the initiation of patient-controlled analgesia developing from concept to actual commercial delivery systems. Although the idea existed it took time to develop the technology. It thus took 10 years for the concept to reach fruition for daily use in patients and another 10 years for the practice of intravenous patient-controlled analgesia (IV PCA) to enter mainstream use in the United States. In the mid-1960s, in Houston, Texas, Sechzar2 instituted a demand system where the patient would push an alert button and the nurse would administer small intravenous doses of morphine. In a 1969 lecture, Scott3 reported 5 years of success with his device that delivered small intravenous boluses of meperidine to laboring women at the University of Leeds. Forrest,4 from the Palo Alto Veterans Administration Hospital, developed the “Demand Dropmaster,” and Keeri-Szanto5 from London, Ontario, developed his “Demanalg” device. The first commercially available PCA device, the “Cardiff Palliator,” came from Rosen’s group6 in Wales and came to market in 1976 (Figures 44.1 and 44.2). Prior to the early 1970s, postoperative pain control was not recognized as an integral part of the recovery process. The landmark 1973 article by psychiatrists Marks and Sachar7 brought to light the gross disregard of patients’ pain complaints and set in motion events in the entire field of medicine to focus on relief of pain for various reasons. These reasons ranged from humani-

Figure 44.2: Professor Michael Rosen.

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The Future of Acute Pain Management

microprocessors caught up with demand for intravenous PCA and large medical device companies were able to mass produce safe and viable PCA machines for use around the world. The development of Acute Pain Services11 led by anesthesiologists working in collaboration with clinical pharmacists and nurses in large teaching centers paved the way for the growth of intravenous PCA, as well as dedicated pain services throughout the various regions in the United States. For the first time, the treatment of acute pain was a dedicated profession while the treatment and disability status of chronic pain patients was argued in the federal government.12 The 1990s were a time of massive research and growth of the acute pain specialty. Peripheral nerve blocks joined the mainstream. The federal government produced a mandate for the treatment acute pain.13 The American Society of Anesthesiologists produced their practice guidelines on acute pain management in 1995,14 and the decade ended with the Joint Health Commission’s15 impact on making pain “the fifth vital sign.” This was a time when multimodal analgesia and preemptive analgesia became buzzwords, and we started using analgesics other than morphine, meperidine, acetaminophen, and local anesthetics for acute pain control. At the same time technology was enhancing the route and mode of delivery of analgesics. The treatment of chronic pain grew as well, and the prescription of opioids for nonmalignant chronic pain became accepted in many parts of the United States.16 Opiates and PCA became the mainstay of acute pain management. However, we began to realize that this practice might not be optimal. As early as 1988, White17 pointed out that intravenous PCA causes harm to some patients and may be associated with human programming error. Also, claims began to surface that the JHACO guideline of pain as a vital sign might be causing practitioners to strive toward unsafe levels of analgesia.18 We have thus been prompted in this early part of the 21st century of acute pain management to focus largely on improving outcomes by minimizing side effects of opioid analgesia. It is well established that opioid reduction must be at least 30% to provide a reduction in opioid side effects and attain a difference in outcome. This reduction in opiate use has been shown in numerous studies to reduce hospital stay and increase patient satisfaction. As aggressive pain treatment with opioid analgesics in the chronic pain setting has become more prevalent, so, too, has iatrogenic opioid addiction and dependence.19,20 This phenomenon has made acute pain management more challenging. Chronic pain patients are presenting for routine surgery and tolerance has made their opioid requirement substantially larger than the usual. We are learning that these patients are better managed with a multimodal plan including regional and neuraxial anesthetics and postoperative nerve and epidural catheters.21 Adjuvant medications, such as ketamine, gabapentin, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs),22 have been very beneficial in this group of patients. Today, outpatient surgery accounts for the majority of operations done in the United States. In the past, patients stayed in the hospital for many days after surgery that today is done on an ambulatory basis. The growth of minimally invasive surgery is mirrored by the growth in day surgery. The management of postoperative pain has had to adjust, as well. The greater impact of opiate side effects in the ambulatory patient has fostered the practice of multimodal analgesics to minimize their use. The use

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of peripheral nerve blockade has become increasingly popular in the ambulatory patient and catheter placement for home use has been implemented successfully in some parts of the country.23 How is the practice and profession of acute pain management going to change in the next 5 years? This is the question we will try to answer. Paradigms shift every so often. We saw this in the 1960s and 1970s when acute pain management did not get much attention. Often technology must advance further for ideas to be realized. We saw this occur in the 1980s when PCA machines were finally safer and more accessible. Today, we are seeing new technology, in the form of iontophoresis,24 that may displace the use of intravenous PCA in the future. The 1990s saw another paradigm shift insofar as patients could go home after surgery. Acute pain management adjusted to fulfill this need. The decade thus far is leading to, perhaps, another paradigm shift. Can the management of acute pain today affect patient outcomes weeks, months, or even years later? W H O W I L L M A NAG E P O S TO P E R AT I V E PA I N IN THE FUTURE?

Several models exist throughout the world regarding the composition of the acute pain service. In the United States, traditionally, the service has been anesthesiologist led with specialized nursing assistance. Health care payers have lessened or eliminated reimbursement for acute pain management services and procedures in various parts of the United States. Surgeons are managing PCA analgesia more often now while pain services focus on regional and epidural catheter placement and the challenging pain patients. In Europe, a nursing-based service with anesthesiologist consultation is the predominate model and is less expensive to run.25 We believe future management of acute pain will involve anesthesiologists, surgeons, and nurses working in collaboration with allied professionals, including physical therapists, pharmacists, social workers, and psychologists. This will differ from our present model of a designated team focusing primarily on the acute postoperative pain needs; rather, this will be a collaborative effort by a multidisciplinary team that designs an overall management plan unique to the patient and will cover management from the time surgery is planned through full recovery and rehabilitation. Thus, this collaboration will be more on a grand scale with both the development of hospital-wide policies created by pain management committees and individual plans generated in advance of any procedure. Pain will need to be addressed prior to even presenting to the hospital. The term prehabilitation will take on more meaning as patients are identified prior to admission and worked into better shape physically for a more productive rehabilitation.26 With our increasing understanding of genetics and genomics and the potential ability to identify patient-specific receptor subtypes, pain pathways, and the development of patient-specific designer drugs, this is likely to include individuals with expertise in these areas becoming involved as members of the pain team. Perioperative pain control will continue to include many of our present techniques and drugs (including many new ideas as described below). Specialists in regional anesthesia will continue as part of this larger pain team to provide nerve blocks and epidurals. The anesthesia team taking care of the patient during the operation will continue to be part of the grand plan to make postoperative pain and side effects minimal. It is important in this model that the anesthesia

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Brian Durkin and Peter S. A. Glass

Figure 44.3: Pain pathway.

team actually doing the anesthetic is included in the perioperative plans and tailors the anesthetic appropriately. We as pain specialists must show health care payers tangible results of these efforts and justify our existence as an integral and cost-effective part of the patients perioperative care. Patient satisfaction and good outcomes should be part of this equation. F U T U R E P H A R M AC E U T I C A L S

Today, we are on the verge of the next exciting time in acute pain management. The arsenal of weapons used to combat pain is ready for enormous growth. As the discovery of new receptors in the pain pathway continues, so does the development of new pharmaceuticals to block or modify these receptors. Cannabinoids, vanilloids (TRPV1 – transient receptor potential V1) peripheral ␬-opioid agonists, melatonin, and acid-sensing ion channels (ASICs) are all terms that may be well known to the acute pain management world in the near future. The dilemma facing acute pain physicians has been treating pain while minimizing side effects of medications. All medications, whether they are opioids, NSAIDs, or other adjuvants, such as gabapentin, have side effects that may limit their use. We must find a balance between these medications and the side effects they cause to reach the best results for pain relief. Future medications will target the dilemma from multiple angles. New medications will be developed to (1) minimize the side-effect profile of current medications and (2) target more specifically newly discovered pain pathways to either decrease the traditional doses or possibly eliminate the need for medications commonly used today. REDUCTION OF SIDE EFFECTS

Present development is occurring in the management of opioidinduced side effects. The use of methylnaltrexone and alvimopan for opioid-induced ileus and constipation will likely be in use in the very near future. These ␮-opioid antagonists do not cross the blood-brain barrier and act on peripheral opioid receptors to

reverse common opioid side effects without affecting the central pain relieving action. Alvimopan has been shown to significantly accelerate gastrointestinal recovery and time to discharge in patients after bowel resection.27 These new ␮-opioid antagonists may make postoperative opioid-induced ileus a term of the past. The most concerning side effect of opioid analgesia is respiratory depression. Morphine-6-glucuronide (presently in commercial development), an active metabolite of morphine, has been shown to have less ventilatory depression than equipotent analgesic morphine doses.28 Another exciting development in the prevention of opioid-induced respiratory depression is work on the 5-HT4(a) receptor. This receptor may be prove to be the magic bullet needed to prevent/reverse opioid-induced ventilatory depression. Treatment of rats with 5-HT4(a) receptor agonist has been shown to reverse fentanyl-induced respiratory depression without loss of fentanyl-induced analgesia.29 However, rats behave very differently from humans, and we wait in anticipation of the same benefit crossing over to humans. N E W A NA LG E S I C S

The pain pathway has many points where intervention can be made. As shown in Figure 44.3, there are many pieces of the pain puzzle that have been filled, but there are several, particularly in the first 3 steps, that will need to be filled in the future. The pain pathway begins with transduction from the point of insult and is then conducted to the central nervous system. Many opportunities exist for future pharmaceuticals to intervene and block or modulate pain perception at these levels and prevent the CNS from ever knowing there was an injury. This section will focus on some of these new analgesics and their possible use in the future (Figure 44.3). Sometimes old things become new again. With the growth of minimally invasive surgery, we are seeing procedures performed that several years ago would require a long convalescence and today are being done as an outpatient. Acetaminophen was once the standard medicine for mild to moderate acute pain, and with the intravenous form available, its use is well established in

The Future of Acute Pain Management

Europe, for mild to moderate perioperative pain and its release is anticipated soon in the United States. There is a large potential for the perioperative use of intravenous acetaminophen in ambulatory surgery where the use of opioids is best minimized and oral intake is not optimal.30 Nonsteroidal anti-inflammatories will be used, as well, and likely include intravenous diclofenac, which provides a more rapid onset of action compared to ketorolac. The hysteria regarding the cyclooxygenase 2 (COX-2) inhibitors will likely calm in the near future, and it is likely that intravenous COX-2 inhibitors will make their debut in the United States, eventually, and add to the multimodal analgesic arsenal. Peripheral ␬-opioid receptor agonists represent another potential class of opioids that may show promise in postoperative pain control in the near future. The current members of the class, butorphanol and nalbuphine, are limited in their use by their partial ␮-opioid receptor agonist activity. Experimental ␬-opioid receptor agonists have been shown to improve chronic visceral pain31 and may prove to be useful in the pain associated with postoperative abdominal distention that is difficult to treat with ␮-opioid receptor agonists and can create or intensify an ileus makingthe distention worse. The search for new nonopioid analgesics continues, and two well-known substances may soon contribute to the perioperative management of pain in new ways. Cannabinoids may become a new class of adjuvant analgesics for chronic neuropathic pain or acute inflammatory pain. Much work has been done looking for pain relief with various derivatives of the active ingredient of marijuana, but no firm results have yet been elucidated. Experiments in the 1970s showed the pain-relieving properties of 9-tetrahydrocannabinol (THC) in humans; however, dysphoric side effects limited their use.32 Further work has shown the synergistic effect of combining THC with opioids to enhance pain relief resistant to opioid alone.33 Perhaps the most promising agent to be derived from the cannabinoids is ajulemic acid. It has been shown to be effective in both inflammatory and neuropathic pain treatment, and it lacks psychotropic side effects and withdrawal symptoms after 1 week of use in human volunteers.34 It works like the NSAIDs on the inflammation pathway but is devoid of their side effects, including gastric irritation and renal artery constriction. Melatonin may be an interesting addition to the management of acute pain. Melatonin is secreted by the pineal gland in a diurnal manner with increased secretion occurring in the evening.35 There has been a well-known observation throughout time that humans with pain have less of that pain at night. Melatonin has been shown to release endogenous ␤-endorphin36 and is being studied for its anti-inflammatory action. Anesthesia in conjunction with surgery has been shown to decrease the normal circadian release of melatonin, and, perhaps, in the future supplementation may prove to be beneficial in postsurgical patients. Capsaicin is currently used for treatment of chronic pain and works by opening the transient receptor potential V1 ion channel found on peripheral C fibers. This channel opening allows calcium influx and attenuates C-fiber sensation. Resiniferatoxin is a more potent capsaicin analog and has been shown to decrease pain response in rats.37 This peripheral response may someday be translated in humans and be beneficial in orthopedic and incisional pain reduction. The ASIC family is a potential target for new pain medicines. The ASIC family consists of 6 subunits (1 a, 1b, 2 a, 2b, 3, and 4), which are expressed in peripheral neurons with the ASIC 1b and

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ASIC 3 subunits showing a high degree of selectivity in sensory neurons. Acidic nociception is likely to occur in many inflammatory and ischemic pain conditions such as rheumatoid arthritis and vascular ischemia, as well as in the routine perioperative setting. NSAIDs have been shown to attenuate the large expression of ASIC in sensory neurons induced by inflammation, as well as directly inhibiting sensory neuron ASIC current.38 The diuretic amiloride has been shown to weakly block ASIC under mild acidic conditions (pH 7.2–6.0) in humans, resulting in attenuated pain perception.39 Work is currently underway on a more selective and potent ASIC blocker without the limitations of amiloride and could potentially be an effective agent in the treatment of inflammatory and ischemic acute or chronic pain in the future.40 With the growing use of low-molecular-weight heparin (LMWH) products, the use of epidural catheters has declined because of the risk of spinal hematoma formation. The risk of deep venous thrombosis (DVT) in many surgical patients is high, and prophylaxis is surely needed. Epidural analgesia has been shown to decrease the incidence in DVT generation by increasing lower extremity blood flow, enhancing postoperative fibrinolysis, and enhancing rehabilitation and patient mobility. However, there is no evidence that the risk reduction of DVT provided by epidural analgesia is better, worse, or no different than that provided by LMWH. The drug manufacturers obviously are in favor of their drugs, so we need to determine ourselves through controlled trials (with the cooperation of surgeons) if LMWH or epidurals are more beneficial in the prevention of deep vein thrombosis, or whether multimodal treatment that includes epidural analgesia and, possibly, LMWH is better. Until this question is answered it would be beneficial to enable the use of epidural anesthesia with its attendant benefits even when LMWH is indicated. An alternative would be to develop long-acting analgesics that do not require indwelling epidural catheters. There have been several attempts to develop encapsulated extended release local anesthetics. Although none have so far come to fruition newer technologies are likely to make these a reality.41 An encapsulated form of mepivacaine formulation is in phase II trials currently. Thus it is likely that extended release forms of local anesthetic may in the future be used as a single shot dose in conjunction with encapsulated, long-lasting opioids for procedures where epidural catheters left postoperatively are contraindicated. These extended release local anesthetics would also likely make continuous peripheral nerve catheters obsolete along with their inherent risks of infection and nerve damage. Genomic research is enlightening our knowledge of disease and medicine, and this is being translated into knowledge of pain and pain medicine. As we learn more about genetics and coding for opioid receptors, we are finding reasons why there is variability in individual pharmacodynamics and pharmacokinetics. This knowledge has resulted in the development of the field of pharmacogenomics, a field with expanding importance in the future. There will be a time in the future when a quick scan of an individual’s DNA will aid dramatically in their postoperative pain control. Perhaps, during preoperative testing, the patient’s buccal mucosa will be swabbed and analyzed. The genetic information will be used to tailor treatment not just in pain management but also for all of perioperative medicine. It is known that people respond differently to all kinds of medications, and part of the reasons, likely, will be found in their genetics.

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The ability to perceive pain is actually a heritable trait, and there are families in the world with the ability to feel no pain. This may or may not be a beneficial trait to have. The congenital indifference to pain condition is a rare and inheritable condition that was first documented in 1932 after the observation of a circus performer who could pierce his body with knives and feel no pain. Recently, the gene mutation SCN9 A has been identified in multiple families around the globe and implicates the loss of function of the sodium channel Nav 1.7.42 Gain of function of this sodium channel has been linked with familial erythermalgia, which is an extremely painful condition of the extremities.43 Current sodium channel blocking medications include the local anesthetics, but they are limited in their selectivity for the Nav 1.7 channel and have cardiac and central nervous system limits. In the future, novel pharmaceuticals will target this channel specifically and may actually lead to the “Holy Grail” of pain management leaving all other medications redundant. F U T U R E D E L I V E RY M E C H A N I S M S

The traditional routes of pain medicine administration are being challenged. Oral, intravenous, and subcutaneous routes will, likely, never be replaced, but the nasal, inhaled, and transcutaneous routes do offer advantages in some situations. As mentioned previously, liposomal-encapsulated medications may offer benefit in the future and offer a longer lasting mode of delivery of opioids, local anesthetics, and anti-inflammatories. Transcutaneous delivery of medications offers several benefits over the more traditional routes of drug delivery. The need for intravenous access is diminished, and the ability to be free of poles and machinery may enhance the rehabilitation process by increasing patient mobility. The concept of iontophoresis to deliver medicine transcutaneously can be traced to Veratti, who described the idea in 1747. In the early 1900s, Leduc demonstrated the concept by delivering strychnine iontophoretically to rabbits, thus inducing convulsions.44 The technique relies on placing drug on the skin in an electrode of the same charge as the drug. An electric current is applied, and the drug is carried with the charge to the deep tissue layers, where it is absorbed by capillaries. The E-trans system currently using fentanyl at a fixed 40␮g bolus could be modified in the future to deliver other doses or medications. The benefit of the system is its portability and, probably, its safety. Most safety issues with intravenous PCA have been traced to programming error, and with a fixed dose device, that error is exponentially reduced. The new E-trans fentanyl system is the result of more than 15 years of research looking for effective demand delivery of transdermal opioids. The technology uses low-intensity direct current to transport fentanyl from the hydrogel reservoir through the dermis and into the circulation, where it travels to the central nervous system. The device resembles a small roach motel and its adhesiveness to the skin allows for easy portability. It has been shown to be as effective as standard morphine IV PCA dosing.24 It is likely that many pain medicines will eventually have the option to be delivered by these unconventional routes, and it is not unimaginable that the transcutaneous administration of opioids could replace intravenous PCA in all but the most opioid-tolerant patients (Figure 44.4). The intranasal route of drug administration also has several unique benefits when compared to the more traditional

On-demand button System controller Electronics and battery Electrode Drug reservoir Adhesive

Figure 44.4: Ionosys fentanyl demand system.

routes. The avoidance of needles and their waste, onset of action almost comparable to intravenous delivery, and the avoidance of the gastrointestinal tract and liver, thus reducing first-pass metabolism, are some of the advantages. The intranasal cavity by design provides an excellent drug delivery route. The mucosal surface area is extensive with the turbinates, providing ample space for drug absorption. The epithelium is highly vascularized and provides for rapid uptake of absorbed drug.45 However, only small, lipophilic drugs are readily absorbed, whereas large, polar medications are not and are at risk for enzymatic degradation.45 The development of one particular delivery system uses chitosan, which is derived from the chitin found naturally in crustacean shells. This protein has been used in extended-release tablets and has been found to be safe and bioadhesive and has demonstrated improved absorption across nasal mucosa. Inhaled fentanyl and intranasal and inhaled morphine are new methods of rapid onset analgesia and could find a place in the acute pain world. Inhalation of opioids has occurred successfully for centuries for both medicinal and recreational reasons. Physical therapy on postoperative day 1 is very common in orthopedics and the need for rapid analgesia in these situations makes inhaled dosing a viable alternative in patients when intravenous PCA is seen as a hindrance to mobility. Often, in these situations, pain is well controlled while patients are in bed but need to be controlled when activity occurs (Figures 44.5 and 44.6). Intranasal ketamine is another development that will likely show benefit in perioperative pain control. The US military is helping to fund this form of ketamine drug delivery as an easily administered, rapid-acting analgesic with a low side-effect profile in the 10- to 50-mg dosing range. Ketamine is well known to decrease postoperative opioid consumption, in some instances up to 50%, and would be an excellent adjuvant for patients with opioid tolerance or side effects.46 The perioperative use of ketamine is currently limited in the United States to intravenous or intramuscular dosing as there is no manufacturer of tablets for oral intake. Ketamine may be an underused tool in the perioperative period and with a convenient intranasal application, it could be highly beneficial to pain management in the future. Liposomal-encapsulated morphine for epidural use has been marketed already and will likely be the first of a host of products that rely on bioerodable delivery systems to extend duration of action of common pain medicines. The ability to provide singleshot dosing of medication to last up to 48 hours may improve

Plasma Fantanyl (ng/mL)

The Future of Acute Pain Management

Proprietary AeroLEFTM Formulation

Patient inhalation by nebulization

(Free + Encapsulated Fentanyl)

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2.5 2 1.5 1 0.5 0

0

10

20 30 40 Time (minutes)

50

60

Rapid and extended plasma levels

Figure 44.5: Inhaled fentanyl via proprietary AeroLEF system results in rapid and sustained pain relief by uptake through the lungs.

on the current standards and diminish the need for both epidural and peripheral indwelling catheters. The use of medications, such as NSAIDs and other adjuvants, will enable patients to sustain effective pain relief long after discharge and when pain is at its peak. Currently, a proprietary bioerodable system delivering meloxicam is in development with a targeted duration of action of 2 weeks post orthopedic surgery. Although there are several attempts to provide long-lasting (>24 hour) analgesics, the value of such prolonged duration is not fully established. As the pain cycle is relatively short in the acute postoperative setting, the need for drugs lasting longer than 24 hours may actually have disadvantages (eg, more rapid tolerance) and thus we caution that in this setting drugs lasting longer than 24 hours need to demonstrate improvement in pain management. D O E S U N C O N T RO L L E D AC U T E PA I N E F F E C T O U TC O M E S ?

This is a question that will be answered in the next 5 years. We believe that it does, and the consequences of poor pain control

will surprise the medical field and society, in general. Much focus has been directed at trying to show that poor acute pain control leads to chronic pain. There are, however, limited data to support what many of us believe is an inherent truth. There are certain types of operations (amputation, thoracotomy, mastectomy, herniorraphy) that are associated with a high incidence of chronic pain syndromes and seem to be related by their inherent high risk of nerve injury. The ability to diminish the risk of chronic pain postsurgically has been shown in several studies, but they have not been uniformally replicated. Obata et al47 showed that preincisional injection of epidural local anesthetic, combined with postsurgical epidural analgesia reduced pain at 6 months from 67% to 33%. Uncontrolled acute postthoracotomy pain has been shown to be a significant predictor of postthoracotomy pain syndrome.48 Orthopedic extremity surgery has associated with it the dreaded complex regional pain syndrome (CRPS). The incidence is reported to range from 1% to 11% in orthopedic extremity injuries49 and is probably below 5% of all orthopedic extremity surgeries. Whatever the actual percentage is, there are a very large number of patients who may be at risk for this debilitating

Figure 44.6: AeroLEF inhaled fentanyl has similar rapid onset to intravenous fentanyl, but results in higher fentanyl blood concentration for a longer time period.

