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Mission Statement of IASP Press速 The International Association for the Study of Pain (IASP) is a nonprofit, interdisciplinary organization devoted to understanding the mechanisms of pain and improving the care of patients with pain through research, education, and communication. The organization includes scientists and health care professionals dedicated to these goals. The IASP sponsors scientific meetings and publishes newsletters, technical bulletins, the journal Pain, and books. The goal of IASP Press is to provide the IASP membership with timely, highquality, attractive, low-cost publications relevant to the problem of pain. These publications are also intended to appeal to a wider audience of scientists and clinicians interested in the problem of pain.

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The Paths of Pain 1975–2005 Editors

Harold Merskey, DM, FRCP, FRCP(C), FRCPsych Professor Emeritus of Psychiatry, University of Western Ontario London, Ontario, Canada

John D. Loeser, MD Departments of Neurological Surgery and Anesthesiology, University of Washington, Seattle, Washington, USA

Ronald Dubner, DDS, PhD Department of Oral and Craniofacial Biological Sciences Dental School, University of Maryland, Baltimore, Maryland, USA

Editorial Committee

Jean-Marie Besson, DSc Sir Michael R. Bond, MD, PhD, DSc, FRSE, FRCS, FRCPsych Ronald Dubner, DDS, PhD Ulf Lindblom, MD, DMSc John D. Loeser, MD Harold Merskey, DM, FRCP, FRCP(C), FRCPsych Barry J. Sessle, MDS, PhD, DSC, FRSC Manfred Zimmermann, Dr-Ing, Dr med


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© 2005 IASP Press® International Association for the Study of Pain® All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by IASP®. Thus, opinions expressed in The Paths of Pain 1975–2005 do not necessarily reflect those of IASP or of the Officers and Councillors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends that there should be independent verification of diagnoses and drug dosages. Library of Congress Cataloging-in-Publication Data

Published by: IASP Press International Association for the Study of Pain 909 NE 43rd Street, Suite 306 Seattle, WA 98105-6020 USA Fax: 206-547-1703 Printed in the United States of America

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This volume is dedicated to Louisa E. Jones The authors and editors are pleased to dedicate this book to Ms. Louisa E. Jones. She is the key person in the development of IASP since its foundation in 1974. She has helped to translate the dream of John J. Bonica into the mature and flourishing association that we celebrate with this volume. Thirty-two years ago, Dr. Bonica organized an international meeting on pain that was held in a former convent in Issaquah, Washington. His administrative assistant for that critical meeting was Louisa Jones. When IASP was fully established, Louisa became its first employee as Executive Secretary. She has guided the development of our association with great skill, integrity, and wisdom. As our Executive Officer, she has played a crucial role in all of our activities. She has chosen to retire following the 2005 Congress, after 32 years of devoted service, and we will miss her greatly. Louisa will always be appreciated by this association, as will her unfailing commitment to its permanent place in science and medicine.

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Contents List of Contributing Authors Foreword Preface 1. 2.

3. 4. 5. 6. 7. 8. 9.

ix xiii xv

The History of Pain Concepts and Treatment before IASP Manfred Zimmermann


The History of the IASP: Progress in Pain Since 1975 Michael R. Bond, Ronald Dubner, Louisa E. Jones, and Marcia L. Meldrum


The Gate Theory, Then and Now Fernando Cervero


Molecular Basis of Receptors Michael S. Gold


The Study of the Genetics of Pain in Humans and Animals Jeffrey S. Mogil


Physiology and Anatomy of the Spinal Cord Pain System William D. Willis, Jr.


Plasticity in Central Nociceptive Pathways Ronald Dubner


Descending Modulation of Pain Michael H. Ossipov and Frank Porreca


Orofacial Pain Barry J. Sessle


10. A Thirty-Year Perspective on the Pathophysiology of Migraine Pain Rami Burstein, Dan Levy, and Moshe Jakubowsky


11. Glia and Pain: Past, Present, and Future Linda R. Watkins and Steven F. Maier


12. Pharmacology of Inflammatory Pain Andy Dray


13. Pharmacological Control of Pain: Non-Opioid Targets Anthony H. Dickenson and Jean-Marie Besson


14. Opiate Analgesia: The Last Forty Years Tony L. Yaksh


15. Neuropathic Pain: From the Nociceptor to the Patient James N. Campbell and Richard A. Meyer


16. Animal Models and Their Clinical Implications Gary J. Bennett


17. Sensory Quantification and Pain Ulf Lindblom


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18. Evaluation of Pain Sensations Richard H. Gracely