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disease. Other operations at risk for postoperative chronic pain include spinal fusion and iliac crest harvest.50 Reuben51 has shown that a perioperative multimodal analgesic regimen combined with an accelerated rehabilitation program can prevent chronic knee pain after anterior cruciate ligament repair at 6 months postoperatively. The use of celecoxib 1–2 hours preoperatively and then every 12 hours for 14 days was associated with decreased CRPS, anterior knee pain, flexion contracture, and scar tissue requiring rearthroscopy. It was also shown that the celecoxib group returned to a higher activity level and full sports participation after 6 months. This type of study on a welldefined population with a well-defined multimodal analgesic regimen that looks beyond the traditional anesthesiologist definition of the perioperative period (6 months) is what has been lacking over the years and what is needed in the future. We have seen many studies fail to show significant outcome differences, using various pain control techniques ranging from oral acetaminophen to epidural PCA for surgery ranging from tooth extraction to coronary bypass. To obtain meaningful results it is essential that studies are better controlled and they are extended further into the future to show that we can make a difference in long-term outcomes. These outcomes may be more important than even preventing chronic pain. We believe that effective acute pain control has even more important outcomes (eg, cancer prevention, DVT prevention) associated with it. The challenge will be in proving it. Good acute pain management means more than lowering pain scores and decreasing nausea. It means getting people back to their lives sooner and in better shape than they were before, therefore the perioperative team must put in a lot more thought and effort for this to occur. Plans for pain management must consider preoperative, intraoperative, and postoperative elements. Pain specialists in the future will consider optimal pain treatment beyond discharge, and all will tailor therapy to optimize quality of life rather than just pain. JHACO had good intentions with their 1999 recommendations regarding pain assessment and treatment; hospitals needed an objective measure and the pain score was born. We believe the future of pain management will need to forget about the pain score and instead look for something that really measures the outcomes that patients desire. What good is a pain score of zero when the patient is just lying in bed for 3 days? Acute pain teams should become “acute rehab teams” or “acute let’s get you home and back to work teams.” The ability to prevent cancer recurrence or myocardial infarction months to years after surgery by controlling the neuroendocrine and sympathetic response to surgical insult with regional anesthesia, analgesia, or targeted pharmaceuticals will elevate the acute pain management field to levels never before imagined. Inflammatory response is something that can and should be avoided perioperatively.52 Liebeskind’s well-known mantra “pain can kill” will soon be shown to be true (Figures 44.7 and 44.8).53 A recent retrospective analysis of breast cancer surgery patients revealed a siginificant difference in outcome regarding cancer recurrence. The groups were separated by anesthetic technique; one group received general anesthesia and IV PCA morphine postoperatively, whereas the other group received paravertebral blockade combined with general anesthesia. The paravertebral block group had significantly less recurrence and metastasis at both 24- and 36-month follow-up.54 Whether the difference in outcome can be attributed to the unilateral sym-

Figure 44.7: Pain Can Kill early manuscript, 1990.

pathetic blockade, improved pain control or diminished use of general anesthetic inhalational agents remains to be learned. This study should provide impetus for further research. The surgical manipulation of cancer cells is bound to set some of these cells off into the circulation during the operation and optimizing the patients immune system to fight off these threats is likely beneficial. Sympathetic blockade by local anesthetic delivered via patient-controlled epidural anesthesia has been shown to improve the immune system response55 and with this improvement it would be expected that both infectious and cancerous complications would be attenuated.

Figure 44.8: John Liebeskind.

The Future of Acute Pain Management

The importance of optimal perioperative pain management must be researched further to look for differences in outcomes that go beyond pain scores, morphine consumption, and patient satisfaction. Granted, these outcomes are important in the routine management of acute pain, but there are higher aspirations to achieve in this field. Well-controlled studies must be constructed with large numbers of patients and followed for years in advance to show relevant differences in outcomes such as cancer recurrence, pulmonary embolism, and myocardial infarction. Perhaps the newly formed American Society of Regional Anesthesia AcutePOP (postoperative pain) initiative will be the platform for collection of data to gain the large numbers needed to find outcome differences that are statistically significant.56 C O N C LU S I O N S

Acute pain management has a bright future. There are many new and exciting pharmaceuticals and delivery mechanisms on the horizon that will improve the management of all types of pain. We can look at the past and see that it takes many years for great ideas to be realized in the world of both acute pain management and medicine as a whole. Technology must catch up before ideas like IV PCA, peripheral nerve blocks, and epidural analgesia can reach a wide market. Our knowledge of the pain pathway is growing daily and new medicines and delivery mechanisms are being developed to take further steps toward eliminating pain. Pharmacogenomics will continue to develop to the point where very specific therapies will be initiated and unwanted side effects eliminated or reduced. There may even be a time when our patients’ DNA is analyzed and the exact pain receptor targeted for optimal patient pain relief. We can achieve nearly zero pain with regional and epidural analgesia; there will be a time when we can do the same with future pain medicines. Acute pain management is a relatively new subspecialty to medicine and, to continue its vitality, must prove its worth. The development of databases that can pool data from various locations across the country will enable researchers to gain the numbers necessary to find that effective acute pain management does make a difference in patient outcomes. We as a specialty are continuously being infringed on by the pharmaceutical and medical device industries in both positive and negative ways. Acute pain physicians must be the leaders for industry. There will be many new advances in technology in the next several years and industry will continue to apply pressure to sell their products. We as a specialty must continue to be the gatekeepers and do what is best for our patients. Most patients do very well after surgery – or do they? Surgery and anesthesia have become very safe over the years and morbidity and mortality in the perioperative period continue to decline. However, we do not know whether patients are suffering insults that occurred perioperatively because of poor pain management that manifests months or years later. Our views of what exactly constitutes perioperative morbidity and mortality may be limited at the present time. It may be time for a new paradigm shift regarding acute pain management and its effect on outcomes. We do know that most of our surgical patients do not have the optimal outcomes we have defined above. Patients still hurt months to years after undergoing what they thought would be

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“routine surgery.” Global recovery including pain relief, patient satisfaction, good health, and perhaps even sustained life must be the essential elements we strive for in the management of acute pain. We as a specialty can make a difference in all of our patients, and we must work harder to prove it.

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21. Mitra S, Sinatra RS. Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology. 2004;101(1):212– 227. 22. Carroll IR, Angst MS, Clark JD. Management of perioperative pain in patients chronically consuming opioids. Reg Anesth Pain Med. 2004;29(6):576–591. 23. Swenson JD, et al. Outpatient management of continuous peripheral nerve catheters placed using ultrasound guidance: an experience in 620 patients. Anesth Analg. 2006;103(6):1436– 1443. 24. Viscusi ER, et al. Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: a randomized controlled trial. JAMA. 2004;291(11):1333– 1341. 25. Rawal N. Organization of acute pain services – a low-cost model. Acta Anaesthesiol Scand Suppl. 1997;111:188–190. 26. White PF, et al. The role of the anesthesiologist in fast-track surgery: from multimodal analgesia to perioperative medical care. Anesth Analg. 2007;104(6):1380–1396, table of contents. 27. Delaney CP, et al. Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies. Ann Surg. 2007;245(3):355–363. 28. Romberg R, et al. Pharmacodynamic effect of morphine-6glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology. 2003;99(4):788– 798. 29. Manzke T, et al. 5-HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science. 2003; 301(5630):226–229. 30. White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg. 2005; 101(5 suppl):S5–S22. 31. Eisenach JC, Carpenter R, Curry R. Analgesia from a peripherally active kappa-opioid receptor agonist in patients with chronic pancreatitis. Pain. 2003;101(1–2):89–95. 32. Noyes R Jr, et al. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol. 1975;15(2–3):139–143. 33. Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004;74(11):1317–1324. 34. Karst M, et al. Analgesic effect of the synthetic cannabinoid CT3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 2003;290(13):1757–1762. 35. Karkela J, et al. The influence of anaesthesia and surgery on the circadian rhythm of melatonin. Acta Anaesthesiol Scand. 2002;46(1):30–36. 36. Shavali S, et al. Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull. 2005;64(6): 471–479. 37. Kissin EY, Freitas CF, Kissin I. The effects of intraarticular resiniferatoxin in experimental knee-joint arthritis. Anesth Analg. 2005;101(5):1433–1439.

38. Voilley N, et al. Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acidsensing ion channels in nociceptors. J Neurosci. 2001;21(20):8026– 8033. 39. Ugawa S, et al. Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. J Clin Invest. 2002;110(8):1185–1190. 40. Jones NG, et al. Acid-induced pain and its modulation in humans. J Neurosci. 2004;24(48):10974–10979. 41. Cereda CM, et al. Liposomal formulations of prilocaine, lidocaine and mepivacaine prolong analgesic duration. Can J Anaesth. 2006;53(11):1092–1097. 42. Cox JJ, et al. An SCN9 A channelopathy causes congenital inability to experience pain. Nature. 2006;444(7121):894–898. 43. Sheets PL, et al. A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity. J Physiol. 2007. 44. Helmstadter A. The history of electrically-assisted transdermal drug delivery (“iontophoresis”). Pharmazie. 2001;56(7):583–587. 45. Anez Simon C, et al. Intranasal opioids for acute pain. Rev Esp Anestesiol Reanim. 2006;53(10):643–652. 46. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004;99(2):482–495, table of contents. 47. Obata H, et al. Epidural block with mepivacaine before surgery reduces long-term post-thoracotomy pain. Can J Anaesth. 1999;46(12):1127–1132. 48. Katz J, et al. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain. 1996;12(1):50–55. 49. Gradl G, et al. Acute CRPS I (morbus sudeck) following distal radial fractures – methods for early diagnosis. Zentralbl Chir. 2003;128(12):1020–1026. 50. Joshi A, Kostakis GC. An investigation of post-operative morbidity following iliac crest graft harvesting. Br Dent J. 2004;196(3):167– 171; discussion 155. 51. Reuben SS, Ekman EF. The effect of initiating a preventive multimodal analgesic regimen on long-term patient outcomes for outpatient anterior cruciate ligament reconstruction surgery. Anesth Analg. 2007;105(1):228–232. 52. Carli F. Postoperative metabolic stress: interventional strategies. Minerva Anestesiol. 2006;72(6):413–418. 53. Liebeskind JC. Pain can kill. Pain. 1991;44(1):3–4. 54. Exadaktylos AK, et al. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006;105(4):660–664. 55. Volk T, et al. Postoperative epidural anesthesia preserves lymphocyte, but not monocyte, immune function after major spine surgery. Anesth Analg. 2004;98(4):1086–1092, table of contents. 56. Liu SS, et al. Announcing the Official Formation of ASRA AcutePOP (Acute Postoperative Pain) Initiative. Reg Anesth Pain Med. 2007;32(3):265–266.

Index

Aaron, L. A., 43 Aasboe, V., 381 Abbott PCA machines, 204 Abboud, T. K., 543 abdominal surgery. See also colectomy; postoperative bowel dysfunction (POBD) bupivacaine for, 224 buprenorphine for, 240 catheter placement for, 221 clonidine-fentanyl (epidural) mixture for, 232 vs. dexmedetomidine, 176 diclofenac for, 60 epidural analgesia for, 180, 221, 467 continuous, 467–468 for elderly patients, 529 EREM for lower abdominal surgery, 106, 328 fentanyl infusions for, 233, 327 hydromorphone (epidural) for, 237 with bupivacaine/ropivacaine, 238 ketamine for, 93, 368, 370 ketorolac for with opioids, 60, 346 preemptive use of, 345 local anesthetic injections for, 132 magnesium (perioperative infusion) for, 179 morphine for epidural, 232, 234 with ibuprofen, 345 intrathecal, 230–232 oxycodone with ibuprofen for, 198 oxymorphone (immediate release) for, 198 parecoxib sodium for, 353 parenteral/oral opioids for, 583 pulmonary response to, 25 remifentanil for, 122 rofecoxib for, 350 ropivacaine for, 224 with fentanyl, 105, 235

tenoxicam for, 346 thoracic epidurals for, 241 upper abdominal/thoracic, 28 and postoperative pain, 36 acetaminophen (paracetamol), 54 for acute postoperative pain, 385 for ambulatory surgery, 481 analgesics for, effects of, 56, 59 antipyretic effects of, 56 classification of, 53–54 clinical actions of, 58 combinations COX-2 inhibitors, 131 hydrocodone, 197 lidocaine, 383 oxycodone, 193, 197, 238 rofecoxib, for oral surgery, 350 tramadol, 198–199 description, 334 for emergency room use, 591–592 intravenous (IV APAP), for ambulatory surgery, 481 mechanism of action, 58, 177–178 for moderate/severe pain, 197 for pediatric pain management, 493 pharmacokinetics of, 58–59 for postsurgical use, 356–358 intravenous (paracetamol), 358–359 oral/rectal, 358 preventive multimodal analgesia with, 177–178 for sickle cell disease, 554 solubilized, in solution, 66 acetanilide, 54, 356 acid-sensing ion channels (ASICs), 672–673 R Actiq oralet (oral transmucosal fentanyl), 194, 198, 572, 574 acupressure, 392 acupuncture, 384–385, 392–395 administered after naloxone, 394 for ambulatory surgery, 482 679

FDA, NIH, WHO approval for, 393 and Gate Control Theory, 394 involvement of neural systems, 395 meridian/acupuncture points, 393 PET/fMRI studies, 395 for postoperative pain, 395–396 and release of endogenous opioids, 394–395 Acute Pain Management: Scientific Evidence (ANZCA), 630, 634 Acute Pain Service (APS)/Acute Pain Management Service (APMS), 227, 425. See also community hospital/ practice setting communication needs, 436–437 economic considerations, 439–440 European criticism of U.S. APMS organization, 435 future considerations, 440 goals and objectives development, 436 governmental aspects, 440 human resource management, 437–438 introduction of PCA, 204 operation and production management, 438–439 organizational role in hospital settings, 433 patient guide to PCA, 215–216 quality assurance issues, 434 respiratory depression monitoring, 417 types of organizations, 433–436 anesthesiologists, 433–434 hospitals/anesthesia groups, 435–436 JCAHO, 433 nurse practitioners, 434 nurses, 434 nursing education, 434 pharmacists, 434–435 psychological component, 434 acute respiratory distress syndrome (ARDS), 25 adaptive purposes of pain, 3

680 adjusted life-years (QALYs), 629. See also economic aspects of healthcare advanced practice registered nurses (APRNs), 598–599 affective-motivation domain, McGill pain questionnaire assessment, 12 African-American patients. See also sickle cell disease OUCHER scale for, 490, 552 undertreatment for pain, 160 women, PCA/ morphine consumption, 34 Agency for Health Care Policy and Research (AHCPR) acute pain management guidelines, 147, 659 Patient Outcome Questionnaire, 664 recommendation for multimodal analgesia, 478 Agency for Health Care Research and Quality, 176 aging, effect of, on nervous system, 515–516. See also elderly patients Alaris System PCA Module, 311 alfentanil for ambulatory surgery, 368, 479 clinical trials, 103–105 elderly sensitivity to, 521 epidural administration, 103–104, 223 and hypnosis, 402 lipophilicity of, 105 ODAC monitoring, 204 for PCA/IV-PCA use, 305 response variability, 35 use, for ambulatory surgery, 368 Alford, J. W., 297 Alfred, D. P., 566 Ali, J., 25 allodynia, 3, 6, 15, 102 from BDNF administration, 17 defined, 21 from IL-1-Beta elevation, 7 from PGE2 application, 15 allyl-2, 5-dimethyl-1-piperazines, 412. See also DPI-3290 alpha-1-acid glycoprotein (AGP), 76 alpha-2 adrenergic receptor agonists, 28, 132–133, 383–384. See also clonidine; dexmedetomidine (MPV-1440); epinephrine; tizanidine dosages, 384 intrathecal administration of, 383 locations/subtypes, 383 properties of, side effects, 383 alpha-2-adrenergic receptors immunologic effects of, 89 interactions with other analgesics, 88–89 and pain modulation, 82–84 pharmacology of analgesia, under different conditions, 84–85 peripheral use of clonidine, 85 postoperative pain condition, 85

Index pharmacology of clinically available adrenergic agonists as analgesics, 85–88 alpha-2 delta membrane stabilizers, 17 alternate theories of pain Gate Control Theory (Melzack and Wall), 4–5, 41–42, 394 neuromatrix theory (Melzick), 42 alvimopan for minimization of opioid-related gastrointestinal distress, 613, 672 for morphine-induced increased GI time, 408 for POBD/POI, 586–587, 672 postoperatively, for abdominal surgery, 408 ambulatory surgery economics annual surgery statistics for U.S., 476 health expenditure statistics, 476 pain control improvement, 478–483 acetaminophen, 481 adjuvant analgesics, 480–481 anticonvulsant type analgesics, 480–481 IV acetaminophen, 481 ketamine, 481 multimodal therapy, 478–479 nonpharmacologic methods, 482–483 acupuncture, 482 protocol based pain control, 483 TENS, 482–483 NSAIDs, 479–480 COX-2 inhibitors, 480 opioid analgesics, 479 patient education, 478 preoperative analgesia, 478 regional blockade, 481–482 pain following, 476–478 patient selection for, 287 postsurgical milestone, 476 sufentanil for, 574 ambulatory surgery, postoperative analgesia ankle block, 295 axillary brachial plexus block, 292 fascia iliaca block, 294 femoral nerve block, 293–294 ilioinguinal/iliohypogastric nerve block, 296 infraclavicular brachial plexus blocks, 289–290 intercostal nerve block, 296 interscalene nerve block, 289–290 intravenous boluses of fentanyl/ morphine/hydromorphone, 196 lumbar plexus blocks, 293 paravertebral nerve block, 295–296 sciatic nerve blocks distal, in popliteal fossa, 295 proximal, 294–295 supraclavicular nerve block, 289–290 wound infiltration for, 296–298

ambulatory surgery, regional anesthesia/analgesia local anesthetics/equipment for, 288 patient selection for, 287 American Academy of Pain Medicine, 634 American Academy of Pediatrics, 548 American Academy of Sleep Medicine Task Force, 422 American College of Critical Care Medicine, 162 American College of Emergency Physicians, 594 American College of Obstetricians and Gynecologists, 537 American Pain Society (APS) Brief Pain Inventory, 664 concern about range order administration, 605–606 “Pain as the 5th Vital Sign” slogan, 147–148 Patient Barriers Questionnaire, 664 Patient Outcome Questionnaire, 664–665 Quality of Care Committee, 664–665 quality/quality improvement issues guidelines for evaluation of quality, 659 recommendations for improvement, 665 studies/evaluations, 665 recommendation against meperidine, 612 “Recommendations for Improving the Quality of Acute and Cancer Pain Management,” 665 American Society for Pain Management Nursing (ASPMN), 149, 163 concern about range order administration, 605–606 guidelines for hierarchy of pain measures development, 604 position statements, 167 American Society of Anesthesiologists (ASA) advocacy for multimodal analgesia, 176, 478 outcome indicators for pain control, 476 patient education section of website, 457 Quality Management Template, 474 American Society of Health-System Pharmacists, 162 American Society of Regional Anesthesia and Pain Medicine (ASRA), 226, 239 guidelines for use of regional techniques with anticoagulants, 246 patient education section of website, 457 amputation, 36 and chronic pain, 642, 675 ketamine for, 372 of lower extremity, 109–110 and neuropathic pain, 116 PNB anesthetics for, 529 analgesia. See also epidural analgesia; intravenous patient-controlled analgesia (IV-PCA); neuraxial analgesia; patient-controlled analgesia (PCA);

Index patient-controlled epidural analgesia (PCEA) 3 step analgesic ladder for cancer pain (WHO), 147 4-step analgesic ladder (Yale-New Haven Hospital), 147 fading of, cold pressor pain model, 116 peri-operative, and NSAIDs, 59 pharmacology of, under different conditions, 84–85 peripheral use of clonidine, 85 postoperative pain, 85 and postoperative cardiovascular function in elderly, 526–527 and postoperative cognitive function in elderly, 523–526 and postoperative endocrine/immune function in elderly, 529–530 postoperative outcomes in elderly, 530–533 and postoperative pulmonary function in elderly, 527–529 preventive, 175 analgesia, postoperative, in outpatients ankle block, 295 axillary brachial plexus block, 292 fascia iliaca block, 294 femoral nerve block, 293–294 ilioinguinal/iliohypogastric nerve block, 296 infraclavicular brachial plexus blocks, 289–290 intercostal nerve block, 296 interscalene nerve block, 289–290 intravenous boluses of fentanyl/ morphine/hydromorphone, 196 lumbar plexus blocks, 293 paravertebral nerve block, 295–296 sciatic nerve blocks distal, in popliteal fossa, 295 proximal, 294–295 supraclavicular nerve block, 289–290 analgesia, regional administration options, 440 economic considerations, 440 epidural/continuous, for sleep disturbances, 29 and improved perioperative outcomes, 531 interference with start of surgery, 438 with local anesthetics, 179–181 for epidural block, 180 for peripheral nerve block, 180 for wound infiltration, 179–180 vs. opioid-based analgesia, 521–523 patient controlled regional analgesia (PCREA), 251 for postoperative pain, 575 use of COX-2 inhibitors/NSAIDs, 29 analgesic infusion pump technology, 308–310 analgesics. See also acetaminophen (paracetamol); COX-2 (cyclo-oxygenase-2) inhibitors; epidural analgesia; morphine;

non-opioid analgesics; opioid analgesics activity sites/interactivity variability of, 377 effects on prostaglandins, 35 endogenous analgesics, 10–11 future development of, 672–674 and gender, 35 interactions with alpha-2-adrenergic agonists, 88–89 with gabapentin/pregabalin, 96–97 new generations of, 17 undermedication from, 3 analgesics, novel delivery systems. See transdermal therapeutic systems (TTS) analgesics, oral dosing, 197–199 R fentanyl oralet (Actiq ), 198 future directions, 200–201 hydrocodone/oxycodone, 197 with ibuprofen compounding, 198 morphine, 197 oxymorphone, 198 short-acting agents, 199 sustained release preparations, 198 tramadol/acetaminophen, 198–199 analgesic tolerance, to opioids acute opioid tolerance, 116–117 after chronic administration, 117–118 described, 116 genetic approaches to, 121 mechanisms of, 118–121 alterations in GTP binding protein coupling, 119 cytokines and innate immunity, 120–121 ion channels, 120 NMDA receptor, 120 protein kinase activation, 119–120 receptor desensitization/tracking, 118–119 anatomy of brachial plexus, 247–248 axillary level, 255–256 below clavicle, 253 of elbow, 260 of lumbo-sacral plexus, 266–267 of respiration, 418–419 of wrist, 264 anesthesia, orthopedic, success of peripheral nerve blocks, 180 anesthesia/anesthetics. See also epidural anesthesia; local anesthesia/anesthetics; Na channels; nerve blocks; regional anesthesia; specific anesthetics listed in the index balanced anesthesia, 133 and cocaine, 70 combined spinal plus epidural (CSE/CSEA), 234 dissociative anesthesia (from ketamine), 91 as effect of alpha-2-AR usage, 88 general anesthesia for ambulatory surgery, 368

681 attenuation of remifentanil hyperalgesia, 386 cardio protective effects, 28 vs. CBT, for children with leukemia, 47 epidural infusion-light, 238 vs. interscalene nerve blocks, 290 with interscalene nerve blocks, 248 with ketamine, 132 light, for single-shot/continuous peripheral blocks, 502 with local-regional blocks, 174 vs. lumbar plexus block with mepivacaine, 267 vs. lumbar plexus-sciatic nerve block, 293 nerve injuries related to, 281 vs. neuraxial anesthesia, 637–638, 642 vs. paravertebral blocks, 295 vs. preemptive analgesia, 36 vs. regional anesthesia, 245, 281, 288, 469 with sciatic block, lateral approach, 507 vs. single-injection regional anesthesia, 132 historical background, 70 inhalational anesthesia, 174, 179, 369, 674 limitations, for sympathetic neuroendocrine/biochemical responses, 172 neuraxial anesthesia, 180 and postoperative cognitive function in elderly, 523–526 and postoperative endocrine/immune function in elderly, 529–530 postoperative outcomes in elderly, 530–533 and postoperative pulmonary function in elderly, 527–529 sensory anesthesia, 73–74, 88 anesthesia/hospital groups, in U.S., 435–436 Anesthesia Patient Safety Foundation (APSF), 213 anesthesiologists. See also American Society of Anesthesiologists; physicians cesarean section opioid choice, 537 leadership of APMS in large centers, 433–434 pain physiology/pathology knowledge of, 30 regional, shortages of, 435–436 relaxation training for patients by, 48 and single bolus injection techniques, 132–133 Angst, M., 104, 123 ankle blocks, 260, 295 anthranilic acids, pharmacokinetics of, 57 antidopaminergics, for nausea and vomiting, 410 anti-emetic treatment of nausea and vomiting, 410–411 antihistamines, for nausea/vomiting, 410

682 anti-neuropathics, 382–383 gabapentin and pregabalin (See also gabapentin and pregabalin) lidocaine/mexilitine 383 (See also lidocaine; mexilitine) anxiety. See also catastrophizing of pain; cognitive-behavioral therapy (CBT); kinesiophobia; psychological aspects of pain associated with hospital admission, 165 burn-related anxiety, 43 descending inhibition by, 14 and fear, 43 and pain, 42–43 Pain Anxiety Symptoms Scale, 43 predictive value of pain postoperative, 42 pre-surgical, 42–43 pre-surgical, predictiveness of, 42–43 ANZCA. See Australian and New Zealand College of Anesthetics (ANZCA) APMS. See Acute Pain Service (APS)/Acute Pain Management Service (APMS) apnea. See sleep disturbances APRNs. See advanced practice registered nurses (APRNs) APS. See Acute Pain Service (APS)/Acute Pain Management Service (APMS) APS. See American Pain Society (APS) arachidonic acid (AA), conversion by COX-2, 5–6 arcuate cingular cortex (ACC), and acupuncture, 395 Ashburn, M. A., 212 Asian-American patients, 34 aspirin (acetyl salicylate). See also salicylates analgesic effects of, 59 anti-inflammatory limitations, 55 commonality with NSAIDs, 53 comparisons with acetaminophen, 59, 177, 493 with celecoxib, 61 inhibition of COX by, 55 for moderate/severe pain, 197 pharmacokinetics of, 57 and platelet clotting function, 64–65 side effects of, 57, 63, 66 aspirin-sensitive asthma, 66 hepatoxicity, 66 peptic ulcers, 63 assessment of pain in emergency department, 589 historical background, 147–149 patient barriers to, 165 patient comfort and satisfaction, 159–160 process of, 150–151 observer pain scores, 150–151 self report scales, 151 types of pain, 149–150 assessment of pain, special populations, 160–164 addictive disorder patients, 163 critically ill patients, 162–163 elderly patients, 161

Index ethnic/racial minorities, 160–161 pediatric patients, 163–164, 489–490 (See also pediatric pain management, assessment/assessment tools) assessment of pain, tools, 151–160 adjunctive tools, 158–159 Leeds Assessment of Neuropathic Symptoms and Signs scale, 159 Neuropathic Pain Scale, 158–159 behavioral/observational tools, 157–158 Behavioral Pain Scale, 158, 163 Critical Care Pain Observation Tool, 157–158, 163 Face, Legs, Activity, Cry and Consolability tool, 157, 161 Pain Assessment in Advanced Dementia Scale, 157 delirium assessment tools Confusion Assessment Method for the ICU, 162 Intensive Care Delirium Screening Checklist, 162 elderly assessment tools Checklist of Nonverbal Pain Indicators, 161 Pain Assessment in Advanced Dementia Scale, 161 in emergency department, 589 numerical rating scale/graphical rating scale, 589 visual analog scale (VAS), 589 multidimensional tools, 154–157 Brief Pain Inventory, 157 Initial Pain Assessment Tool, 154 McGill Pain Questionnaire, 12, 33, 111, 156–157 OLD CART tool, 154–156 Short-Form McGill Pain Questionnaire, 157 Pain Anxiety Symptoms Scale, 43 pediatric patients (See pediatric pain management) Roland Disability Questionnaire, 44 subjective sedation-assessment scales, 162 Motor Activity Assessment Scale, 162 Richmond Agitation-Sedation Scale, 162 Riker Sedation-Agitation Scale, 162 Vancouver Interaction and Calmness Scale, 162 Tampa Scale of Kinesiophobia, 43 unidimensional pain rating scales, 151–154 Faces Pain Scale (FPS), Iowa Pain Thermometer (IPT), 154 Numeric Rating Scale (NRS), 151, 162 Verbal Rating Scale (VRS), 151–153 Visual Analog Scale (VAS), 153, 162 Wong-Baker FACES Rating Scale, 154 AstromorphTM (morphine), 230 attenuation of pain induced pathophysiology cardiac surgery, 28 cytokine response, 28–29 persistent pain, 29–30

sleep disturbances/return to functionality, 29 thoracic/upper abdominal surgery, 28 thromboembolism, risk of, 28 tissue breakdown/infection risk, 29 vascular surgery, 28 Aubrun, F., 35 Auroy, Y., 281, 289 Austin, K. L., 303 Australia, opioid trends study, 114 Australian and New Zealand College of Anesthetics (ANZCA), 630–631, 634 Australian Pain Society, 634 autonomic nervous system aging’s effect on, 516 fight or flight response, 567 and opioid dependence, 400 AvinzaTM (sustained release morphine), 565 axillary brachial plexus block, 255–259 block techniques nerve stimulation, 257–258 paresthesia method, paresthesia/trans-arterial, 259 ultrasound guidance, 258–259 complications, 259–260 indications, 256 pearls, 260 pediatric patients, 505 continuous technique/dosage, 505 single shot technique/dosage, 505 postoperative analgesia in outpatients, 292 axon reflex, positive feedback loop from, 102 back pain abnormal brain chemistry in, 14 auricular acupuncture for, 482 epidural abscesses and, 226 and kinesiophobia, 43 lidocaine patch for, 324 morphine study, 117 Pain Anxiety Symptoms Scale (PASS) measurement, 43 and psychogenic pain disorder, 150 QALYs measurement for, 629 systemic opioids for, 130 Bailey, P. L., 420 Ballantyne, J. C., 207 Bamgbose, B. O., 382 barriers to pain control, 164–166 of healthcare providers, 165–166 overcoming, 166 of patients, 165 Bartfield, J. M., 590 Beauchemin, K. M., 50 Beecher, H. K., 25, 41, 110 Behavioral Pain Scale (BPS), 158 behavioural based pain assessment scales, pediatric patients, 490–493 Children and Infants Postoperative Pain Scale (CHIPPS), 490

Index Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS), 164, 491 Face, Legs, Activity, Cry and Consolability (FLACC) tool, 157, 492 Individualized Numeric Rating Scale (INRS), 493 Non-Communicating Children’s Pain Checklist-Postoperative Version (NCCPC-PV), 492–493 objective pain scale (OPS), 492 Pain Indicators for Communicatively Impaired Children, 492 Pediatric Pain Profile (PPP), 491 Bell, J. R., 114 Benedetti, F., 110 Bennett, G. J., 110 benzocaine, 76, 78 benzodiazepines, 57, 88 administration for anxiety, 575 co-dependence on, 568 and drug abuse, 391 magnification of neuronal inhibition, 420 pre-anesthesia administration, 368 restriction in elderly patients, 239, 242, 521 Bernards, C. M., 103 Bessler, H., 7 betamethasone, 381 Bier block (intravenous regional anesthesia), 293 biofeedback, 14, 554 biomedical model of pain, 41 Birnbach, D. J., 538 Bisgaard, T., 381–382 Bispectral Index (BIS), for brain monitoring, 369 Black Box Warning (of FDA) against use of LMWH, 246 against use of NSAIDs and COX-2Is, 355 bladder dysfunction, improvement from methylnaltrexone, 411. See also genitourinary system, adverse effects of opioids Blount, R. I., 45–46 Borgbjerg, F. M., 422 Borgeat, A., 237, 281 Boss, A. P., 297 bowel dysfunction, from opioid use, 407–408 brachial plexus. See also parascalene block (brachial plexus), pediatric patients; peripheral nerve blocks of upper limb anatomy of, 247–248 axillary level, 255–256 axillary brachial plexus block, 255–259 block techniques nerve stimulation, 257–258 paresthesia/trans-arterial, 259 ultrasound guidance, 258–259 complications, 259–260 indications, 256 pearls, 260 infraclavicular brachial plexus blocks, 253–255

block techniques nerve stimulation, 254 ultrasound guidance, 254 complications, 254–255 brain derived neuropathic factor (BNDF), 17 brain imaging studies, 44, 395 brainstem (RVM), 14 brain stem, opioid migration to, 104 “breaking mechanism” in spinal cord, 10 breast surgery and chronic pain, 109, 134, 642 dexamethasone for, 381 ketamine for, 370 and perioperative paravertebral block, 111 and sentinel node biopsy, 111, 295 Brief Pain Inventory (BPI), 151, 157 Brodsky, Jay B., 626 Bromage, P. R., 23 Brown, D. L., 251 Brull, R., 290 Buggy, D. J., 384 Buntin-Mushock, C., 118 bupivacaine, 72 as adjuvant, for postcesarean analgesia, 539 cardiovascular system toxicity from, 77 combinations with epidural morphine, 234 epinephrine, 75 fentanyl infusion, 233 morphine/morphine infusion, 234, 315 continuous infusions, 233 epidural administration of, 72, 224 for interscalene block, 249 intrathecal administration, 232 ketamine enhancement of, during wound infiltration, 91 lipophilicity of, 72 onset of action, 72 protein binding properties, 73 selectivity for sensory fibers, 74 use of, for motor block, 226 buprenorphine (partial mu receptor agonist), 38 for abdominal surgery, 240 avoidance of, with drug addicts, 570 description, 196 for epidural analgesia, 221 as adjuvant, 224 glucoronidation of, 38 intrathecal, for postcesarean delivery, 543 for neuraxial analgesia, 239–240 parenteral dosages of, 197 and substance abuse, 565–566 sublingual formulations, 566 Burnham, P. J., 255 burn-related anxiety, 43 butorphanol avoidance of, with drug addicts, 570 binding of kappa receptors (OPR2 ), 193 description, 195 for emergency room use, 592 Buvanendran, A., 183, 235, 350

683 calcitonin gene related protein (CGRP) enhancement of PGEs, 7 mediated stimulation of, 6 morphine’s effect on, 124 release inhibition by opioid receptors, 102 calcium/calmodulin dependent kinase type 2 (CaMKII), 119 calcium channel blockers, 382–383. See also gabapentin and pregabalin CaMKII. See calcium/calmodulin dependent kinase type 2 (CaMKII) Campbell, James, 147–148 Canadian Medical Association Journal, 396 cannabinoids, 672. See also marijuana use; 9-tetrahydrocannabinol (THC) as adjuvant analgesic, 384, 673 Capdevila, X., 29, 268–269, 289, 481 capnography, for monitoring intubated patients, 424 Capogna, G., 539 capsaicin, 673 carbonation (carbon dioxide) of anesthetics, 75 cardiac surgery aspirin-related risks, 64 attenuation of pain induced pathophysiology, 28 background infusion following, 210 and clonidine, 89 CPOT validity/reliability for, 163 and ketamine, 93 PCA vs. nurse administered analgesia for, 205 Cardiff Palliator pump (PCA system), 204, 303, 670–671 cardiovascular system effects of alpha-2-AR, 87 effects of NSAIDs vs. COX-2s, 355–356 Guidelines for Advanced Cardiac Life Support, 78 morbidity complication, 638–639 side effects to from bupivacaine, 77 from NSAIDs, 63 from opioids, 406 Carr, E.C.J., 165 Casati, A., 271 Cashman, J. N., 214, 417 catabolism of prostaglandins (PGEs), 54–55 catastrophizing of pain, 42, 44, 49 catechol-O-methyltransferase (COMT) gene influence of genetic variability on morphine dosages, 192 and morphine requirements in cancer patients, 37 Catley, D. M., 422 caudal block, for pediatric patients, 498–500 complications, 500 continuous technique, 499 contraindications, 499 drugs, 499 indications, 498 landmarks, 498 materials, 498

684 caudal block, for pediatric patients (cont.) single-shot technique, 498 CBT. See cognitive-behavioral therapy (CBT) CelebrexTM , 480 celecoxib, 53, 235, 245 adjuvant use, 238 affinity for COX-2, 58 analgesic effects of, 61–62 vs. aspirin, 61 perioperative use, 676 postoperative dosage recommendation, 480 preemptive use, 361, 483 with pregabalin, 182, 383, 481 vs. rofecoxib, 350 use of, in surgical pain, 347 Yale-New Haven Hospital dosing guidelines, 480 Centers for Medicare and Medicaid Services (CMS), 440 central nervous system (CNS). See also brainstem (RVM); periaqueductal gray (PAG) region (of CNS) aging’s effect on, 515–516 analgesic influences on, 377 and central sensitization, 9–10, 15, 26 functional imaging studies, 12 of infants, 487, 496 mu opioid receptor locations, 407 NMDA receptor locations, 89, 120, 125 nociceptive activation of, opioid inhibition of pain signals to, 102, 188 pathophysiological pain response, 26–27 plasticity of, 94, 172 proinflammatory cytokines analgesic effects on, 28 and prostanoid synthesis, 15 and secondary hyperalgesia, 4, 26 side effects of local anesthetics, 77, 280–281 toxicity of, from local anesthetics, central sensitization and CNS, 9–10, 15, 26, 173 following peripheral inflammation, and PGEs, 15 importance of prostanoids for, 17 physiology of, 172–173 superoxides (SO) mediation of, 16 transcription dependent, 10 Cepeda, M. S., 35 cerebrospinal fluid (CSF), 103–104, 221–222 cesarean delivery diclofenac for, epidural hydromorphone for, 233, 235 epidural/intrathecal fentanyl for, 122, 233 with dilute bupivacaine, 234 epidural morphine for, 106, 230 epidural liposomal morphine, 223 extended release (EREM), 328 and intravenous tenoxicam, 346 and ketamine/local anesthetic/ bupivacaine, 91 neuraxial vs. intravenous analgesia, 537 and pain catastrophizing, 44

Index Chadwick, H. S., 543 Chaplan, S. R., 234–235 Chauvin, M., 105 Chayen, D., 267 Checklist of Nonverbal Pain Indicators (CNPI), 161 chemoreceptor trigger zone (CTZ) mediation of nausea and vomiting, 408–409 receptors found in, 409 Chen, X., 120 CHEOPS. See Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) Chestnut, D. H., 233 Chia, Y. Y., 35 children. See pediatric pain management index entries Children and Infants Postoperative Pain Scale (CHIPPS), 490 Children’s Comprehensive Pain Questionnaire, 552 Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS), 164, 491 Chinese patients, 35 chloroprocaine lipophilicity of, 72 onset of action, 72 pKa properties, 72 cholecystokinin (CKK) peptide mediated stimulation of, 6 upregulation following nerve injury, 17 chronic pain. See also central sensitization; McGill pain questionnaire; persistent pain; postoperative pain acute pain transition to, xiii, 17, 26–27, 109–110 amputation and, 642, 675 analgesic undermedication as cause of, 3 aspirin/NSAIDs used for, 66 assessment tools (See assessment of pain, tools) breast surgery and, 109, 134, 642 and buprenorphine/norbuprenorphine, 38 and CaMKII, 119 classifications neuropathic, 4, 17 nociceptive, 4 definition, 3 epidural analgesia and, 642 epidural clonidine for, 88 factors increasing susceptibility to, 30 following surgical trauma, 25 gabapentin/pregabalin for, 96, 182 growing numbers of patients with, 166 and inguinal hernia repair, 109 morphine for, 193 National Pain Foundation statistics, 166 and NMDA receptor antagonists, 178 observer scoring of, 150–151 and pain catastrophizing, 44 partner-assisted pain management for, 50 PCA administration of analgesics, 199 and perioperative pain interventions, 134 predictors of, 110

prospective observational studies, 123 self-report scales, 151 surgeries associated with, 109 and temporomandibular disorder (TMJ), 44 from thoracotomies, 109, 111, 370, 642, 675 and VAS scores, 27 chronic persistent pain, incidence of, post-surgery, 134 Chu, L. F., 115, 123 City of Hope National Medical Center, PRN program, 603 classification of pain, 3–4, 149–150 hyperalgesia (See hyperalgesia) idiopathic pain, 149–150 mixed pain, 149–150 neuropathic pain (See neuropathic pain) nociceptive pain (See nociceptive pain) physiological pain, 3 psychogenic pain, 149–150 clinical trials appropriate conduction determination, 647 author establishment of testability/clinical relevance, 647 Bonferroni Correction, 653 Kaplan-Meier survival curves, 653 Kruskal-Wallis one-way analysis of variance, 653 One-Way Analysis of Variance, 653 primary efficacy variable definition, 647–651 pain measurement, 649 significant pain reduction, 649 summary measures, 650–651 purpose of, 646–647 Spearman’s Rank Correlation, 653 Type I errors, 652 Type II errors, 652–653 Wilcoxon Signed Rank test, 653 ClinicalTrials.gov database, 647 clonidine. See also DuraclonTM (injectable clonidine) adjuvant use with children, 497 axillary block, 505 caudal block, 499 epidural block, 499–502 fascia iliaca block, 506 femoral block, 506 ilioinguinal/iliohypogastric block, 509 parascalene block, 504 sciatic block (lateral approach), 507 subgluteal approach, 508 alternative approach offered by, 28 and cardiac surgery, 89 and central neural blockade improvement, 233 classification, 28 combinations bupivacaine-sufentanil, 370 epidural morphine, 539, 544 fentanyl, 232 intrathecal morphine, 232

Index local anesthetics, 75 thoracic epidural morphine, 232 description/properties/uses, 85–86, 176–177 for epidural analgesia, 84, 86, 221 as adjuvant, 224 hemodynamic effects of, 87 immune protective properties of, 89 improvement of neuraxial analgesia, 238 injury site direct administration of, 89 interaction with analgesia, 88, 288 intra-articular administration, 479 intrathecal administration, 75, 85–86, 88 with morphine, 176, 232, 544 lipophilicity of, 86–87 mechanism of action, 224 non analgesic effects, 87–88 cardiovascular/hemodynamic, 87 hormonal influences, 88 respiratory, 88 sedation, anxiolysis, anesthesia, 88 OIH attenuation by, 133 for opioid-dependent patients, 571 partial agonist properties of, 383 patches, for transdermal drug delivery, 324 peripheral use of, 85 pharmacology of, 85–86 respiratory effects of, 88 coagulation-related morbidity, 641–642 cocaine anesthetic properties of, 70 as racemic mixture, 72 substance abuse, 565 Cochrane Database Review, chronic pain data, 111 codeine, 381–382 with acetaminophen, 353, 358, 495 for children, 494–495 decreased use, in hepatic impairment, 38 for dental/ENT surgeries, 198 description, 195, 495, 613 vs. fentanyl/sufentanil, 190 mechanism of action, 587 metabolism pathways, 193 for sickle cell disease, 555 Coderre, T. J., 174 cognitive-behavioral therapy (CBT), 45–46. See also psychological aspects of pain for acute/persistent pain, 14 general anesthesia vs., 47 hypnosis, 47 for sickle-cell pain, 553–554 cognitive-evaluative pain factors, 42 Cohen, L. L., 46, 175 cold pressor pain model, 116, 122 colectomy emerging therapies for, 586–587 endogenous opioids, postsurgical release, 584 exogenous opioids, administration of, 584 effects on bowel function, 584–585 epidural analgesia, benefits of, 585 peripheral opioid antagonists, 586–587

minimally invasive/laparoscopic surgery, 584 NSAIDs/COX-2 inhibitors, 585–586 opioid-associated POBD, 583–584 Collins, V. J., 251 Coloma, M., 381 combined spinal epidural anesthesia/ analgesia (CES/CSEA), 234 R Combunox , 193, 198, 479 Community Epidemiologic Work Group (CEWG), 565 community hospital/practice setting. See also Acute Pain Service (APS)/Acute Pain Management Service (APMS) creation of conducive environment, 458 documentation, 470 effective pain management preparations, 456–458 interdisciplinary approach, ancillary staff, 457 nonsurgeon physicians, 457–458 nurses/nursing extenders, 457 public, 457 surgeons, 458 leadership roles, 456–457 follow-through, 470–474 complication management, 471 for inpatients, 470–471 for outpatients, 470 quality improvement (QI), 471–474 pain management formulation/ implementation, 458–470 management options, continuous epidural analgesia, 467–468 continuous perineural analgesia, 468 intravenous PCA, 466–467 single-dose epidural opiates, 467 single-dose intrathecal opiates, 467 single-injection nerve blocks, 467 multimodal analgesia, 458–460 realities of setting, 455–456 cultural issues, 456 infrastructure challenges, 455–456 personnel issues, 456 regional techniques, pragmatic approach, 469–470 “comfort zone” operation, 469 cost-consciousness, 469 delay avoidance, 469–470 progressive, logical learning, 469 complex regional pain syndrome (CRPS) ketorolac for, 65 lidocaine patch for, 324 multimodal therapy for, 183 from orthopedic extremity surgery, 675 perioperative regional anesthesia for, 134 Compton, P., 123 COMT gene. See catechol-Omethyltransferase (COMT) gene

685 conduction, described, 8 Confusion Assessment Method for the ICU (CAM-ICU), 162 congenital indifference to pain (CIP) condition, 674 congestive heart failure, 38 consequences of poorly controlled pain cardiovascular pulmonary function/maladaptive behaviors, 21 CONSORT (CONsolidated Standards Of Reporting Trials), 632, 651. See also research in acute pain management continuous epidural analgesia. See epidural analgesia, continuous Continuous Quality Improvement (CQI), 311 continuous quality improvement (CQI) plans, 603 Controlled Substances Act, 609 Cook, P., 271 Cornish, P. L., 608 cortical reception and responses, 12–14 Cortinez, L. I., 122 “Cost Savings in the Operating Room” letter to editor (Brodsky), 626 Cottam, D. R., 36 Coumadin, 241 for deep venous thromboses (DVT), 246 vs. LMWH, 246 COX-2 (cyclo-oxygenase-2) and AA conversion, 5–6 expression of, NF-kB upregulation, 15 glucocorticoid inhibition of, 381 IL-1-Beta induction of, 15 induction of in CNS by IL-1-Beta cytokine, 180 intracellular Ca++ ion activation, 10 mediation of excitotoxicity, 15 relationship to coxibs, 53 COX-2 (cyclo-oxygenase-2) inhibitors, 17. See also celecoxib; etoricoxib; lumiracoxib; parecoxib; rofecoxib; tenoxicam; valdecoxib with acetaminophen/NSAIDs, 178 as adjuvant to opioid use, 131 for ambulatory surgery, 480 avoidance of, in renal patients, 356, 361 Black Box Warning, against use of, 355 cardiac morbidity concerns from use of, 166 and colectomy, 585–586 increased marketing of, 114 intrathecal administration, 16 and laparoscopic cholecystectomy, 182 in multimodal analgesia, 245, 479, 570, 575 vs. NSAIDs bone/wound healing effects, 356 gastrointestinal system, 356 for postoperative pain, 178 renal effects, 356 in perioperative pain, 346–347 pre-incision administration, 478 reduced PGE synthesis from, 29

686 COX-2 (cyclo-oxygenase-2) (cont.) safety and tolerability of, 355 for sickle cell disease, 554 tainting of, with rofecoxib (scandal), 245 use for opioid-dependent patients, 571 coxibs for acute postoperative pain, 385 with glucocorticoids, 382 historical background, 53–54 limitations of, 17 pharmacokinetics of, 58 preemptive/multimodal administration, 30 relationship to cyclo-oxygenase-2, 53 Cozzi, L., 554 Crile, L. W., 173, 179 Critical Care Pain Observation Tool (CPOT), 157–158 Crohn’s disease, 64 Crone, L.A.L., 540 “Crossing the Quality Chasm” report (Institute of Medicine), 655 culture or race. See also African-American patients; Hispanic patients impact on pain management, 34–35 issues in community practice setting, 456 cupping, 392 Curlin Medical 4000 CMS (IV-PCA multitherapy pump), 311, 317 cytochrome P450 37 2D6 (CYP2D6), cytokines. See also Interleukin 1-Beta (IL-1-Beta); Interleukin 6 activation of transducer molecules, 7 and development of persistent pain, 25 and increased peripheral edema/allodynia, 21 proinflammatory, analgesic effects on CNS, 28 release of, from superoxide mediated injury, 16 response of, 28–29 Dahan, A., 422 Dahl, J. B., 234, 543 Dahlstrom, B., 37 Dampier, C. D., 551–552 Das, D. A., 48 Dauri, M., 297 Davies, P. W., 540 Decade of Pain Control and Research (law provision, U.S. Congress), 114, 149 Declaration of Helsinki, 646. See also research in acute pain management deep venous thrombosis (DVT), 25, 28, 246, 641. See also Virchow’s triad De Kock, M., 370 delirium. See also postoperative cognitive dysfunction (POCD)/ postoperative delirium in elderly patients assessment tools Confusion Assessment Method for the ICU (CAM-ICU), 162

Index Intensive Care Delirium Screening Checklist, 162 from meperidine, 411 Demanalg PCA system, 204, 670 Demand Dropmaster PCA system, 204, 670 dementia. See also postoperative cognitive dysfunction (POCD)/ postoperative delirium in elderly patients as barrier to pain assessment, 165 pain assessment tools, 157–158, 161 DepoDurTM (prolonged duration epidural morphine), 240, 538 DepoFoamTM (extended release epidural morphine), 327 Descartes, Rene, 4, 172 descending pathways of pain described, 14 modulation of pain perception, 102 design theory of IV-PCA pumps, 302 of patient-controlled epidural analgesia, 314 of perineural ambulatory analgesia systems, 318 dexamethasone, 381–382 for nausea/vomiting, 410 with rofecoxib, 382 dexmedetomidine (MPV-1440), 86–87 FDA approval for sedative use in ICU, 383 lipophilicity of, 86 mechanisms of action, 176–177 partial agonist properties of, 383 R dextromethorphan. See also MorphiDex administration methods, 132 combinations ketorolac, 345 tenoxicam, 345 for OIH modulation, 128 preventive multimodal effects, 179 use in opioid tolerance reduction strategy, 120 dextropropoxyphene, 38 dezocine, avoidance of, with drug addicts, 570 diabetic neuropathy, 4 diclofenac for abdominal surgery, 60 analgesic effects of, 60 for arthroscopic surgery, 60 for children, 385 efficacy of, in preemptive analgesic therapy, 344 evaluation for postoperative pain usage, 335–339 postoperative use, 60, 346 with prednisone, 382 preemptive use of, 345 topical patch for transdermal drug delivery, 324–325 transdermal delivery system, 324 differential sensory nerve blocks, 74 R Dilaudid , 194, 232–233 Ding, E. L., 16

diphenhydramine, for pruritus, 237, 306 Dirks, J., 480 distal sciatic nerve block (in popliteal fossa), 295 distal upper extremity nerve blocks, 292–293 distraction (management strategy), 45–46 reassurance vs., 46 topical anesthetics vs., 46 DNA scanning, 673 documentation, for community hospital/practice setting, 470 Doering, S., 384 Dolin, S. J., 214, 417 R Dolophine , 195 dopamine COMT inactivation of, 37 and epidural clonidine, 87 and opioid-induced euphoria, 115 dose escalation of opioids, analgesic paradox of, 116 Doverty, M., 123 DPI-125, and respiratory depression, 412 DPI-3290, and respiratory depression, 412 Drakeford, M. K., 232 droperidol adverse effects, 214 for nausea/vomiting, 237, 242, 306, 410, 613 for opioid-induced pruritus, 214 drug abuse/drug addiction. See opioid dependence/substance abuse Drug Abuse Warning Network, 391 Drug Addiction Treatment Act (DATA 2000), 565–566 Drug Enforcement Administration (DEA), 609 Dunbar, S. A., 121, 124 DuraclonTM (injectable clonidine), 232 DuragesicTM (fentanyl patch), 324, 574 DuramorphTM (morphine), 230, 232 dynorphins, 395 economic aspects of healthcare business plans vs. economic studies, 623 costs, costs/cost definitions cost vs. charges, 625 direct, indirect, intangible, 626 explicit, implicit, total, 625 fixed/variable, 626 opportunity costs, 627–628 total, average, marginal, 626–627 economic studies cost-benefit and cost-effective, 628–629 cost minimization, 628 perspectives every day example, 624 hospital example, 624 and system thinking, 628 revenue, educational techniques, for sickle-cell pain, 553 Egdahl, R. H., 23

Index eicosanoid family, 54. See also prostaglandins (PGEs) Eisenhower, Dwight D., 433 elastomeric pumps (non-electric infusion devices), 319–320 elbow blocks, 260–262, 293 block technique nerve stimulation, 260–262 ultrasound guidance, 262 complications, 262 elderly patients alfentanil sensitivity, 521 analgesia/anesthesia choice and cardiovascular function (postoperative), 526–527 and cognitive function (postoperative), 515, 523–526 and endocrine/immune function (postoperative), 529–530 postoperative outcomes, 530–533 and pulmonary function (postoperative), 527–529 assessment tools Checklist of Nonverbal Pain Indicators (CNPI), 161 Pain Assessment in Advanced Dementia Scale (PANAID), 161 benzodiazepine restriction for, 239, 242, 521 definition of, 514–515 emergency department treatment, 590 epidural infusion-light general anesthesia for, 238 and fentanyl PCEA, 235 and IV-PCA, 166, 196 non-advisability of, 196 methodology debates about, 514 naloxone, for respiratory depression, 236 nervous system and aging, 515–516 neuroaxial regional anesthesia/peripheral nerve blockade vs. opioid-based analgesia, 521–523 pain assessment considerations, 161, 521 perioperative management development, 514 pharmacodynamic alterations in, 520–521 pharmacokinetic alterations in, 520 postoperative cognitive dysfunction (POCD), 515–517, 523–526 recommendations for, 533 sensitivity to alfentanil, 521 electropharmacology of local anesthesia, 71 emergency department (ED) assessment/prevalence of pain in, 589 discharge diagnoses with pain complaint, 589 illegitimate opioid procurement attempts, 590 oligoanalgesia problem in, 589–590 pain treatment/procedural sedation in, 590–591 substance abuse visits, 565 treatment (specific) modalities, 591–594 alternative delivery routes, 592

nonopiods, 591 opioids, 591–592 patient-controlled analgesia (PCA), 592 procedural sedation and analgesia (PSA), 592–594 emergency physicians assessment accuracy issues, 590 as cause of pain, 589 endogenous opioids, 37, 584. See also dynorphins; endorphins; enkephalin (ENK) and acupuncture, 394–395 description, 10–11 mechanism of action, 14 and TENS, 397 endorphins, 10–11, 37, 42, 188, 395, 410, 584 Engbloom, D., 15 enkephalin (ENK), 10–11, 188, 395, 584. See also endogenous opioids enoxaparin, 245 environmental conduciveness, in community practice setting, 458 epidural analgesia for abdominal surgery, 180 choice of adjuvants, 224 choice of agents (See epidural analgesia, choice of agents) for colectomy, 585 continuous administration, in community practice setting, 467–468 effect on postoperative outcomes (See also under randomized controlled trials) background, 637 cardiovascular morbidity, 638–639 chronic pain, 642 coagulation-related morbidity, 641–642 cognitive decline/delirium, 642 economic outcomes, 643 length of stay, 643 multimodal therapy approach, 643 gastrointestinal morbidity, 640–641 infectious/immune complications, 642 major morbidity, 638 mortality, 637–638 patient-reported outcomes, 642–643 health-related quality of life, 643 patient satisfaction, 643 quality of recovery, 643 pulmonary morbidity, 639–640 factors affecting efficacy of (See also epidural analgesia, choice of agents) catheter location, 221 cerebrospinal fluid, 222 improvements from, 29, 36 vs. IV-PCA, 29 preemptive analgesic effects of, 174–175 risk factors of, 224–226 catheter problems, 224–226 dural puncture, 225 epidural hematoma, 225–226 hypotension, 226 infection, 226

687 motor block, 226 respiratory depression, 226 single-dose administration, in community practice setting, 467 superiority following orthopedic surgery, 180 for sympathetic hypertensive response, 28 thoracic, 28 epidural analgesia, choice of agents, 221–224 alfentanil, 223 chloroprocaine/lidocaine, 73 epidural morphine, 222 fentanyl, 223 hydromorphone, 222–223 liposomal morphine, 223 local anesthetics, 223–224 combined with opioids, 224 opioids, 221–222 sufentanil, 223 epidural analgesia, continuous, 233–235 fentanyl infusions, 233–234 hydromorphone infusions, 234–235, 237–239 local anesthetic infusions, 233 morphine infusions, 234 spinal morphine plus epidural infusion, 234 epidural anesthesia, 27 bupivacaine for, 72 continuous, suppression of sympatho-adrenal responses, 28 vs. general anesthesia, followed by epidural analgesia, 28 thoracic following CABG surgery, 28 and improved pulmonary function, 28 epidural blocks, 29 as adjuvant to opioid therapy, 133 local anesthesia/regional analgesia for, 180 in pediatric patients, 500–502 complications, 500–502 continuous technique, 500–502 contraindications, 499 drugs, 499–502 indications, 500 landmarks, 500 materials, 500 single shot technique, 500 epidural bolus dosing, 232–233 epidural hematoma causes of, 225–226 risk of, from LMWH, 239, 245 epidural infusion-light general anesthesia, 238 epidural morphine. See also DepoDurTM (prolonged duration epidural morphine); extended release epidural morphine (EREM) age related reductions, 33 clinical trials, 106–107 combinations bupivacaine, 234 clonidine, 539, 544 ketamine, 367, 370

688 epidural morphine (cont.) local anesthetics, 538 description, 222 vs. epidural fentanyl, 133, 539 intrathecal administration, 230 vs. intrathecal morphine, 543 mechanism of action, 28 vs. parenteral opioids, 232 for postoperative pain management, 117 and respiratory depression, 407, 540 side effects nausea/vomiting, 237, 409, 540 pruritus, 237 single dose, vs. continuous infusion, 232 epidural opioids adverse effects associated with, 236–237 nausea and vomiting, 237 pruritus, 237, 495 respiratory depression, 226, 236, 417 urinary retention, 237 combinations ketamine, 179 local anesthetics, 29, 133 parenteral opioids, 179, 196 continuous infusion of, 233–235 critical studies/clinical trials alfentanil, 103–105 fentanyl, 105–106 morphine, extended, 106–107 sufentanil, 106 following intraoperative ketamine, 92 function at spinal level, 102 as gold standard for pain management, 102 intrathecal/single bolus administration, 230–233 for patients on chronic opioid therapy vs. opioid-naive patients, 133 pharmacokinetics of, 103–105 postadministration migration to brain stem, 104 safety factors, 239 epidural patient-controlled analgesia (Epi-PCA). See patient-controlled epidural analgesia (PCEA) epinephrine as additive to local anesthetics, 75, 288 COMT inactivation of, 37 for epidural analgesia, 221 as adjuvant, 224, 539 partial agonist properties of, 383 post-surgical trauma increases, 23 EREM. See extended release epidural morphine (EREM) Erikson, C. J., 554 erythema, from opioid histamine release, 411 Etches, R. C., 210, 421 ethnic/racial minorities. See also African-American patients; Hawaiian patients; Hispanic patients assessment considerations, 160–161 healthcare provider perceptions of, 165 etidocaine, 72 lipophilicity of, 72

Index onset of action, 72 pKa properties, 72 sensory/motor block, lack of separation, 74 Etienne, July, 248 etomidate, for emergency room use, 592, 594 etoricoxib, 346, 353–355 E-trans fentanyl delivery system, 674 evidence-based medicine (EMB) in acute pain management, 634–635 challenges of practitioners, 632–633 defined/described, 630 distinguishing features of, 630–631 evidence recommendations NHMRC of Australia, 633 Scottish Intercollegiate Guidelines, 633 and expert-based opinion, 631 guidelines development, 631 limitations of, 633 quality and validity issues, 632 synthesizing medical evidence, 631–632 excitatory post synaptic potentiation (EPSP) phenomenon, 15 “exhaustion stage” (sympatho-adrenal response), 22 extended release epidural morphine (EREM). See also DepoDurTM (prolonged duration epidural morphine); DepoFoamTM (extended release epidural morphine) for cesarean section, 328 clinical trials, 106–107 description, 327–329 for hip arthroplasty/elective cesarean delivery, 106 length of analgesic effects, 106 for lower abdominal surgery, 106 Face, Legs, Activity, Cry and Consolability (FLACC) tool, 157, 492 Faces Pain Scale (FPS), 154, 489 facial expressions, of others in pain, 44–45 failure mode and effects analysis (FMEA) procedure, 614 Farney, R. J., 422 fascia iliaca block, 294 Fassoulaki, A., 112 Faymonville, M. E., 48 fear and pain-related anxiety, 43 similarity to pain catastrophizing, 44 Feeney, S. L., 42 femoral nerve block, 270–274 block technique nerve stimulation, 271 ultrasound guidance, 271–273 complications, 273 pearls, 273 postoperative analgesia in outpatients, 293–294 fenbufen, efficacy of, in preemptive analgesic therapy, 344 R fentanyl, 38. See also Actiq oralet; DuragesicTM ; FentoraTM ;

IONSYSTM (fentanyl iontophoretic transdermal system) for abdominal surgery, 233, 327 for ambulatory surgery, 479 for arthroscopic surgery, 60 clinical trials, 105–106 vs. codeine, 190 combinations clonidine, 232 ketamine, 370 lidocaine, 543 midazolam, 402, 593 continuous epidural infusion, 233–234 combined with bupivacaine/ropivacaine, 233 description, 194 diffusion into epidural fat, 222 efficacy at mu receptors, 190 elderly sensitivity to, 521 for emergency room use, 592–593 epidural administration, 223 for postcesarean delivery, 538–539, 542 vs. epidural bupivacaine, 233–234 E-trans fentanyl delivery system, 674 heroin, fentanyl-laced, 565 intrathecal administration, 122, 232, 328 with dilute bupivacaine, 234 for IV-PCA use, 206, 305, 466–467 limitations, as postoperative analgesic, 543 lipophilicity of, 191, 194, 311, 316, 409, 538–539 lockout interval investigations, 210 mechanism of action, 587 nonmedical usage, 565 ODAC monitoring, 204 parenteral dosages of, 197 for PCEA use, 105, 235 side effects of, 194, 391, 409, 571 and substance abuse, 565 tolerance to, 117 transdermal delivery system, 197, 324–325, 466 fentanyl, epidural, 223 clinical trials, 105–106 combinations clonidine/local anesthetic, 176, 232 vs. epidural morphine, 133 extending action of, 538 vs. IV fentanyl infusions, 105 for postcesarean delivery, 538–539, 542 side effects of, 542 fentanyl iontophoretic transdermal system (Fentanyl ITS), 326–327 FentoraTM (rapidly disintegrating oral fentanyl), 572, 574 fibromyalgia, brain imaging studies for, 44 “fight-flight reaction” (sympatho-adrenal response), 22 Filitz, N., 38 Fillingim, R. B., 35 Fishbain, D. A., 566 5-HT4(a) agonist, 672 FlectorTM Patch (diclofenac epolamine topical patch), 324

Index Flood, P., 384 flurbiprofen, efficacy of, in preemptive analgesic therapy, 344 Folke, M., 422 fondaparinux, 245–246 Food and Drug Administration (FDA) accidental injury warnings (MAUDE), 309 approval of acupuncture, 393, 395 approval of transdermal patches, 324 warning against use of LMWH, 239, 246 France, C. R., 43 Fuller, J. G., 538 functional magnetic resonance imaging (fMRI), 12–13 facial expressions study, 45 for fibromyalgia, 44 future of acute pain management delivery mechanisms development, 674–675 outcomes influenced by uncontrolled pain, 675–677 pain management in the future, 671–672 pain management in the past, 670–671 pharmaceutical development, 672 analgesic development, 672–674 reduction of side effects, 672 gabapentin for ambulatory surgery, 479–480 limiting usage factor of, 245–246 gabapentin and pregabalin (calcium channel blockers), 382–383 as adjuvant to opioid therapy, 132 anticonvulsants/voltage gated calcium channels, 93–94 description, 382–383 immune modulatory effects, 97 pharmacology of, 96 nonanalgesic effects/side effects, 96 potency/mechanisms of action under different pain conditions, 94–96 for ambulatory surgery, 480 peripheral use, 96 postoperative pain condition, 94–96 preventive multimodal analgesia with, 182 synergy with other analgesics, 96–97 Gagliese, L., 33, 161 Galer, B. S., 118, 120, 128 Gambling, D., 106 gamma-aminobutyric acid (GABA) activate opioid, 10–11 mediation of spinal mechanisms underlying NE antinociceptive action, 83 stimulated release by opioids, 102 Gan, T. J., 480 gastrointestinal system. See also colectomy; postoperative bowel dysfunction (POBD); postoperative ileus (POI) effects of opioids, 407–408 morbidity complication, 640–641 neural regulation (intrinsic/extrinsic) of, 584 NSAIDs side effects, 63–64

vs. COX-2 inhibitors, 356 enteropathy, 64 Gate Control Theory (Melzack and Wall), 4–5, 41–42, 394 gender, impact on pain management, 35 gene polymorphisms impact on pain management, 37 influence of, on opioid activity, 192 and persistent pain, 21 general anesthesia for ambulatory surgery, 368 attenuation of remifentanil hyperalgesia, 386 cardio protective effects, 28 vs. CBT, for children with leukemia, 47 epidural infusion-light, 238 vs. interscalene block, 290 with interscalene nerve blocks, 248 with ketamine, 132 light, for single-shot/continuous peripheral blocks, 502 with local-regional blocks, 174 vs. lumbar plexus block with mepivacaine, 267 vs. lumbar plexus-sciatic nerve block, 293 nerve injuries related to, 281 vs. neuraxial anesthesia, 637–638, 642 vs. paravertebral blocks, 295 vs. preemptive analgesia, 36 vs. regional anesthesia, 245, 281, 288, 469 with sciatic block, lateral approach, 507 vs. single-injection regional anesthesia, 132 genetic approaches, to analgesic tolerance of opioids, 121 genitourinary system, adverse effects of opioids, 411 Gibson, S. J., 161 Giebler, R. M., 240 Gieraerts, R., 540 Gimbel, J. S., 479–480 Ginsberg, B., 198, 210 Glasson, J. C., 36 glucocorticoids, 377–382 beneficial effects of, 382 clinical actions of, 379–381, 385 analgesic, 381–382 effect mechanisms, 378–379 molecular actions of, 379 overview, 377–378 preemptive effects of, 385 side effects of, 382 Gomoll, A. H., 298 Gordon, D., 665 Gottschalk, A., 297 Govindarajan, R., 240 Grachev, I. D., 14 Graf, C., 162 Green, C. R., 160 Gross, R. T., 43 GTP binding protein coupling, 119 guanfacine, additive to local anesthetics, 75 GuardrailsTM software (for Continuous Quality Improvement), 311

689 Guidelines for Advanced Cardiac Life Support, 78 Guidelines for Good Clinical Practice (GCP) of the International Conference of Harmonization (ICH), 646. See also research in acute pain management Guignard, B., 122 Gwirtz, K. H., 418 gynecological surgery, 35, 42, 165 COX-2 inhibitors, pre-/postsurgery, 479 intraoperative ketamine for, 368 and opioid induced bowel dysfunction, 200 preemptive use of sustained release ibuprofen, 345 Hadzic, A., 290–291, 293 hallucinogen abuse, 565 Halsted, William Stewart, 70, 248. See also interscalene nerve block Handoll, H., 255 Hansen, E. G., 122 Harmon, T. M., 48 Hartrick, C. T., 107, 206 Harvard PCA system, 204 Hawaiian patients, 34 Hays, P., 50 Health Care Financing Administration (U.S.), 583 healthcare providers, barriers to pain control, 165–166 Health Related Quality of Life (HRQoL), 651 Hebl, J. R., 268 Helme, R. D., 161 hematologic/cardiovascular effects of NSAIDs vs. COX-2s, 355–356 hemodynamic effects of clonidine, 87 hepatic disease, 38 herniorrhaphy, 36 heroin abuse of, 565 and post-surgical pain, 37 herpes simplex virus labialis (HSVL), 540, 542 Herpes Zoster, 4 Herr, K., 158, 161 Herrick, I. A., 206 Herz, A., 222 Hess, P. E., 538 High-Alert Medications (of ISMP), 614–615 Hill, H. F., 311 Hispanic patients, 35. See also sickle cell disease customized OUCHER scale, undertreatment for pain, 160 historical background of acute pain management, 670–671 of anesthesia, 70 multimodal, 175 of coxibs, 53–54 of IV-PCA, 204, 302–303 of local anesthetic epidural injections, 314 of NSAIDs-description, 53

690 historical background (cont.) of opioid use, 114 of para-aminophenols, 54 of PENS/TENS, 397 of prostaglandin physiology, 54–55 on quality improvement issues, 659 of salicylates, 53 of therapeutic touch (TT)/massage therapy, 400 Hodgkin, Sir Alan, 70 Hoenecke, H.R.J., 297 Hoffman, H. G., 48–49 holistic medicine, 392. See also acupressure; cupping; moxibustion; non-pharmacological therapy acupuncture (See acupuncture) hypnosis (See hypnosis) magnet therapy, 399–400 music therapy, 402–403 osteopathic manipulation (OMT), 401 TENS/PENS (See percutaneous electrical nerve stimulation; transcutaneous electrical nerve stimulation) therapeutic touch/massage therapy, 400–401 HolterTM roller pump, 302 Hood, D. D., 123 hormonal effects of clonidine, 88 Hospira Gemstar (multitherapy PCA pump), 311–313, 317 Huang Di Nei Jing (The Yellow Emperor’s Classic of Internal Medicine), 392 Hudcova, J., 207 Hume, D. M., 23 humoral mediators, 28 Huxley, Sir Andrew, 70 hydrocodone description, 193–194 mechanism of action, 587 metabolism pathways, 193 for moderate/severe pain, 197 oral dosing of, 197 with ibuprofen compounding, 198 plus ibuprofen, for short term management, 198 for sickle cell disease, 555 and substance abuse, 564–565 hydromorphone (hydrophilic mu-1 selective opioid agonist), 103, 194 for abdominal surgery, 237 for ambulatory surgery, 479 continuous epidural infusions of, 234–235 epidural administration (bolus dosing), 232–233 co-administered with epidural lidocaine, 233 dosing guidelines, 238–239 drug preparation/analgesic assessment, 239 history and evolution, 237–238 patient monitoring/safety, 239 precautions/contraindications, 239 hydrophilicity of, 316 intrathecal administration, 232

Index for IV-PCA use, 305 parenteral dosages of, 196 for PCEA use, 235–236 for postcesarean analgesia, 539 for sickle cell disease, 556 and substance abuse, 565 as therapeutic alternative for pain control, 196 hydroxyzine, 306 hyperalgesia, 102. See also opioid-induced hyperalgesia (OIH); primary hyperalgesia; secondary hyperalgesia; thermal hyperalgesia of chest wall/upper abdomen, 25 classifications, 3–4 M40403 prevention of, 16 and NMDA activation “windup,” 9–10 pathophysiological pain response, 21–22 from PGE2 application, 15 hyperglycemia, 23 hyperpathia, 3 hypertension, post-surgical, 23, 28 hypervolemia (stress-induced), 24 hypnosis, 47–48, 401–402 cognitive-behavioral therapy vs., 47 conscious sedation enhancement by, 47–48 patient susceptibility to, 48 PET/fMRI research on, 402 pharmacological/nonpharmacological methods, 402 self-hypnosis, 47, 402 for sickle-cell disease, 554 hypocarbia, 28 hypotension, from opioid administration, 406 hypoxia, 28 hysterectomy, 34, 193, 205, 230, 384 low dose IV naloxone, 411 preemptive rofecoxib, 350 ibuprofen analgesic effects of, 59–60 for children, 385 compounded with hydrocodone/oxycodone, 198 for moderate/severe pain, 197 vs. placebo, for post-surgical pain, 60 plus hydrocodone, 198 plus oxycodone, 198 side effects, 64, 131 sustained-release, preemptive use, with morphine PCA, 345 Ilfeld, B. M., 29, 290, 292 ilioinguinal/iliohypogastric block, in pediatric patients, 509 imagery, facilitation descending pathways by, 14 IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials), 651. See also research in acute pain management immunologic effects of alpha-2-AR agonists, 89

of clonidine, 89 of gabapentin and pregabalin, 97 of ketamine/NMDA receptor agonists, 93 Individualized Numeric Rating Scale (INRS), 493 indomethacin efficacy of, in preemptive analgesic therapy, 344 evaluation for postoperative pain usage, 335–339 postoperative use, 346 inflammatory “triple response” (Lewis), 21 infraclavicular brachial plexus blocks, 253–255 block techniques nerve stimulation, 254 ultrasound guidance, 254 complications, 254–255 pearls, 255 postoperative analgesia in outpatients, 289–290 ultrasound guidance, 254 inguinal hernia repair, and chronic pain, 109 inhalational anesthesia, 174, 179, 369, 674 Initial Pain Assessment Tool, 154 Institute for Safe Medication Practices (ISMP), 306, 614 identification of epidural medication errors, 614–615 identification of PCA errors, 614 Institute of Medicine (IOM), 160, 655, 666 Institution Review Board (IRB), 647. See also research in acute pain management intensity theory (Sydenham) Intensive Care Delirium Screening Checklist, 162 Intention-to-Treat (ITT) analysis, 651. See also randomized controlled trials (RCTs) intercostal nerve block, 296 Interleukin 1-Beta (IL-1-Beta) and COX-2 induction in CNS from peripheral inflammation, 180 elevated levels, and allodynia, 7, 21, 25, 28 humoral induction of COX-2, 15 Interleukin 6 elevated levels, and allodynia, 21, 25, 28 post-surgical increase, 28 International Association for the Study of Pain (IASP) on decision-making about opioids, 631 endorsement of evidence-based medicine, 630 pain, defined, 3, 149, 391 neuropathic pain, 4 International Committee of Medical Journal Editors (ICMJE), 647 International Conference of Harmonization (ICH), 646 International Narcotics Control Boards, 631 interscalene nerve block, 248–251. See also Halsted, William Stewart; Winnie, Alon

Index background information, 248–249 block techniques nerve stimulation technique, 249–250 pearls, 251 ultrasound guided technique, 250–251 complications of, 251 indications for, 249 postoperative analgesia in outpatients, 289–290 side effects of, 290 intrathecal analgesia administration in children, 498 dose determination, 467 for postcesarean delivery, 543 intrathecal anesthesia/administration adverse effects of, 236–237 alpha-2 adrenergic receptor agonists, 383–384 BDNF signaling molecule, 17 bupivacaine, 75, 232, 234, 328 buprenorphine, 543 cholinesterase inhibitor, 83 clonidine, 75, 83, 85–86, 88 with morphine, 176, 232, 544 COX-2 inhibitors, 16 dexmedetomidine, 87 fentanyl, 122, 232, 328 with dilute bupivacaine, 234 gabapentin, 94, 96 glycine, 125 guidelines for, 233 hydromorphone, 232 ibuprofen, 124 ketamine, 92 ketorolac with morphine, 121 MK-80, 120 morphine, 232, 407, 411, 417–418 with bupivacaine, 234 with clonidine, 176, 232 epidural, 230 intrathecal vs. intravenous, 420 neostigmine, 384 nitric oxide (NO), 16 postcesarean analgesia, 543 adjunct therapy, 544 single boluses of opioids, 230–233 single-dose administration, in community practice setting, 467 intrathecal bolus dosing, 230–232 intravenous patient-controlled analgesia (IV-PCA), 28, 369–370. See also patient-controlled analgesia (PCA); patient-controlled epidural analgesia (PCEA) advantages, 425 in community practice setting, 466–467 dosing requirements, 304–305 for elderly/ill opioid-dependent patients, 166, 196 historical background, 204, 302–303 influence of ethnicity on prescribing, 35 with intrathecal/epidural morphine, 230 opioids for use with, 305–306

and parenteral opioid therapy, 196 patient outcomes postoperative morbidity, 207 satisfaction, 207 for postcesarean analgesia, 538, 544–545 vs. regional block/epidural analgesia for knee flexion, 29 risk factors of, 306 safety issues, 306–308, 425 study of bupivacaine/fentanyl, 106 and systemic opioids, 28 intravenous patient-controlled analgesia (IV-PCA), analgesic efficacy of comparisons with other analgesic techniques conventional opioid analgesia, 205 epidural analgesia, 205 intranasal PCA, 205 subcutaneous PCA, 205 transdermal PCA, 206 opioids used with IV-PCA, comparison of, 206 intravenous patient-controlled analgesia (IV-PCA), devices/systems. See also analgesic infusion pump technology; Cardiff Palliator pump (PCA system); HolterTM roller pump; On Demand Analgesia Computer; Prominject PCA infusion pump clinical management, 305–306 commercially available systems, 311–314 Alaris System PCA Module, 311 Curlin Medical 4000 CMS, 311 Hospira Gemstar, 311–313 Smith Medical CADD-Prizm PCS IITM , 313–314 cost effectiveness, 308 design theory, 303 features/modes of operation, 304–305 minimum effective analgesic concentration (MEAC), 303, 308 pharmacokinetic drug delivery systems, 310–311 safety issues, 306–308 accidental purging protection, 306–307 bar-code readers, 307 computer-based pump programming, 307–308 error-reduction features, 307 overmedication, 306 respiratory depression, 306 intravenous regional anesthesia (Bier block), 293 ion channels and analgesic tolerance to opioids, 120 blocking agents, 17 IONSYSTM (fentanyl iontophoretic transdermal system), 197, 206, 326–327 iontophoresis, analgesic delivery system, 325–327, 674 Iowa Pain Thermometer (IPT), 151, 154 Ishiyama, T., 235

691 ISMP. See Institute for Safe Medication Practices (ISMP) isoproterenol (beta 1/beta 2 receptor agonist) for epidural analgesia, 221 as adjuvant, 224 IV-PCA. See intravenous patient-controlled analgesia (IV-PCA) Jay, S., 47 Joint Commission on Accreditation of Healthcare Organizations (JCAHO) APMS education role, 433 and assessment of pain, 589 concern about range order administration, 605–606 mandated evaluation of pain scores for all patients, 148–149 medication reconciliation, defined, 608 pain management standards, 114, 175, 601, 604, 608, 659–660, 666 patient medication safety goal, 608 Joly, V., 122, 127 Kaba, A., 383 kappa receptors (OPR2 ) butorphanol/nalbuphine binding of, 193 mediation of spinal/visceral analgesia, 189 for relief of visceral pain, 201 Katz, J., 42–43, 175, 370 Katz, Sir Bernard, 70 Keeri-Szanto, M., 670 Kehlet, H., 27, 29 Kemper, P. M., 230 ketamine (NMDA receptor agonist). See also S(+)ketamine for abdominal surgery, 93, 368 adjuvant use with children, 497 administration in perioperative period, 368–369 adjunct to sedative during local anesthesia, 369 in ambulatory ENT surgery, 369 ambulatory surgery (excluding ENT), 368 postsurgical, 369 for ambulatory surgery, 481 analgesic effects of, 366 preemptive, 366–367 and cardiac surgery, 93 combinations bupivacaine, during wound infiltration, 91 epidural morphine, 367, 370 parenteral/epidural opioids, for emergency room use, 592–593 enhancement of opioid-induced analgesia, 367 importance of opioid dose, 368 epidural administration, 221, 371–372 as adjuvant, 224 lipophilicity of, 92

692 ketamine (cont.) for major surgery amputation, 372 postoperative, abdominal surgery, 370 postoperative, persistent pain prevention, 370 thoracic surgery, 370–371 and opioid combination, for PCA use, 206 for opioid-dependent patients, 571 and opioid-induced hyperalgesia, 125–127, 368 and opioids, for PCA use, 206 pharmacology/pharmacokinetics of, 91–92, 366 postoperative infusion of, 367 preemptive multimodal effects, 30, 385 preventive effect in remifentanil-induced hyperalgesia, 368–369 preventive multimodal effects, 178–179 side effects of, 366 ketamine and NMDA receptor agonists NMDA receptors and pain modulation, 89–90 immune modulatory effects, 93 interaction with other analgesics, 92–93 pharmacology under different pain states, 90–91 nonanalgesic effects, 92 peripheral use of ketamine, 91 postoperative pain conditions, 91 ketoprofen, 55 efficacy of, in preemptive analgesic therapy, 344 pediatric use, 494 postoperative use, 346 preemptive IV, in laparoscopic cholecystectomy, 345–346 ketorolac for ambulatory surgery, 479 analgesic effects of, 60–61 for complex regional pain syndrome, 65 with dextromethorphan for laparoscopic-assisted vaginal hysterectomy, 345 efficacy of, in preemptive analgesic therapy, 344 for emergency room use, 591 evaluation for postoperative pain usage, 335–339 with opioids, for abdominal surgery, 60 postoperative use, 346 preemptive use in hip replacement surgery, 345 in laparoscopic cholecystectomy, 345–346 reduction of thromboxane A2 , 355 for sickle cell disease, 554 starting perioperative dosage, 385 kinesiophobia, 43–44 Klaastad, O., 255 Klein, S. M., 289, 293 Koch, T., 119 Koppert, W., 16, 123 Koscielniak-Nelson, Z., 255 Kotani, N., 395–396

Index Kotelko, D. M., 538 Lang, E. V., 45, 47 Lao, L., 396 laparoscopic surgery cholecystectomy ketoprofen, 345–346 postoperative tenoxicam, 345 for colectomy, 182, 584 dexamethasone following, 381 ketamine, for gynecological surgery, 368 piroxicam, for bilateral hernia repair, 345 preoperative ketorolac/dextromethorphan, 345 reduction of complications with, 584 Roux-en-Y gastric bypass, use of ON-Q bupivacaine pain pump, 36 Lasagna, L., 110 Lavand’homme, P., 370 Lean methodology, for quality/quality improvement, 658 Lecht, C. H., 538 Lee, L. H., 122 Lee, Y., 381 Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale, 159 de Leon-Casasola, O. A., 117 levobupivacaine, 72 epidural administration of, 224 with morphine, 315 Lewis, T., 21 Liang, D. Y., 124 lidocaine combinations epinephrine, 75 fentanyl, 543 hydromorphone (epidural), 233 paracetamol/NSAIDs, 383 description, 383 iontophoresis, 327 lipophilicity of, 72–73 onset of action, 72 patches, for transdermal drug delivery, 324 protein binding properties, 73 transdermal delivery system, 324 LidodermTM transdermal patch, 324 LidositeTM Topical System (lidocaine iontophoresis), 327 lipophilicity alfentanil, 105 bupivacaine, 72 chloroprocaine, 72 clonidine, 86–87 dexmedetomidine, 86–87 etidocaine, 72 fentanyl, 191, 194, 311, 316, 409, 538–539 ketamine, 92 lidocaine, 72–73 mechanisms of action, 103, 316 mepivacaine, 72–73 procaine, 72 sufentanil, 106, 133, 191, 409, 539 tetracaine, 72 liposomal morphine, epidural, 223

Liu, S. S., 235–236, 288, 297, 381–382, 585 Livingston, E. H., 583 local anesthesia/anesthetics for abdominal surgery, 132 action at sites unrelated to Na channels/nerve block, 71 for ambulatory regional anesthesia/analgesia, ambulatory local anesthetics/equipment for, 288 carbonation of, 75 continuous epidural infusion, 233 electropharmacology of, 71 epidural administration, 223–224 combined with opioids, 224 with epidural morphine, 538 and equipment, for regional anesthesia/analgesia, 288 ketamine as adjuvant, 369 maximum doses of, 73–74 mechanisms of action, 496 modification by vasodilators, 76 for pediatric pain management, 496–497 pharmacodynamics of, 73 physiochemical properties of, 72–73 preemptive analgesia with, 180–181 racemic mixtures, 72 with regional analgesia for epidural blocks, 180 for peripheral nerve blocks, 180 for wound infiltration, 179–180 side effects (toxic) of, 76–78 allergies, 78 cardiovascular toxicity, 77–78 central nervous system, 77, 280–281 methemoglobinemia, 78 treatment of, 78 single (S-) enantiomers, 72 sodium bicarbonation of, 75 structures of, 72 use of additives with, 74–75 lockout intervals of IV-PCA pumps, 105–106, 205, 210, 304 for morphine, 304 long term potentiation (LTP) factors necessary for development of, 10, 15 onset/reversibility of, 15 R Lortab , 193 low-molecular weight heparin (LMWH) vs. Coumadin, 246 for deep venous thromboses (DVT), 246 growing use of, 673 and risk of epidural hematoma, 226, 239, 245–246 lumbar plexus blocks, 267–274, 293–294 fascia iliaca block, 294 femoral nerve block, 270–274, 293–294 ilioinguinal/iliohypogastric nerve block, 296 paravertebral nerve block, 295–296 postoperative analgesia in outpatients, 293 psoas compartment block, 267–268 peripheral nerve stimulation, 268–269 ultrasound guidance, 268–269

Index lumiracoxib, 346 analgesic effects of, 62 lungs, pathophysiological pain response, 24–25 MacLaren, J. E., 46 magnesium as analgesic adjuvant, 384 preventive multimodal effects of, 179 magnetism, 399–400 magnet therapy, 399–400 application of, 399 complex magnetic burst field applications, 400 low frequency magnetic fields, 400 Manimala, M. R., 46 Manne, S. L., 46 Manufacturer and User Facility Device Experience Database (MAUDE), 309, 614 Marhoffer, P., 270–271 marijuana use, 188, 565, 568. See also cannabinoids; 9-tetrahydrocannabinol (THC) Marks, R. M., 302, 670 massage therapy. See therapeutic touch (TT)/massage therapy mastectomy, 27, 36, 111, 480 chronic pain association, 675–677 lidocaine patch for, 324 persistent pain risk factors, 483 Matheny, J. M., 267 Mayer, D. J., 119, 394, 397 MC1R. See melanocortin-1-receptor (MC1R) McCaffery, Margo, 149 McCartney, C. J., 175, 292 McCormack, J. P., 197 McCracken, L. M., 43 McGill Pain Questionnaire (MPQ), 12, 33, 111, 151, 156–157 ratings of elderly patients, 161 Short-Form McGill Pain Questionnaire (SF-MPQ), 157 MDMA (“Ecstasy”) abuse, 565 Meadowsweet herb (Spirea ulmaria), 53. See also salicylates Meagher, L., 538 mechanisms of action acetaminophen, 58, 177–178 agents with lipophilicity, 103 alvimopan, 587 clonidine, 85, 88 of clonidine, 224 codeine, 587 endogenous opioids, 14 epidural morphine, 28 fentanyl, 587 gabapentin, 96 gabapentin/pregabalin, 94–96 hydrocodone, 587 local anesthetics, 496 morphine, 587

naproxen, 60 NMDA receptor antagonists, 92 NSAIDs on prostaglandin synthesis inhibition, 53, 55 side effects, 62 opioid analgesics, 88 opioid-induced respiratory depression, 419–420 oxycodone, 587 prostaglandins (PGEs), 55–56, 63 tissue injury from surgery, 366 medical report passport system, for sickle-cell disease, 554 Medical Society Patient Care Assessment Committee (Massachusetts), 425–426 Medication Errors Reporting (MER) Program, 614 medication therapy management (MTM) by pharmacists, 607–608 definition, 607 federal/state regulations, 607 medication reconciliation, 607–608 patient counseling, 607 problems of, 607 USP MEDMARX program, 608 Mehta, Y., 240 melanocortin-1-receptor (MC1R), 37 melatonin, 672–673 Melzack, R., 156 Gate Control Theory, and acupuncture, 394 neuromatrix theory of pain, 42 membrane stabilizing drugs: anti-neuropathics, 382–383 gabapentin/pregabalin (calcium channel blockers), 382–383 lidocaine/mexelitine (sodium channel blockers), 383 Mendell, L. M., 109 Menigaux, C., 106 meperidine American Pain Society recommendation against, 612 delirium from, 411 description, 195 effect on cardiovascular system, 406 effect on serotonin, 195 for emergency room use, 592 for IV-PCA use, 36, 206, 305 for moderate/severe pain, 197 ODAC monitoring, 204 for postcesarean analgesia, 539, 543 for sickle cell disease, 556 as therapeutic alternative for pain control, 196 meperidine PCA, 36–37, 103 mepivacaine, 72 additive to epinephrine, 75 lipophilicity of, 72–73 onset of action, 72 protein binding properties, 73 metabolic derangements, 4

693 methadone description, 194–195, 613 during intraoperative/postoperative period, 574 and OIH, 121–122 and opioid switching, for OIH modulation, 127 ora, for patients with high morphine tolerance, 574 parenteral dosages of, 197–199 for postsurgical/medical related pain, 197 for sickle cell disease, 556 and substance abuse, 564–566 methadone maintenance therapy (MMT), 566–567 methohexital for emergency department use, 593 methylnaltrexone for blocking peripheral effects of opioids, 408 for minimization of opioid-related gastrointestinal distress, 613, 672 for opioid-induced bladder dysfunction, 411 for POBD/POI, 586–587 methylprednisone, 381 metoclopramide, for nausea/vomiting, 210, 237, 242, 407, 613 mexilitine, 383 midazolam for emergency room use, 592–593 for epidural analgesia, 221 as adjuvant, 224 Miguel, R., 106 Milligan, K., 118 minimally invasive surgery. See laparoscopic surgery minimum effective analgesic concentration (MEAC), 303, 308 Mitra, S., 576 MK-801 NMDA (non-competitive) antagonist, 120, 125 Mogil, J. S., 37 Moiniche, S., 174–175, 179–180 Molke, J. F., 239 Monitoring the Future Study (2006), 565 Moore, P. A., 382 R MorphiDex , 128 morphine back pain study, 117 cardiovascular system effects of, 406 combinations bupivacaine/levobupivacaine/ropicaine, 315 with ibuprofen, with ketorolac, in ED, 591 description/uses of, 193 dosing/dosage requirements COMT gene’s genetic variability, 192 epidural bolus dosing, 232–233 intrathecal bolus dosing, 230–232 effect on calcitonin gene-related protein, 124

694 morphine (cont.) epidural administration, 28, 222–223 continuous epidural infusion, 234 spinal, plus epidural infusion, 234 extended morphine, clinical trials, 106–107 extended release epidural morphine (EREM), 327–329 glucoronidation of, 38 hydrophilicity of, 316 intramuscular, and sedation, 416–417 intrathecal administration in cesarean sections, 543 with clonidine, 176, 232, 544 and respiratory depression, 417–418 intravenous administration for elderly/pediatric patients, 33 for emergency room use, 592 vs. epidural administration, 370 influence on sleep, 422 vs. intramuscular morphine, 495 vs. intrathecal administration, 407, 420 for IV-PCA use, 206, 305 lockout intervals, 304 lockout interval investigations, 210 mechanism of action, 587 microdialysis delivery of, 421 for moderate/severe pain, 197 vs. nalbuphine, female response, 37 oral dosing of, 197 oral vs. intravenous, bioavailability of vs. oral, 574 for PCEA use, 235 for postcesarean analgesia, 538 pruritus from, 411 for sickle cell disease, 556 as standard parenteral opioid, 196 and substance abuse, 564 sustained release preparations, 198 morphine, epidural. See also DepoDurTM (prolonged duration epidural morphine); extended release epidural morphine (EREM) age related reductions, 33 clinical trials, 106–107 combinations bupivacaine, 234 clonidine, 539, 544 ketamine, 367, 370 local anesthetics, 538 description, 222 vs. epidural fentanyl, 133, 539 intrathecal administration, 230 vs. intrathecal morphine, 543 mechanism of action, 28 vs. parenteral opioids, 232 for postoperative pain management, 117 and respiratory depression, 407, 540 side effects nausea/vomiting, 237, 409, 540 pruritus, 237 single dose, vs. continuous infusion, 232 morphine-3-glucuronide (M3G), 38, 127 morphine-6-glucuronide (M6G), 37–38, 672

Index motivational-affective pain factors, 42 moxibustion, 392 R MS Contin (controlled release morphine), 193, 198, 556 Multicentre Australian Study of Epidural Anesthesia (MASTER), 638 multimodal analgesia, 245–246. See also preemptive analgesia; preventive multimodal analgesia for ambulatory surgery, 478–479 anesthesiologist initiation of, 30 background/description, 175–176, 332, 335, 433 and clinical outcomes, 182–183 with clonidine, 479 with COX-2 inhibitors, 479 definition, 82 with epidural bupivacaine, morphine, ketamine, 372 with gabapentin, 479 goal/theme of, 361 implementation in community practice setting, 458–460 NMDA antagonist/NSAIDs administration, 182 for opioid dependent drug addicts, 570–571 for postcesarean delivery, 545 mu opioid receptors, 118 actions/structure of, 11 activation in medial thalamus, 12, 14 binding of kappa receptors (OPR2 ), 193 central/peripheral nervous system locations, 407 endocytosis of, 191 mediation of TENS, 397 polymorphism, 192, 304 and sublingual buprenorphine, 196 Murphy, D. F., 239 Muscoli, C., 16 music therapy, 402–403 facilitation descending pathways by, 14 myocardial ischemia (perioperative), 23–24, 172, 526 N-(4-hydroxyphenyl) acetamide, 54 nabumetone (NSAID), 56, 342–344 Na channels anesthetic actions at unrelated sites, 71 electrophysiology of, 70–71 structure/function of, 70 nalbuphine avoidance of, with drug addicts, 570 binding of kappa receptors (OPR2 ), 193 for blunting respiratory depression, 407 for emergency room use, 592 intrathecal, for postcesarean section, 543 vs. morphine, female response, 37 for pruritus, 539–540 nalmefene, for nausea/vomiting, 411 naloxone and acupuncture, 394 PENS/TENS, 397 for IV-PCA related pruritus, 306

for nausea and vomiting, 411, 540 and opioid combination, for PCA use, 207 for pruritus, 214, 237, 412, 540 for reduction of opioid induced bowel function, 586 for respiratory depression, 236, 242, 407, 613 reversal of intrathecal opiates, 174 for urinary retention, 411 naltrexone, 193, 325, 407 for reduction of opioid induced bowel function, 586 for reversing respiratory depression, 407 naphthylalkanones, 57–58 naproxen analgesic effects of, 60 efficacy of, in preemptive analgesic therapy, 344 evaluation for postoperative pain usage, 335–339 postoperative use, 346 preemptive use of, 345 Narcotic Addict Treatment Act (1974), 565 narcotics (schedule II) management, by pharmacists, 608–609 R Nasal Stadol , 195 National Health and Medical Research Council (NHMRC) of Australia, 633 National Health Expenditure Accounts data, 476 National Hospital Ambulatory Medical Care Survey, 594 National Institutes of Health (NIH) approval of acupuncture, 393, 395 National Library of Medicine database, 647 National Pain Foundation, 166 National Survey on Drug Use and Health (NSDUH), 391, 565 Naulty, J. S., 538–539 nausea and vomiting anti-emetic treatment of, 410–411 CTZ mediation of, 408–409 dexamethasone for, 410 multimodal approach to, 409 nalmefene for, 411 naloxone for, 540 ondansetron for, 237 from opioids, 133, 199, 237, 332, 377, 408–411, 540 from PCA/management of, 214, 306 phenothiazines for, 613 scopolamine patch for, 237, 410, 613 serotonin for, 410, 613 negative affect (anxiety) and pain, 42 negative-pressure pumps (non-electric infusion devices), 321 Negre, I., 230 neonatal considerations, 545–548 meperidine absorption in gastrointestinal tract, 546 nursing mothers/medications, 537 safety of acetaminophen, 58

Index neostigmine (acetylcholinesterase inhibitor), 83 for epidural analgesia, 221 as adjuvant, 224, 384 nephrectomies, 36, 237 nerve blocks. See also axillary brachial plexus block; elbow blocks; interscalene nerve block; peripheral nerve blocks; supraclavicular nerve block; wrist block differential sensory nerve blocks, 74 and Na channels, 70, 73 peripheral, as adjuvant to opioid use, 132–133 single-injection, in community practice setting, 467 volumes/concentrations of anesthetics during, 73 neural plasticity, 10, 14 neuraxial analgesia advantages of, 230 adverse effects of spinal opioids, 236–237 nausea and vomiting, 237 pruritus, 237 respiratory depression, 236, 407 urinary retention, 237 continuous epidural analgesia, 233–235 buprenorphine, 239–240 combined spinal morphine/epidural infusion, 234 fentanyl infusions, 233–234 hydromorphone infusions, 234–235, 237–239 local anesthetic infusions, 233 morphine infusions, 234 patient-controlled epidural analgesia, 235–236. (See also patient-controlled epidural analgesia) for postcesarean delivery, 545 for postoperative pain, in opioid-dependent patients, 575 single boluses of intrathecal/epidural opioids, 230–233 epidural bolus dosing, 232–233 intrathecal bolus dosing, 230–232 neuraxial analgesia, patient controlled systems background information, 314 clinical management, 315–316 commercially available PCEA infusion devices Curlin Medical 4000 CMS, 317 Hospira Gemstar, 317 Smiths Medical CADD-Prizm PCS II, 317 delivery variables/infusion rates, 314–315 design theory, 314 safety issues, 317 systems, 316–317 neuromatrix theory of pain (Melzick), 42 neuropathic pain, 16–17 allodynic/hyperpathic aspects of, 26 associated disease states, 4

characteristics of, 4 defined, 4 description, 150 mechanisms of development, 16 nonadaptiveness of, 16 research focus for, 16–17 neutrophil aggregation, prostaglandin inhibition of, 55–56 Ng, K. F., 206, 270 nicotine, 384, 568 Nikolajsen, H. C., 537 9-tetrahydrocannabinol (THC), 673 nitric oxide synthetase (NOS), 10, 16, 26 NMDA (N-methyl-d-aspartic acid) receptor antagonists (NMDARA), 125. See also dextromethorphan; ketamine; MK-801 NMDA (non-competitive) antagonist perioperative administration for multimodal analgesic effects, 182 preemptive analgesia with, 179 preemptive analgesic with, 174–175 preventive multimodal effects of, 178–179 NMDA (N-methyl-d-aspartic acid) receptors and analgesic tolerance to opioids, 120 and cAMP/protein kinases production, 15 and clinical hyperalgesia, 9–10 CNS locations, 89 described, 9 indirect reduction of opioid sensitivity, 17 ketamine’s affinity for, 366 locations of, 120 for OIH modulation, 125 overactivation of, and excitotoxicity, 15 pharmacology under different pain states, 90–91 postoperative pain conditions, 91 phosphorylation of, 15 plasticity changes, 15 and SOD activation, 16 spinal/supraspinal, activation of, 15 substrates of, 125 nociceptive pain. See also hyperalgesia defined/subdivisions, 3, 149–150 minimization by non-opioid analgesics/adjuvants, 377 NMDA receptors increase of, 366 Non-Communicating Children’s Pain Checklist-Postoperative Version (NCCPC-PV), 492–493 non-opioid analgesics. See also acetaminophen; aspirin; COX-2 (cyclo-oxygenase-2) inhibitors; ibuprofen; ketoprofen; naproxen alpha-2 adrenergic receptor agonists, 383–384 anti-neuropathics calcium channel blockers, 382–383 sodium channel blockers, 383 cannabinoids, 384 glucocorticoids, 377–382. (See also glucocorticoids) magnesium, 384 neostigmine, 384

695 nicotine, 384 principles of employment, 377 for sickle cell disease, 554–555 non-opioid analgesics, clinical applications of, 385–387 acute post-operative pain, 385–386 perioperative, early phase, 385–386 postoperative at home/without IV access at hospital ward, 386 in PACU/hospital, 386 preoperative, 385 other pain types, 386–387 non-pharmacological therapy, 384–385 nonsteroidal anti-inflammatory drugs (NSAIDs). See also COX-2 (cyclo-oxygenase-2) inhibitors; diclofenac; fenbufen; flurbiprofen; indomethacin; ketoprofen; ketorolac; naproxen; piroxicam; tenoxicam for acute postoperative pain, 385 for ambulatory surgery, 479–480 Black Box Warning, against use of, 355 cardiac morbidity concerns from use of, 166 and colectomy, 585–586 combinations with glucocorticoids, 382 with lidocaine, 383 with tramadol/acetaminophen, 198–199 vs. COX-2 inhibitors bone/wound healing effects, 356 gastrointestinal system, 356 for postoperative pain, 178 renal effects, 356 efficacy of, in preemptive analgesic therapy, 344 for emergency room use, 591 hematological/cardiovascular effects, vs. COX-2s, 355–356 historical background coxibs, 53–54 NSAIDs-description, 53 para-aminophenols, 54 salicylates, 53 inhibition of COX by, 55 inhibition of prostaglandin synthesis, 177 limitations of, 17 mechanisms of action, 335, 342 for opioid-dependent patients, 571 for pediatric pain management, 493–494 perioperative administration for multimodal analgesic effects, 182 and peri-operative analgesia, 59 pharmacokinetics of of acetaminophen, 58–59 acetic acids, 57 anthranilic acids, 57 aspirin, 57 coxibs, 58 general principles, 56–57 naphthylalkanones, 57–58 oxicams, 58

696 nonsteroidal anti-inflammatory drugs (cont.) propionic acids, 57 pyrazolones, 57 and platelet aggregation/risks of bleeding, 355 for postcesarean delivery, 545 preemptive analgesia with, 385 preemptive/preventive/multimodal administration, 30, 174–175, 177–178 pre-incision administration, 478 reduced PGE synthesis from, 29 review of, for postoperative pain usage, 335–339 safety and tolerability of, 355 for sickle cell disease, 554, 558 side effects of, 62–66 nonsteroidal anti-inflammatory drugs (NSAIDs), and surgical pain management background information, 335–339 perioperative use COX-2 inhibitors, 346–347 celecoxib, parecoxib, 350–353 rofecoxib, 347–350 valdecoxib, 350–353 postoperative use, 346 acetaminophen, intravenous (paracetamol), 358–359 oral/rectal, 358 diclofenac, 346 etoricoxib, 353–355 indomethacin, 346 ketoprofen, 346 ketorolac, 346 naproxen, 346 propacetamol, 358 rofecoxib, tenoxicam, 346 tramadol, 346 pre-incisional use, 342–346 diclofenac, 345 ibuprofen, sustained-release, 345 ketoprofen, 345–346 ketorolac, 345 naproxen sodium, 345 piroxicam, 345 tenoxicam, 345 nonsteroidal anti-inflammatory drugs (NSAIDs), side effects of, 62–66 aspiring-sensitive asthma, 66 cardiovascular system, 63 gastrointestinal system, 63–64 enteropathy, 64 peptic ulcers, 63–64 hepatotoxicity, 66 injection site damage, 66 platelet clotting function, 64–65 renal function, 65–66 norbuprenorphine, 38 Nordberg, G., 104 norepinephrine (NE), 10–12 acupuncture’s influence on, 395

Index COMT inactivation of, 37 post-surgical trauma increases, 23 role in descending pathway, 14 spinal, antinociceptive effect of, 83 tramadol’s inhibition of uptake of, 306, 495, 555, 591–592 normeperidine seizures from, 411 toxicity, from PCA, 214–215 norpethidine, for IV-PCA use, 206 novel analgesic drug delivery systems. See transdermal therapeutic systems (TTS) NSAIDs. See nonsteroidal anti-inflammatory drugs (NSAIDs) nSTT (lateral neo-spinothalamic tract), 12 nuclear factor-kappa B (NF-kB), 15 Number Needed to Treat/Harm (NNT/NNH), 632. See also evidence-based medicine (EMB) Numeric Rating Scale (NRS), 151, 162, 649 NumorphanTM (oxymorphone), 305 nurses. See also American Society for Pain Management Nursing (ASPMN) ASPMN position statements, 167 influences on pain assessment by, 165 IV-PCA protocols, 208–209 nurse-based pain programs, 604 nursing issues alternative agent-controlled analgesia, 606 analgesia by catheter techniques, 605 nonverbal patient assessment, 604–605 patient monitoring, 605 range order administration, 605–606 observer scoring of patient pain, 150–151 pain resource nurse (PRN) programs for, 603–604 role diversity of, 603 role model programs/preceptorships for, 604 nurses, as clinical coordinators, 597–598 characteristics of coordinators, 598–599 advanced practice registered nurses (APRNs), 598–599 organization structure, 599 responsibilities clinical practice, 601–602 continuous quality improvement (CQI), 603 delineate responsibilities, 599–601 establishment of policies/procedures, 601 general responsibilities, 603 multidisciplinary education, 602 patient education, 603 patient flow, 599 objective pain scale (OPS), 492 obstructive sleep apnea (OSA) from opioid use, 377, 421 use of OCA without background infusion, 211 Ochroch, E. A., 111

ODAC. See On Demand Analgesia Computer (ODACTM ) odds ratio (OR) method for analgesic efficacy comparisons, 650 OIH. See opioid-induced hyperalgesia (OIH) OLD CART assessment tool, 154–156 oligoanalgesia (underuse of analgesics), in emergency department, 589–590 Olofsen, R., 35 Olsen, Y., 114 Olstad, O. A., 381 Omnibus Budget Reconciliation Act (1990), 607 ondansetron, for nausea/vomiting, 237 On Demand Analgesia Computer (ODACTM ), 204, 303 Ong, C. K., 175, 179, 181 On-Q C-BlocTM Continuous Peripheral Nerve Block System, 36, 319–320 R OPANA (immediate release oxymorphone), 198 R Opana ER , 194, 198 R Opana Injectable , 194, 305 R Opana IR , 194 opioid analgesics adverse events related to use, 199–200 for ambulatory surgery, 479 annual sales statistics (U.S.), 564 Australia, opioid trends study, 114 benefits of, 377 central/peripheral, and preventive multimodal analgesia, 181–182 classification of, 192–193 dosage requirements, orthopedic procedures, 36 dose escalation, analgesic paradox of, 116 and drug abuse, 391 effects on bowel function, 584–585 for emergency room use, 591–592 genetic polymorphisms influence on, 192 historical background, 114, 188 increasing usage of, 114 clinical implications of, 114 interactions with alpha-2 adrenoceptor agonists, 88 for IV-PCA use, 305–306 lipophilicity of, 316 mechanisms of action, 88 multicompartment pharmacokinetics of, 310 opioid disinhibition mechanism, parenteral, and vital capacity, and patient size, 36–37 PCA consumption of, 117. (See also patient-controlled analgesia, opioids for) for pediatric patients, 494–496 major, 495–496 weak, 495 pharmacology of pharmacokinetics, 190–191 receptors, 188–190 tolerance/hyperalgesia, 191–192

Index physician prescribing patterns in U.S. (1992–2001), 114 preemptive analgesic effects of, 174–175, 182 prolonged usage of adaption to, 115 adaptive mechanisms, 115 for sickle cell disease, 555–556 systemic and cytokine response, U.S. opioid trends, 114 opioid analgesics, side effects, 199–200, 377, 391 cardiovascular, 406 constipation, 133, 199, 223, 332, 407–408 dermatological, 411–412. (See also pruritus) gastrointestinal, 407–408 genitourinary, 411 nausea/vomiting, 408–411 neurological, 411 respiratory, 406–407 opioid analgesics, tolerance to, 117–118, 191–192 acute opioid tolerance, 116–117 described, 116 genetic approaches to, 121 mechanisms of, 118–121 alterations in GTP binding protein coupling, 119 cytokines and innate immunity, 120–121 ion channels, 120 NMDA receptor, 120 protein kinase activation, 119–120 receptor desensitization/tracking, 118–119 and OIH, 115 vs. opioid-induced hyperalgesia, 115–116, 121, 191–192 opioid dependence/substance abuse aspects of disorder opioid tolerance, 567 physical dependence, 567 case management examples, 576–578 cross addictions/poly-drug abuse, 568 drug abuse statistics, 565 Drug Addiction Treatment Act (DATA 2000), 565–566 DSM-IV criteria, 565, 568 emergency department (ED) visits, 565 impact on pain management, 37 methadone maintenance therapy (MMT), 566–567, 574 Monitoring the Future Study (2006), 565 Narcotic Addict Treatment Act/Opioid Treatment Program (OTP), 565 National Survey on Drug Use and Health reports, 565 need for knowledge about, 564 opioid antagonist therapy (OAT), 566–567 and pain management issues, 566–567 patient management assessment issues, 567–570 goals and strategies, 570–571

multimodal analgesia approach, 570–571 opioid medications, 571–572 patient prescription increases, 564 perioperative management dose tapering, 575–576 intraoperative period, 574 postoperative period, 574–575 neuraxial analgesia, 575 regional analgesia, 575 preoperative period, 574 prescribed opioids, 565 and abuse of opioids, 566 treatment with opioid agonists, 565–566 opioid dependence/substance use disorder aspects of disorder criteria and definitions, 567 opioid-induced hyperalgesia (OIH), 121–128 avoidance of dose escalation, 116 as complication of opioid analgesics, 391 defined, 114–115, 192 distribution of opioids, 124–125 mechanisms of, 123–124 peripheral effects, 123–124 spinal effects, 124 supraspinal effects, 124 multimodal therapy modulation of, 125–128 dextromethorphan, 128 ketamine, 125–127, 368 methadone and opioid switching, 127 NMDA receptors, 125 vs. opioid dosage, 121 vs. opioid tolerance, 115–116, 121 serotonin and, 124 sufentanil’s impact on, 133 therapeutic occurrences of, 121–123 methadone maintenance therapy, 121–122 observational studies in chronic pain, 123 perioperative opioid exposure, 122 preemptive administration of opioid/COX-2 inhibition, 182 volunteers for experimental pain methods, 122–123 underlying pathways, 116 very high doses, 125 opioid naive patients, perioperative therapy management, 133 balanced anesthesia, 133 treatment of suspected OIH, 133 opioids, future challenges impact of chronic persistent pain post-surgery, 134 lack of high quality evidence, 133–134 optimal adjuvant use, 134 usefulness of preoperative detoxification, 134 opioids, patient use management, 128–133 adjuvant medications/treatments COX inhibitors/paracetamol, 131 epidural block, 133 gabapentin, 132

697 infiltration/wound lavage, 132 NMDA receptor antagonists, 131–132 peripheral nerve block, 132–133 regional anesthesia, 132 intraoperative considerations, 128–130 perioperative considerations, 128 postoperative considerations, 130 preoperative considerations, 128 OPR2 receptors. See kappa receptors (OPR2 ) oral dosing of analgesics, 197–199 R fentanyl oralet (Actiq ), 198 hydrocodone/oxycodone, 197 with ibuprofen compounding, 198 morphine, 197 oxymorphone, 198 short-acting agents, 199 sustained release preparations, 198 oral nutrition, 29 organ impairment/failure, impact on pain management, 37–38 orthopedic surgery acetaminophen/NSAIDs following, 178 ambulatory infraclavicular block, 292 celecoxib, postsurgical utilization, 347 in children, continuous peripheral pump vs. elastomeric pumps, 319 CombunoxTM for, 479 continuous peripheral nerve block, 289 COX-2 inhibitors, 245 epidural analgesia vs. peripheral nerve block/PCA, 178 epidural morphine, 230 etoricoxib for, 353 ketamine for, 369, 481 ketorolac, preemptive, 345 meloxicam for, 675 and negative affect study, 42 open surgeries, 36 oxymorphone (IR) vs. oxycodone, 198 paracetamol vs. propacetamol, 359 pentazocine/piritramide/metamizol study, 106 rofecoxib, perioperative use, 350 sleep disturbances from, 27 osteopathic manipulation (OMT), 401 OUCHER scales for African-American/Hispanic self-assessment, 490, 552 for pediatric self-assessment, 163, 490 outpatients. See ambulatory surgery index entries; postoperative analgesia, in outpatients overmedication IV-PCA incidents, 306 of pediatric patients, 163 Oxford Pain Validity Scale (OPVS), 334 oxicams, 53, 57–58 oxycodone, 188 with acetaminophen, vs. valdecoxib, 353 vs. codeine, 195 description, 193 extended-release, 460 for IV-PCA use, 212 mechanism of action, 587

698 oxycodone (cont.) metabolism pathways, 193 for moderate/severe pain, 197 oral bioavailability of, 574 oral dosing of, 197 with ibuprofen compounding, 198, 479 R immediate release (OPANA ), 198, 479 for sickle cell disease, 555–556 vs. rofecoxib, for oral surgery, 350 and substance abuse, 564–565 for visceral pain, 386 R Oxycontin , 114, 193, 198, 556, 565, 574 R  OxyIR (oxycodone elixir), 193 R oxymorphone. See also OPANA (immediate release oxymorphone) description, 194 for IV-PCA use, 305 as pain control alternative, 196 parenteral dosages of, 196–197 as therapeutic alternative for pain control, 196 P450 enzymes CYP 37–38 2D6, CYP 38 3A4, PAG. See periaqueductal gray (PAG) pain. See also chronic pain; chronic persistent pain; pathophysiology of acute pain; perioperative pain; persistent pain; postoperative pain; preoperative pain adaptive purposes of, 3 ascending pathways, 12 catastrophizing of, 42, 44, 49 classification of, 3–4, 149–150 conduction, 8 cortical reception/responses, 12–14 defined, 3, 109, 149, 391 descending pathways, 14 modulation, 10–12 molecular level interactions, 102 perception of, 4–5 physiological pain, 3 progression from acute to chronic, 109–110 quality of life consequences of, 24, 27, 147, 151 theories of Gate control theory (Melzack/Wall), 4–5 intensity theory (Sydenham), specificity theory (Descartes), 4 of Woolf, 5 transduction, 5–7 transmission, 8–10 Pain Anxiety Symptoms Scale (PASS), 43 Pain Assessment in Advanced Dementia Scale (PAINAD), 157 “Pain as the 5th Vital Sign” slogan (APS), 147–148 Pain Care 3000TM , 320–321 3200TM , 4200TM (spring-powered pumps), pain control,. See also holistic medicine; individual analgesia entries

Index barriers to, 164–166 of healthcare providers, 165–166 overcoming, 166 of patients, 165 patient expectations from, 166 pain-free injuries, 41 Pain Indicators for Communicatively Impaired Children, 492 Pain Pump 1TM (negative-pressure pump), 321 Pain Relief Scale, 649 pain resource nurse (PRN) programs, 603–604 Pain Standards by Joint Commission on Accreditation of Healthcare Organizations (JCAHO), 114, 175, 601, 604, 608, 659–660, 666 Palmer, C. M., 538, 543 p-aminobenzoic acid (PABA), 76 papaveretum, 60 para-aminophenols, 54 paracetamol. See acetaminophen parascalene block (brachial plexus), pediatric patients, 504 continuous technique/dosages, 504–505 dosages, 505 single shot technique/dosages, 504 paravertebral nerve block, 295–296. See also peripheral nerve blocks for breast cancer patients, 676 perioperative, 111 supplemental to interscalene block, 290 parecoxib, 16, 56 for ambulatory surgery, 480 analgesic effects of, 61, 350–353 clinical trials in Europe, 346 in epidural block, 180 IV, for ambulatory surgery, 480 postoperative use, 61 starting preoperative dosage, 385 parenteral nutrition, 29 parenteral opioid therapy, 196–197 for abdominal surgery, 583 buprenorphine, 197 vs. epidural morphine, 232 fentanyl, 197 future directions, 200–201 hydromorphone, 196 intravenous patient-controlled analgesia, 196 ketamine, methadone, 197–199 oxymorphone, 196–197 and respiratory depression, 418 risks of, postcesarean delivery, 545 for sickle cell disease, 556 vs. single dose epidural morphine, 232 parents relation to children’s pain, 45 use of CBT during venipuncture procedures, 46–47 Parker, R. K., 34, 235–236 Parkinson, S. K., 267

Pasero-McCaffery Opioid-induced Sedation Scale, 605 Passar, E. P., 583 pathophysiology of acute pain attenuation of pain induced pathophysiology cardiac surgery, 28 cytokine response, 28–29 persistent pain, 29–30 sleep disturbances/return to functionality, 29 thoracic/upper abdominal surgery, 28 thromboembolism, risk of, 28 tissue breakdown/infection risk, 29 vascular surgery, 28 hyperalgesia, 21–22. (See also hyperalgesia) key target organs central nervous system, 26–27 heart, 24 hearth/lungs, 24–25 injury site, 25–26 vascular system, 25 neuroendocrine responses, 23–24 in sickle cell disease, 550–551 sympatho-adrenal responses, 22–23 patient-controlled analgesia (PCA). See also intravenous patient-controlled analgesia (IV-PCA); patient-controlled epidural analgesia (PCEA) adverse events reports to MAUDE database, 614 background infusion, with/without PCA, 210–211 and body size of patients, 36–37 devices used for, 204 for emergency room use, 592 and hypnosis, 47 intravenous, vs. epidural analgesia, 29 intravenous and cytokine response, neonatal manifestations, in breastfeeding mothers, 545–546 for opioid-dependent patients, 571 opioids for dosage requirements, 36 drug combinations with, 206–207 peak consumption levels, 117 postoperative, 117 patient’s guide to (Royal Adelaide Hospital), 215–216 by pediatric patients, 33–34 pharmacists standardization of orders, 616 respiratory depression from, 417 for sickle cell disease, 556–557 success limitations with IV-VC, 28 unexpected deaths from, 425–426 younger vs. older patients, 33 patient-controlled analgesia (PCA), complications, 212–215 equipment-related errors, 213 nausea and vomiting/management of, 214 normeperidine toxicity, 214–215 operator errors, 212

Index opioid-related, 213 patient-related errors, 212–213 pruritus/management of pruritus, 214 respiratory depression, 213–214 patient-controlled analgesia (PCA), devices/systems. See intravenous patient-controlled analgesia (IV-PCA), devices/systems patient-controlled analgesia (PCA), safe/effective use requirements, 207–212 background infusion, 210 bolus dose, 209–210 duration of delivery, 210 in opioid-tolerant patients, 210 dose limits, 211 education patients, 207–208 staff, 208 loading dose, 209 lockout interval, 210 monitoring requirements, 209 patient factors comorbidities obstructive sleep apnea, 211 renal impairment, 211–212 psychological, 211 PCA prescription, 209 standard orders/nursing procedure protocols, 208–209 patient-controlled epidural analgesia (PCEA). See also intravenous patient-controlled analgesia (IV-PCA); neuraxial analgesia, patient controlled systems; patient-controlled analgesia (PCA) advantages of, 235 with background infusion, 224 fentanyl PCEA, 105, 235 hydromorphone PCEA, 235–236 morphine PCEA, 235 for motor block, 226 study of bupivacaine/fentanyl, 106 University of Kentucky technique evaluation, 235 patient controlled regional analgesia (PCREA), 251 Patient Global Impression of Change Scale (PGIC), 649 patients. See also postoperative analgesia, in outpatients in chronic pain, growing numbers of, 166 expectations from pain control, 166 pain control barriers of, 165 selection for ambulatory regional anesthesia/analgesia, 287 patients, opioid naive, perioperative therapy management, 133 balanced anesthesia, 133 treatment of suspected OIH, 133 Patient Safety and Quality Improvement Act (2005), 666 patients consuming opioids, management of, 128–133

adjuvant medications/treatments COX inhibitors/paracetamol, 131 epidural block, 133 gabapentin, 132 infiltration/wound lavage, 132 NMDA receptor antagonists, 131–132 peripheral nerve block, 132–133 regional anesthesia, 132 intraoperative considerations, 128–130 perioperative considerations, 128 postoperative considerations, 130 preoperative considerations, 128 patient variables (in pain management) age, 33–34 anesthetic technique, 36 culture or race, 34–35 gender, 35 gene polymorphisms, 37 organ impairment/failure history, 37–38 patient size/opioid pharmacokinetics, 36–37 psychological factors, 35–36 site/extent of surgery, 36 warning patients of pain possibility, 45 Paul, J. E., 480 Pautex, S., 161 Pavlin, D. J., 44 PCA. See patient-controlled analgesia (PCA) PCREA. See patient controlled regional analgesia (PCREA) PDSA cycle, for quality/quality improvement, 656–657 pediatric pain management background information, 487 emergency department treatment, 590, 593 local anesthetics, 496–497 adjuvants clonidine (See clonidine, adjuvant use with children) ketamine, 497 operative/post-traumatic pain, 488–489 pharmacology, 493–496 acetaminophen, 493 NSAIDs, 493–494 opioids, 494–496 major, 495–496 weak, 495 procedure-related pain, 487–488 and use of PCA, 33–34 pediatric pain management, assessment/assessment tools, 489 behavioural based scales, Children and Infants Postoperative Pain Scale (CHIPPS), 490 Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS), 164, 491 Face, Legs, Activity, Cry and Consolability (FLACC) tool, 157, 492 Individualized Numeric Rating Scale (INRS), 493

699 Non-Communicating Children’s Pain Checklist-Postoperative Version (NCCPC-PV), 492–493 objective pain scale (OPS), 492 Pain Indicators for Communicatively Impaired Children, 492 Pediatric Pain Profile (PPP), 491 self-assessment, 489–490 Children’s Comprehensive Pain Questionnaire, 552 Faces Pain Scale, 154, 489 numeric scale, 490 OUCHER scale, 163, 490 Pain Descriptors, 490 Poker Chip Tool (PCT), 490 Varni-Thompson Pediatric Pain Questionnaire, 552 Word Graphic Rating Tool, 490 pediatric pain management, central blocks, 497–502 caudal block, complications, 500 continuous technique, 499 contraindications, 499 drugs, 499 indications, 498 landmarks, 498 materials, 498 single-shot technique, 498 epidural block, 500–502 complications, 500–502 continuous technique, 500–502 contraindications, 499 drugs, 499–502 indications, 500 landmarks, 500 materials, 500 single shot technique, 500 pediatric pain management, peripheral nerve blocks, 502–511 brachial plexus blocks axillary block, 505 parascalene block, 504 complications, 502–503 contraindications, 502 indications, 502 lumbosacral plexus blocks fascia iliaca block, 506–507 femoral block, 505–506 materials, 503 sacral plexus blocks, 507–509 ilioinguinal/iliohypogastric block, 509 penile block, 509–511 sciatic block lateral approach, 507 popliteal approach, 508–509 subgluteal approach, 507–508 pediatric pain management, strategies orthopedic surgery, continuous peripheral pump vs. elastomeric pumps, 319 pain management strategies cognitive-behavioral therapy, 46–47 distraction, 45–46 reassurance, 46

700 pediatric pain management, strategies (cont.) virtual reality, 48 pain of, relationship of parents to, 45 and sickle cell pain, 551 assessments, 551–552 Pediatric Pain Profile (PPP), 491 Pendleton, J. M., 590 penile block, in pediatric patients, 509–511 PENS. See percutaneous electrical nerve stimulation (PENS) pentazocine, avoidance of, with drug addicts, 570 peptic ulcers, side effect of NSAIDs, 63–64 R Percocet , 193 percutaneous electrical nerve stimulation (PENS)(electroacupuncture), 392, 397–399 historical background, 397 and naloxone, 397 research studies of, 398 and serotonin, 397 side effect reduction through, 399 periaqueductal gray (PAG) region (of CNS), 12 actions of, 14 and acupuncture, 395 stimulation of serotonin release, 102 perineural ambulatory analgesia systems background, 317–318 basic considerations, 318–319 clinical management/safety issues, 319 commercially available non-electric infusion devices elastomeric pumps, 319–320 negative-pressure pumps, 321 spring-powered pumps, 320–321 continuous administration, in community practice setting, 468 cost effectiveness of, 319 design theory, 318 for outpatient orthopedic shoulder/foot surgery, 481 systems, 318 perioperative pain aggravation of, via psychological factors, 118 in elderly patients, management of, 521 ultrasound guided PNP placement, 531 management considerations, 128 multimodal analgesia strategy, 82, 245–246 blocking of NMDA receptor, 178 COX-2 inhibitors, 333, 346–347 NSAIDs, 59, 177 opioids/OIH, 122 in opioid tolerant patients, management of, 576 paravertebral blockade for, 111 perioperative paravertebral block, 111 peripheral kappa opioid agonists, 672 peripheral nerve blocks as adjuvant to opioid use, 132–133 complications of, 280–281 cardiovascular toxicity, 281 central nervous system toxicity, 281

Index local anesthetic toxicity, 280–281 management of, 281 peripheral nerve injuries, 281–282 enhancement by clonidine, 176 equipment needed for performance of, 246–247 increased uses of, 245 local anesthesia/regional analgesia for, 180 of lower limb, 266–274 for orthopedic anesthesia, 180 in pediatric patients (See pediatric pain management, peripheral nerve blocks) for postoperative analgesia in outpatients, 288–296 use if indwelling nerve catheter, for extending benefits, 246 and use of LMWH, 246 peripheral nerve blocks of lower limb, ankle blocks, 295 lumbar plexus blocks, 267–270, 293 fascia iliaca block, 294 femoral nerve block, 270–274, 293–294 ilioinguinal/iliohypogastric nerve block, 296 paravertebral nerve block, 295–296 psoas compartment block, 267–268 sacral plexus blocks, 274–280 infragluteal sciatic nerve block, 276 popliteal sciatic nerve block, 276–280 sciatic nerve block, 274–276 distal, in popliteal fossa, 295 proximal, 294–295 peripheral nerve blocks of upper limb, 247–248 axillary brachial plexus block, 255–259, 292 distal upper extremity nerve blocks, 292–293 elbow blocks, 260–262, 293 infraclavicular brachial plexus blocks, 253–255, 289–290 intercostal nerve block, 296 interscalene nerve block, 248–251, 289–290 supraclavicular brachial plexus nerve block, 290–291 wrist block, 262–266 peripheral nerve catheters, 245–246, 250, 266, 436 peripheral sensitization, 5, 7, 89, 109, 172–173 analgesic inhibition of, 335 consequences of, 172 mediation of, 15 physiology of, 172–173 and primary hyperalgesia, 91 persistent pain. See also chronic pain allodynic/hyperpathic aspects of, 26 attenuation of pain induced pathophysiology, 29–30 cognitive therapy for, 14 defined, 109

developmental risk factors, 27 development of, role of cytokines, 25 following ambulatory surgery, 476–477 following thoracotomy, 27 gabapentin and, 132 and genetic polymorphisms, 21 from IL-1-Beta elevation, 7 impact of primary/secondary analgesia, 22 interventions for decreasing, 110–112 ketamine and, 366–367, 370 link with kinesiophobia, 43 from nerve injury, 27 and NMDA-mediated excitatory neurotransmission, 89 PASS assessment for, 43 possible role of psychological interventions, 42 post-surgical, evidence of, 109 risk factors linked to, 483 role of limbic system, 12 transition from acute pain, 3, 14–16, 109–111 treatment crossover, with acute pain, 112 use of perioperative paravertebral block, 111 personnel issues, in community practice setting, 456 Pert, C. B., 670 pethidine, 60, 206 phantom body pains, 42 Pharmaceutical Research and Manufacturers of America (PhRMA), 647. See also research in acute pain management pharmaceuticals, future use/development of, 672 pharmacists. See also Institute for Safe Medication Practices (ISMP) confrontations with physicians, over scheduled narcotics, 609 drug formulary management/policy development drug formularies, 609–610 medication guidelines, 610 therapeutic substitution programs, 610 drug selection, dosage, adverse effects allergy identification, 613 nonopioid analgesics, 612 opioids, 612–614 infusion device selection considerations, 610–611 intraspinal solution preparation, stability, sterility, 611–612 medication therapy management (MTM), 607–608 definition, 607 federal/state regulations, 607 medication reconciliation, 607–608 patient counseling, 607 problems of, 607 schedule II narcotics management, 608–609 USP MEDMARX program, 608

Index pain management education, 608 reduction of pain medication errors, 614–615 role in Acute Pain Management Services, 434–435 route of administration considerations for pain treatment, 611 standard order set development, 615–617 epidural infusions, 616 PCA orders, 616 pharmacodynamics alterations of, in elderly patients, 520–521 of local anesthesia, 73 pharmacokinetic drug (IV-PCA) delivery systems, 310–311 pharmacokinetics acetaminophen, 58–59 alterations of, in elderly patients, 520 anthranilic acids, 57 aspirin, 57 coxibs, 58 ketamine, 366 naphthylalkanones, 57–58 opioid analgesics, 310 opioids, epidural, 103–105 oxicams, 58 propionic acids, 57 pyrazolones, 57 phenacetin, 54 phenothiazines, 613 phenylephrine, 75, 78 physicians. See also anesthesiologists; emergency physicians acceptance of inevitability of pain, 165 compounding local anesthetics with additives, 70 confrontations with pharmacists, over scheduled narcotics, 609 influence of patient ethnicity on prescriptions, 34–35 observer scoring of patient pain, 150–151 opioid prescribing patterns (1992–2001), 114 and recent prominence of pain management, 114 piritramide, 106 piroxicam, 58, 334 analgesic effects of, 61 efficacy of, in preemptive analgesic therapy, 344 evaluation for postoperative pain usage, 335–339 half-life of, 58 oral postoperative use of, 345 sublingual, for inguinal hernia repair, 345 Pleym, O., 35 Pluijms, W. A., 27 POBD. See postoperative bowel dysfunction (POBD) POI. See postoperative ileus (POI) Pomeranz, B., 397 popliteal sciatic nerve block complications, 280 nerve stimulation technique, 276–277

pearls, 277, 280 ultrasound guidance technique, 277–280 Portenoy, R. K., 118 positive emission tomography (PET) scanning, 12 postcesarean analgesia epidural analgesics adjuvant therapy, 539, 542 lipophilic opioids, 538–539 fentanyl, 538–539, 542 hydromorphone, 539 meperidine, 539 sufentanil, 539 morphine, 538 side effects, 539–542 intrathecal analgesics, 543 adjunct therapy, 544 IV-PCA, 538, 544–545 multimodal therapy, 545 neonatal considerations, 545–548 posterior aspect of the anterior cingulate gyrus (PAACG), 13–14 postoperative analgesia, in outpatients ankle block, 295 axillary brachial plexus block, 292 fascia iliaca block, 294 femoral nerve block, 293–294 ilioinguinal/iliohypogastric nerve block, 296 infraclavicular brachial plexus blocks, 289–290 intercostal nerve block, 296 interscalene nerve block, 289–290 intravenous boluses of fentanyl/ morphine/hydromorphone, 196 lumbar plexus blocks, 293 paravertebral nerve block, 295–296 sciatic nerve blocks distal, in popliteal fossa, 295 proximal, 294–295 supraclavicular nerve block, 289–290 wound infiltration for, 296–298 postoperative bowel dysfunction (POBD), 583–584, 586–587. See also colectomy; postoperative ileus (POI) postoperative cognitive dysfunction (POCD)/postoperative delirium in elderly patients, 515–517, 523–526 postoperative hypersensitivity state (“spinal windup”), 172–173 postoperative ileus (POI) associated complaints, 583–584 defined, 583 emerging therapies for, 586–587 Postoperative Ileus Management Council, 583 postoperative nausea and vomiting (PONV). See nausea and vomiting postoperative pain. See also intravenous patient-controlled analgesia (IV-PCA); patient-controlled

701 analgesia (PCA); individual analgesics throughout the index and alpha-2-adrenergic receptors, 85 anxiety as predictor of, 42 APMS management of, 435 consequences of lack of relief, 172 developmental factors for, 25 and epidural morphine/local anesthetics, 117 evidence of, 109 future management of, 671–672 goal (primary) for relief of, 172 interventions for decreasing, 110–112 and ketamine/NMDA receptor agonists, 91 and NSAID use, 346 and pain catastrophizing, 44 in patients receiving IV/oral opioids, 29 persistent, following thoracotomy, 27 predictors of, 110 use of paravertebral block, 111 and use of PCA in children, postsynaptic tyrosine kinase b (TrkB) receptors, 17 Powers, R. D., 556 Practice Change Program (University of Wisconsin at Madison), 604 preemptive analgesia, 36, 173–175 with alpha-2 agonists, 177 with alpha-2-delta ligands, 182 with COX-2 inhibitors, 478–479 with local anesthetics, 180–181 with NMDA antagonists, 174–175, 179 with NSAIDs, 178 with opioids, 182 prefrontal cortex (PFC), and acupuncture, 395 pregabalin. See also gabapentin and pregabalin for ambulatory surgery, 481 with celecoxib, 383 linear kinetics of, 246 pre-incisional use of NSAIDS, for surgical pain, 342–346 preoperative pain, and NSAIDs, 342–344 preparation in community practice setting, 456–458 interdisciplinary approach, 457–458 ancillary staff, 457 nonsurgeon physicians, 457–458 nurses/nursing extenders, 457 public, 457 surgeons, 458 preventive multimodal analgesia. See also preemptive analgesia with acetaminophen/NSAIDs, 177–178 with alpha-2 agonists, 176–177. (See also clonidine; dexmedetomidine) with alpha-2-delta ligands, 182. (See also gabapentin and pregabalin) benefits for knee surgery, 183 with local anesthetics/regional anesthesia, 179–181 epidural block, 180 peripheral nerve block, 180

702 preventive multimodal analgesia (cont.) wound infiltration, 179–180 with NMDA receptor antagonists, 179. (See also dextromethorphan; ketamine; magnesium) with opioids (central/peripheral), 181–182 prilocaine, 72 and methemoglobinemia, 78 onset of action, 72 primary hyperalgesia. See also central sensitization; opioid-induced hyperalgesia (OIH); peripheral sensitization; secondary hyperalgesia described, 3–4, 6, 21 and prostaglandins, 177 role of NO, 16 and spinal windup, 172–173 procaine additive to epinephrine, 75 lipophilicity of, 72 metabolization to PABA, 76 procedural sedation and analgesia (PSA), for the emergency department (ED), 592–594 ProDalfganTM (intravenous acetaminophen), 481 Prominject PCA infusion pump, 204, 303 propionic acids, pharmacokinetics of, 57 propofol for ambulatory surgery, 368 for emergency room use, 592–594 propoxyphene, for mild to moderate pain, 612–613 PROSPECT (Europe) project, 483, 634–635 prostaglandin endoperoxidase synthesis (PEH), 54 prostaglandins (PGEs) AA conversion to, 5–6 analgesic effects on CNS, 28 and central sensitization, 15, 177 CGRP enhancement of, 7 exacerbated inflammatory responses from, 28 and excitotoxicity, 15 inhibition of synthesis by NSAIDs, 177 mechanisms of action, 55–56, 63 analgesic effects, 56 neutrophil aggregation, inhibition of, 55–56 synthesis, inhibition of, 55 mediation of presynaptic/postsynaptic plasticity changes, 15 physiology of, 54–55 catabolism, 54–55 synthesis, 54 and renal function and blood flow, 65 and NSAIDs, 65–66 prostaglandin physiology, 65 renin/vasopressin, interaction with, 65 and tubular function, 65 and transcription dependent central sensitization, 10

Index prostanoids CNS synthesis control of, 15 and GlyRa3 activation, 15 importance in central sensitization, 17 protein kinase activation, and analgesic tolerance to opioids, 119–120 proximal sciatic nerve block, 294–295 pruritus management of, from PCA use, 214, 306, 412 nalbuphine for, 539–540 naloxone for, 237, 412, 540 from opioids, 133, 199, 223, 237, 332, 377, 407–408, 411, 539, 542 psoas compartment block, 267–268 complications, 269 pearls, 269–270 peripheral nerve stimulation, 268–269 ultrasound guidance, 269 pSTT (paleo neo-spinothalamic tract), 12 psychological aspects of pain. See also cognitive-behavioral therapy (CBT) anxiety factor, 42–43 and fear, 43 catastrophizing of pain, 44 conceptual background, 41–42 future directions, 49–50 impact on pain management, 35–36 social contexts, 44–45 psychological interventions cognitive-behavioral therapy (CBT), 46–47 distraction, 45–46 hypnosis, 47–48 virtual reality, 48–49 psychological techniques for sickle-cell pain, 553 psychoprophylaxis, 384 Pud, D., 122 pulmonary system. See also respiration/respiratory rate; respiratory depression (opioid-induced) postoperative pulmonary complications (PPC), 639–640 pulmonary embolism, 25, 641 pulse oximetry Alaris System PCA module, 311 for monitoring cesarean delivery, 543 in emergency department, 593 respiratory depression, 213, 416–417, 424 with smart pump technology, 321 pyrazolones, pharmacokinetics of, 57 quality/quality improvement (QI). See also Acute Pain Service (APS)/Acute Pain Management Service (APMS) American Pain society recommendations for quality improvement, 665 studies/evaluations, 665

APMS/nurse practitioners, role of, 434 clinician’s behavior, approaches for changing, 667 continuous programs for development, 660–663 implementation, 663–664 maintenance, 664 Continuous Quality Improvement (CQI), 311 definition, 148, 655 epidural analgesia, benefits to, 29, 180 femoral-sciatic nerve block, benefits to, 294 GuardrailsTM software, 311 historical background on initiatives, 659 indicators and measures, 664–667 ambulatory settings, 666–667 patient safety, 665–666 lack of clinical evidence, 133–134 measurement of, in health care, 655–656 methodology, 656–658 Lean methodology, 658 PDSA cycle, 656–657 Six Sigma process, 657–658 NSAIDs, for improved quality of recovery, 311 Patient Safety and Quality Improvement Act (2005), 666 perioperative treatments, long-term consequences, 82 quality management (QM), 434 Quality Management Template (ASA), 474 and validity issues Agency for Health Care Research and Quality, 176 in evidence-based medicine, 632 for nurses, as clinical coordinators, 603 QUOROM (Quality Of Reporting Of Meta-analysis) statement, 632 Raimer, C., 268 Ramsay score (RS), sedation scale, 425 randomized controlled trials (RCTs) cardiovascular morbidity, 639 coagulation-related morbidity, 642 CORTRA meta-analysis (neuraxial anesthesia vs. general anesthesia), 637–638 and evidence-based medicine, 631 gastrointestinal morbidity, 641 as “gold standard” of clinical trials, 651 Multicentre Australian Study of Epidural Anesthesia, 638 on postoperative analgesia, 637 on preemptive analgesia, 174–175 on static magnetic therapy, 400 Veterans Affairs Cooperative Studies Program, 638 Rapp, S. E., 117 Rawal, N., 296–297, 538 Ready, L. B., 232, 417, 543 “Recommendations for Improving the Quality of Acute and Cancer Pain Management” (APS), 665

Index regional analgesia administration options, 440 economic considerations, 440 epidural/continuous, for sleep disturbances, 29 and improved perioperative outcomes, 531 interference with start of surgery, 438 and local anesthetics, 179–181 with local anesthetics for epidural block, 180 for peripheral nerve block, 180 for would infiltration, 179–180 vs. opioid-based analgesia, 521–523 patient controlled regional analgesia (PCREA), 251 for postoperative pain, 575 use of COX-2 inhibitors/NSAIDs, 29 regional anesthesia. See also axillary brachial plexus block; elbow blocks; infraclavicular brachial plexus blocks; interscalene nerve block; lumbar plexus blocks; multimodal analgesia; peripheral nerve blocks of upper limb; postoperative analgesia, in outpatients; sacral plexus blocks; supraclavicular nerve block; wrist block as adjuvant to opioid therapy, 132 for cesarean delivery, 537 chloroprocaine for, 72 clonidine for, 75, 85, 176 continuous, suppression of sympatho-adrenal responses, 28 deafferentation by, prior to surgery, 36 decreased wake-up times with, 438 as fastest growing subspecialty, 437 vs. general anesthesia, 245 and inhalational anesthesia, 174, 179 integration into acute pain management, 436 intraoperative considerations, 129 local anesthesia/anesthetics with for epidural blocks, 180 for peripheral nerve blocks, 180 for wound infiltration, 179–180 logistics/equipment needed for performance of, 246–247 non-specific binding by nearby membranes/tissues, 73 for patients on chronic opioid therapy, 132 perioperative, and reduction of regional pain syndrome, 134 with postoperative COX-2 inhibitor, 183 for postoperative pain, in opioid-dependent patients, 575 for sickle cell disease, 557 single-injectional, 180 ultrasound revolutionizing of, 440 regional cerebral blood flow (rCBF), 12 remifentanil (mu-opioid agonist), 38, 116, 122, 368–369 for abdominal surgery, 122 for IV-PCA use, 206 for PCA/IV-PCA use, 305

tolerance to, 117 use, for ambulatory surgery, 368 renal function effects of NSAIDs vs. COX-2 inhibitors, 356 side effects of NSAIDS, 65–66 prostaglandin physiology, 65 renal blood and prostaglandins, 65 renal tubular function and prostaglandins, 65 renin/vasopressin, interaction with, 65 renin/vasopressin/interaction with, 65 and tubular function, 65 research in acute pain management believability of results, 651–653 clinical trials appropriate conduction determination, 647 author establishment of testability/clinical relevance, 647 Bonferroni Correction, 653 Kaplan-Meier survival curves, 653 Kruskal-Wallis one-way analysis of variance, 653 One-Way Analysis of Variance, 653 primary efficacy variable definition, 647–651 pain measurement, 649 significant pain reduction, 649 summary measures, 650–651 purpose of, 646–647 Spearman’s Rank Correlation, 653 Type I errors, 652 Type II errors, 652–653 Wilcoxon Signed Rank test, 653 study design influence on interpretation, 651 “resistance stage” (sympatho-adrenal response), 22 respiration/respiratory rate anatomy/physiology of, 418–419 fentanyl’s influence on, 192 hydromorphone’s influence on, 232 increase of, as response to pain, 25 naloxone’s influence on, 236 role in monitoring respiratory depression, 162–164, 209, 417 respiratory depression (opioid-induced) definition/incidence (in perioperative period), 416, 418 effects of opioids, 332, 406–407 measurement of, 420–421 mechanisms of, 419–420 monitoring, 422–424 capnography, 424 guidelines, Acute Pain Services, 417 by pharmacists, 613 pulse oximetry, 424 respiratory rate, 424 prediction of in postoperative setting, 425–426 risk factors epidural analgesia, 226, 236 neuraxial opioid administration, 236, 407

703 parenteral opioids, 418 PCA, 213–214, 417 sedation as early indicator, 411, 416–417 sedation scores, role of, and sleep disturbances, influence on, 421–422 treatment of, 241–242 DPI-125, 412 DPI-3290, 412 nalbuphine, 407 naloxone, 236, 242, 407, 613 naltrexone, 407 Reuben, S. S., 383, 478, 481, 676 Richman, J. M., 289 Riker Sedation-Agitation Scale, 162 risk factors of epidural analgesia catheter problems, 224–226 dural puncture, 225 epidural hematoma, 225–226 hypotension, 226 infection, 226 motor block, 226 respiratory depression, 226, 417 of IV-PCA therapy, 306 linked to development of persistent pain, 483 for persistent pain development, 27 Robertson, K., 538 Rodgers, A., 245 Roe, B. B., 670 rofecoxib, 53, 235. See also celecoxib for abdominal surgery, 350 affinity for COX-1, 58 for colectomy, 585–586 with dexamethasone, 382 gastrointestinal (GI) outcome research study (VIGOR), 355 removal from market, 63, 235, 346, 480 side effects of, 65 in surgical pain, 347–350 vs. valdecoxib, 353 VIGOR research study, 355 Rogers, M. L., 110 Roland Disability Questionnaire, 44 Romberg, R., 37 Romundstad, L., 379, 381 ropivacaine, 72 as adjuvant, for postcesarean analgesia, 539 for brachial plexus blocks, 73, 112 combinations with fentanyl infusion, 233 morphine, 234, 315 continuous infusions, 233 with fentanyl, 233 with morphine, 234 epidural administration of, 224 onset of action, 72 selectivity for sensory fibers, 74 use of, for motor block, 226 Rosen, M. A., 539 Rosenberg, J., 422 Ross, R., 539

704 Rossbach, M., 121 Royal College of Anesthesiologists, 634 Saarela, M. V., 45 Sachar, E. J., 302, 670 sacral plexus blocks, 274–280 infragluteal sciatic nerve block, 276 popliteal sciatic nerve block, 276–280 sciatic nerve block, 274–276 distal, in popliteal fossa, 295 pediatric patients, 507–509 proximal, 294–295 safety issues Anesthesia Patient Safety Foundation (APSF), 213 COX-2 (cyclo-oxygenase-2) inhibitors, 355 epidural opioids, 239 hydromorphone, 239 for IV-PCA therapy, 306–308 accidental purging protection, 306–307 bar-code readers, 307 computer-based pump programming, 307–308 error-reduction features, 307 overmedication, 306 respiratory depression, 306 JCAHO goals, 608 neonatal considerations/acetaminophen, 58 neuraxial analgesia, patient controlled systems, 317 perineural ambulatory analgesia systems, 319 salicylates historical background, 53 inhibition of prostaglandin synthesis, 591 side effects, 57 Samad, T. A., 16 Sanchez, B., 297 Sandler, A., 105 Sartain, J.B., 207 schedule II narcotics management, by pharmacists, 608–609 Schug, S. A., 425 sciatic nerve block, 274–276 distal, in popliteal fossa, 295 pediatric patients, 507–509 proximal, 294–295 single-injections/techniques, 298 Scimeca, M. M., 566 SCN9 gene mutation, 674 scopolamine patch (transdermal), for nausea/vomiting, 237, 410, 613 Scott, D. A., 105 Scott, J. S., 670 Sechzar, P. H., 670 Sechzer, Phillip, 302 secondary hyperalgesia, 3–4, 102. See also central sensitization; opioid-induced hyperalgesia (OIH); peripheral sensitization; primary hyperalgesia defined/described, 4, 21–22, 370 gabapentin and pregabalin for, 480

Index and peripheral/central sensitization, 172–173, 370 and prostaglandins, 177 role of nitric oxide, 16 role of NO, 16 and spinal windup, 172–173 underlying spinal mechanisms, 91 Woolf on, 5 secondary somatosensory cortex (SII), Sedlacek, K., 554 Seib, R. K., 480 selective serotonin reuptake inhibitors (SSRIs), 17 self-hypnosis, 47 sentinel node biopsy, 111 serotonin acupuncture’s influence on, 395 PENS/TENS, 397 agonists of, for pruritus treatment, 412 ketamine (systemic) effect on, 91 meperidine’s effect on, 195 for nausea/vomiting, 410, 613 and OIH, 124 release of, stimulated by PAG/RVM, 102 role in pain, 14 sensitization of nociceptors, 21 tramadol’s inhibition of uptake of, 306, 495, 555, 591–592 Seventh American College of Chest Physicians Consensus Conference, 246 sevoflurane, for ambulatory surgery, 368 Seyhan, T. O., 384 Shapiro, B., 552, 557 Shaw, I., 422 Short-Form McGill Pain Questionnaire (SF-MPQ), 157 Sia, S., 255 sickle cell disease background/description, 550 in children, 551 assessments, 551–552 chronic pain in, 557 medical management of, 552–553, 558 antibiotics, 553 blood transfusions, 552–553 oxygen, 552 sickling inhibition compounds, 553 nonpharmacologic approaches, 553–554 cognitive-behavioral techniques, 553–554 educational/psychological techniques, 553 hypnotherapy/biofeedback, 554 medical report passport system, 554 TENS/physical therapy, 554 pain assessment for, 551–552 ethnicity of patients/providers, 552 general considerations, 551–552 sickle-cell specific considerations, 552 pathophysiology of, 550–551 pharmacologic approaches, 554–557 adjuvants, 557 nonopioid analgesics, 554–555

NSAIDs, 554, 558 opioids, 555–556 patient controlled analgesia, 556–557 regional techniques, 557 treatment barriers, 557–558 Sidebotham, D., 425 side effects of aspirin, 57, 63, 66 aspirin-sensitive asthma, 66 hepatoxicity, 66 peptic ulcers, 63 of benzocaine, 78 of cannabinoids, 384 of codeine, 195 of epidural opioids, 236–237 liposomal morphine, 223 for postcesarean analgesia, 539–542 fentanyl, 194, 391, 409, 571 of fentanyl, 194, 391 of glucocorticoids, 382 of hydromorphone, 194 of interscalene nerve block, 290 of ketamine, 366 of local anesthetics, 76–78 of meperidine, 195 of methadone, 194–195 of morphine, 193, 391 of neostigmine, 384 of NSAIDS, 62–66 cardiovascular system, 63 gastrointestinal system, 63–64 platelet clotting function, 64–65 renal function, 65–66 of opioids/opioid-related adverse events, 199–200, 377, 391, 406 cardiovascular, 406 dermatological, 411–412 gastrointestinal, 407–408 genitourinary, 411 nausea/vomiting, 408–411 neurological, 411 respiratory, 406–407 reduction of, as concern for future, 672 salicylates, 57 Sinatra, R. S., 481, 576 Singelyn, F. J., 297 single (S-) enantiomers, 72 single-injections/techniques anesthesiologists and, 132–133 of clonidine, 87 dosages of long acting medications, 439, 467 intrathecal administration of single boluses of opioids, 230–233 of ketamine, 366, 369 of morphine epidural, extended-release, 106 with liposomes, 223 of peripheral nerve blocks axillary brachial plexus, 292 femoral nerve block, 294, 297, 467 interscalene block, 290 lower limb, 266 lumbar plexus, 268

Index for postoperative pain, 288 sciatic nerve block, 298 upper limb, 247 of regional anesthesia, 180 single-voxel proton magnetic resonance spectroscopy (H-MRS), 14 Six Sigma process, for quality/quality improvement, 657–658 Sjostrom, S., 233–234 S(+)ketamine, 91–92 Slappendal, R., 342–344 sleep disturbances, 27. See also American Academy of Sleep Medicine Task Force apnea, defined, 422 attenuation of pain induced pathophysiology, 29 improvements from epidural analgesia, 29 obstructive sleep apnea (OSA) from opioid use, 377, 421 use of OCA without background infusion, 211 from opioid use, 377, 411 and respiratory depression, 421–422 Smith Medical CADD-Prizm PCS IITM (ambulatory pump), 313–314, 317 social contexts of pain, 44–45 facial expressions of others in pain, 44–45 parental relation to children’s pain, 45 warning patients of pain, impact of, 45 Society of Critical Care Medicine (SCCM), 162 Society of Obstetric Anesthesia and Perinatology (SOAP), 537 somatic nociceptive pain, 3 Sparks, L., 45–46 specificity theory (Descartes), 4 SPID. See summed pain intensity difference (SPID) spinal windup (postoperative hypersensitivity state), 172–173 spinothalamic tract (STT), 12 spring-powered pumps (non-electric infusion devices), 320–321 R Stadol , 195 Stevens, R. D., 268 Stone, Edward, 53 stressors (psychological) descending inhibition by, 14 role in pain experience, 42. (See also neuromatrix theory of pain) structures of local anesthetics, 72 Strulov, L., 44 subjective sedation-assessment scales, 162 R Suboxone (sublingual buprenorphine), 566 substance abuse (by patients), impact on pain management, 37 Substance Abuse and Mental Health Services Administration (SAMHSA), 391 Substance-P (sP), 6 substance use disorder (SUD), 564, 568 basic aspects criteria/definitions, 567 opioid tolerance, 567

patient assessment issues, 567–570 physical dependence, 567 patient management goals/strategies, 570–571 opioid medications, 571–572 perioperative management dose tapering, 575–576 intraoperative period, 574 postoperative period, 574–575 neuraxial analgesia, 575 regional analgesia, 575 preoperative period, 574 R Subutex (sublingual buprenorphine), 566 sufentanil for ambulatory surgery, 574 clinical trials, 106 description, 195–196 diffusion into epidural fat, 222 efficacy at mu receptors, 190 elderly sensitivity to, 521 epidural administration, 223, 370 impact on OIH, 133 lipophilicity of, 106, 133, 409, 539 for PCA/IV-PCA use, 304–305 for postcesarean delivery, 539 intrathecal administration, 543 and preoperative methadone, 133 Sumerians, cultivation of opioids, 114 summed pain intensity difference (SPID), 650 superoxide dismutase (SOD) description, 16 and excitotoxicity, 15 superoxides (SO) mediation of central sensitization, 16 and NMDA receptor activation, 16 supraclavicular nerve block, 251–253, 290–291 block techniques nerve stimulation technique, 251–252 ultrasound guided technique, 252–253 complications of, 253 postoperative analgesia in outpatients, 289–290 Sweitzer, S. M., 124 Swenson, J. D., 571 Swinkels-Meewisse, I.E.J., 43 sympathetic nervous system alpha/beta receptor mediation of, 82 morphine’s influence on, 406 post surgical hypertension and, 514 stimulation of, effect on gastrointestinal tract, 584 tonic inhibitory control of inflammation, 89 sympatho-adrenal system pathophysiological pain response, 22–23 accelerated coagulation, 23 diminished microcirculatory blood, 23 increased peripheral vascular resistance, 23 increased post-surgical hypertension, 23 renal hypoperfusion, 23 synthesis of prostaglandins (PGEs), 54

705 Tampa Scale of Kinesiophobia, 43 Tamsen, P., 36 Task Force on Acute Pain Management (American Society of Anesthesiologists) advocacy for multimodal analgesia, 176, 478 Taylor, S., 421 temporomandibular disorders (TMD), 44 tenoxicam for abdominal surgery, 346 analgesic effects of, 61 efficacy of, in preemptive analgesic therapy, 344 half-life of, 58 intravenous, for cesarean section, 346 peak synovial fluid concentrations, 62 postoperative use, 345–346 TENS. See transcutaneous electrical nerve stimulation (TENS) Teoh, W. H., 234 Teschemacher, H., 222 tetracaine for elective hip/knee arthroplasty, 232 intrathecal administration, 234 lipophilicity of, 72 onset of action, 72 pKa properties, 72 prolongation of use via intrathecal clonidine, 75 tetrodotoxin (from Japanese Puffer fish), 383 THC. See 9-tetrahydrocannabinol (THC) theories of pain Gate control theory (Melzack/Wall), 4–5 intensity theory (Sydenham), specificity theory (Descartes), 4 of Woolf, 5 therapeutic touch (TT)/massage therapy, 400–401, 488, 571 historic background, 400 osteopathic manipulation (OMT), 401 thermal hyperalgesia, 3–4, 6–7 Thomas, J. S., 43 Thomas Jefferson University Hospital, 616 thoracotomies, 23, 25, 36, 370 clinical trials/epidural analgesia, 111 functional epidural catheter use, 241 hydromorphone for, 237 intrathecal morphine use, 232 meperidine by PCA, 36 osteopathic like practices, 401 and pain chronic, 109, 111, 370, 642, 675 chronic persistent, 134 persistent, 27 types of incisions, 111 3 step analgesic ladder for cancer pain (WHO), 147 tizanidine, 383 Tobias, J. D., 117 Todd, K. H., 160 “To Err is Human” study (Institute of Medicine), 655 Torgeson, W. S., 156

706 Torrie, J. J., 425 total hip arthroplasty (THA) benefit of lumbar plexus block for, 268 clonidine/local anesthetic for, 176 EREM for, 328 intramuscular morphine for, 197 IV PCA/iontophoretic fentanyl for, 206 rectal indomethacin for, 346 total knee arthroplasty (TKA) benefit of lumbar plexus block for, 267 femoral/sciatic nerve block, 271, 455, 467 intrathecal clonidine/morphine for, 176 ketamine, low dose, 179 multimodal analgesia, 459 valdecoxib/morphine for, 353 TOTPAR (time-weighted resultant summation value), 650. See also research in acute pain management R tramadol. See also Ultracet for children, 494 combined with acetaminophen, 198–199, 591–592 description, 195 inhibition of uptake of serotonin, 306 for IV-PCA use, 206, 305–306 postoperative use, 346 for sickle cell disease, 555 tranquilizer abuse, 565 transcutaneous electrical nerve stimulation (TENS), 384–385, 392, 397–399 for ambulatory surgery, 482–483 historical background, 397 mu receptor mediation of, 397 and naloxone, 397 research studies of, 398 and serotonin, 397 for sickle-cell disease, 554 side effect reduction through, 399 transdermal therapeutic systems (TTS), 323–325 alternatives to, 325–329 extended release epidural morphine (EREM), 327–329 fentanyl iontophoretic transdermal system, 326–327 iontophoresis, 326–327 lidocaine iontophoresis, 327 clonidine patches, 324 diclofenac epolamine patch, 324–325 fentanyl patches, 324 design modifications, 325 IONSYSTM (fentanyl iontophoretic transdermal system), 197, 206, 326–327 lidocaine patches, 324 mechanisms of action, 323 scopolamine patch, 237, 410, 613 transient receptor potential V1 (TRPV1), 672 Treiber, H., 230 Tryon, W. W., 554 tumor necrosis factor (TNF-alpha) and allodynia, 25 post-surgical increase, 28

Index Turner, J. A., 44 Ty, T. C., 41 Ulrich, R. S., 50 R Ultracet , 198 ultrasound guidance axillary brachial plexus block, 258–259 elbow blocks, 262 femoral nerve block, 271–273 infraclavicular brachial plexus blocks, 254 interscalene nerve block, 250–251 popliteal sciatic nerve block, 277–280 psoas compartment block, 268–269 wrist block, 266 Umrey, W. F., 249 underreporting of/undertreatment for pain, 160, 165 University of Kentucky, PCEA technique evaluation, 235 University of Wisconsin at Madison Practice Change Program, 604 urology surgery, 36 urticaria, from opioid histamine release, 411 Usichenko, T. I., 396 USP MEDMARX program, 608, 614 valdecoxib, 54, 334. See also parecoxib analgesic effects of, 61, 350–353 with parecoxib, for laparoscopic cholecystectomy, 353, 480 removal from market, 346, 355, 480 side effects of, 355 Vandermeulen, E., 246 Vane, John, 55 vanilloids, 672 Varni-Thompson Pediatric Pain Questionnaire, 552 vascular system, pathophysiological pain response, 25 vasoconstrictors, as additive to local anesthetics, 75 vasodilators, properties of, 76 verapamil (calcium channel blocker), 221, 224 Vera-Portocarrero, L. P., 124 Verbal Descriptor Scale (VDS), 151 Verbal Rating Scale, 649 Veterans Hospital Administration, 5th Vital Sign strategy implementation, 148 Villa, H., 476 Virchow’s triad (hypercoagulability, venous stasis, endothelial injury), 25 virtual reality (management strategy), 48–49 visceral nociceptive pain, 3 Viscusi, E. R., 311 Visual Analog Scale (VAS), 151, 153, 162, 649 Von Dossow, V., 89 Wachta, M., 481 Walch, J. M., 50 Walco, G. A., 551 Walder, B., 207, 305 Wall, P. D., 4–5, 41, 109, 174, 394

Wallerian degeneration, 4 Wang, H., 16 Weinberg, R. J., 16 White, P. F., 235–236, 295 white patients, 34 Williams, B. A., 270, 294 Williams, S. R., 253 willow tree (Salix alba), 53. See also salicylates Wilson, J. E., 590 “windup” transcription process, 6 onset/reversibility of, 15 Winnie, Alon, 248, 251, 267–269 Wong-Baker FACES Rating Scale, 154 Woodhouse, A., 206, 210 Woolf, C. J., 5, 9–10 World Health Organization (WHO) acetaminophen recommendations, 356 approval of acupuncture, 393, 395 on decision-making about opioids, 631 endorsement of evidence-based medicine, 630 3 step analgesic ladder for cancer pain, 147, 391 would infiltration ketamine enhancement of bupivacaine, 91 by local anesthetic, 174–175 with ketamine, 179 with regional analgesia, 179–180 for postoperative analgesia in outpatients, 296–298 wrist block, 262–266 block techniques blind, 264–265 peripheral nerve stimulation, 265 ultrasound guidance, 266 complications of, 266 wrist anatomy, 264 Yale Medical School, 166 Yale-New Haven Hospital celecoxib dosing guidelines, 480 4-step analgesic ladder, 147 intrathecal morphine administration, 230 with bupivacaine, 234 regional anesthesia for cesarean delivery, 537 use of continuous epidural infusions/PCA, 237 Yale Pain Management Service, 199 epidural PCA orders/patient management guidelines, 240–242 management of Epi-PCA, 241 treatment of respiratory depression (and other adverse effects), 241–242 Yaster, M., 557 Youngstrom, M., 538 Yuan, C. S., 408 Zayfert, C., 43 Zeltzer, L., 554 Zubieta, J. K., 14

Functional measures A. Brain areas functionally related to pain processing.

(3) (2) Inf. Par

SI (1)

DLPFC

ACC

Pro. Mot (2)

(1) 5.II

(3) OFC

Insula (1+2) Hip/Ento (3)

SI Med. PFC (5) ACC (1+2+3) PCC

A. Ins

ACC

P. Ins Hip

OFC

PCC

Sensory Affective

(1) Early Identification

Cognitive =

+

(2) Recognition & Immediate Reaction

=

+

(3) Evaluation & Sustained Behaviore

B. Example of functional MRI response to painful stimulation.

A. Ins ACC

PCC ACC

Insula

Thalamus

Figure 1.11: Cortical regions related to pain processing as determined by function Magnetic Resonance Imaging (fMRI). The highlighted areas have been found to be particularly active: (ACC) Anterior cingulate cortex, (S1) Primary somatosensory cortex (Primarily involved in pain localization), (S2) Secondary somatosensory cortex, (OFC) orbitofrontal cortex, (DLPFC) Dorsolateral prefrontal cortex, (Pre-Mot) Premotor cortex, (Med.PFC) Medial Prefrontal cortex, (P.Ins) Posterior insula, (A.Ins) Anterior insula, (Hip) Hippocampus, (Ento) Entorhinal cortex From: David Borsook, Eric A Moulton, Karl F Schmidt, Lino R Becerra Molecular Pain 2007, 3:25.

Figure 17.1: Anatomical dissection demonstrating the brachial plexus within the interscalene groove.

Figure 17.6: Anatomical dissection of the brachial plexus in the supraclavicular region.

Figure 17.13: Axillary block anatomy.

Figure 17.21: Elbow block anatomy.

Figure 17.26: Wrist block anatomy.

Figure 17.33: Femoral nerve lying on top of iliacus muscle as it passes under the inguinal ligament. Key: blue line = femoral vein; red line = femoral artery.

Figure 17.37: Branching of femoral nerve distal to the inguinal crease. Key: blue line = femoral vein; red line = femoral artery.