19. Brain Imaging of Pain: A Thirty-Year Perspective M. Catherine Bushnell


20. Central Pain Jörgen Boivie


21. Therapeutic Electrical Neurostimulation from a Historical Perspective Björn A. Meyerson and Bengt Linderoth


22. Terms and Taxonomy: Paper Tools at the Cutting Edge of Study Harold Merskey


23. Epidemiology of Pain Michael Von Korff and Linda LeResche


24. Musculoskeletal Pain James P. Robinson, Dean Ricketts, and David Hanscom


25. Neck Pain Nikolai Bogduk


26. Low Back Pain Gordon Waddell


27. From Fibrositis and Psychogenic Rheumatism to Fibromyalgia Harvey Moldofsky and Harold Merskey


28. Psychological Contributions to the Understanding and Treatment of Pain Frances J. Keefe, Kim E. Dixon, and Rebecca W. Pryor 403 29. Psychiatry and Pain: Causes, Effects, and Complications Harold Merskey


30. Children—Not Simply “Little Adults” Patricia A. McGrath


31. Neural Blockade and Neuromodulation in Persistent Pain Management Paul M. Murphy and Michael J. Cousins


32. Opioid Treatment for Cancer Pain and Chronic Noncancer Pain Dwight E. Moulin


33. Topical Agents for Neuropathic Pain: A Systematic Review C. Peter N. Watson


34. Multidisciplinary Pain Management John D. Loeser


35. The Future of Pain Therapy: Something Old, Something New, Something Borrowed, and Something Blue Allan I. Basbaum




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Contributing Authors Allan I. Basbaum, PhD Departments of Anatomy and Physiology and W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, California, USA Gary J. Bennett, PhD Department of Anesthesia, Faculty of Dentistry, and Centre for Research on Pain, McGill University, Montreal, Quebec, Canada Jean-Marie Besson, DSc INSERM Unit 161, Ambroise Paré Hospital, BoulogneBillancourt, France Nikolai Bogduk, MD, PhD Department of Clinical Research, Royal Newcastle Hospital, University of Newcastle, Newcastle, New South Wales, Australia Jörgen Boivie, MD Department of Neurology, University Hospital, Linköping, Sweden Michael R. Bond, Kt, MD, PhD, DSc, FRSE, FRCS, FRCPsych University of Glasgow, Glasgow, United Kingdom Rami Burstein, PhD Departments of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center; Department of Neurobiology and the Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA M. Catherine Bushnell, PhD McGill Centre for Research on Pain, Montreal, Quebec, Canada James N. Campbell, MD Department of Neurosurgery and Applied Physics Laboratory, Johns Hopkins University, Baltimore, Maryland, USA Fernando Cervero, MD, PhD Anaesthesia Research Unit, McGill University, Montreal, Quebec, Canada Michael J. Cousins, AM, MD, FANZCA, FRCA, FFPMANZCA, FAChPM (RACP) Pain Management Research Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia. Anthony H. Dickenson, PhD Department of Pharmacology, University College London, London, United Kingdom Kim E. Dixon, PhD, MBA Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA Andy Dray, PhD AstraZeneca Research and Development, Montreal, Quebec, Canada Ronald Dubner, DDS, PhD Department of Biomedical Sciences, University of Maryland Dental School, Baltimore, Maryland, USA Michael S. Gold, PhD Department of Biomedical Sciences, Dental School; Program in Neuroscience; and Department of Anatomy and Neurobiology, Medical School, University of Maryland, Baltimore, Maryland, USA


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Richard H. Gracely, PhD Chronic Pain and Fatigue Research Program, Departments of Internal Medicine, Rheumatology and Neurology, University of Michigan and VA Medical Center, Ann Arbor, Michigan, USA David Hanscom, MD Private Practice in Orthopedics, Seattle, Washington, USA Moshe Jakubowsky Departments of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center; Department of Neurobiology and the Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA Louisa E. Jones, BS International Association for the Study of Pain, Seattle, Washington, USA Frances J. Keefe, PhD Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA Linda LeResche, ScD Department of Oral Medicine, University of Washington, Seattle, Washington, USA Dan Levy, PhD Departments of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center; Department of Neurobiology and the Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA Ulf Lindblom, MD, DMSc Department of Clinical Neurosciences, Section of Neurology, Karolinska Institute; Gรถsta Ekman Laboratory for Sensory Research, Department of Psychology, Stockholm University, Stockholm, Sweden Bengt Linderoth, MD, PhD Department of Clinical Neuroscience, Section of Neurosurgery, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden John D. Loeser, MD Departments of Neurological Surgery and Anesthesiology, University of Washington, Seattle, Washington, USA Steven F. Maier, PhD Department of Psychology and Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado, USA Patricia A. McGrath, PhD Department of Anesthesia, Divisional Centre of Pain Management and Research, The Hospital for Sick Children; Brain and Behavior Program, Research Institute at The Hospital for Sick Children; and the Department of Anesthesia, The University of Toronto, Toronto, Ontario, Canada Marcia L. Meldrum, PhD John C. Liebeskind History of Pain Collection, Louise M. Darling Biomedical Library, and Department of History, University of California, Los Angeles, California, USA Harold Merskey, DM, FRCP, FRCPC, FRCPsych Professor Emeritus of Psychiatry, University of Western Ontario, London, Ontario, Canada Richard A. Meyer, PhD Department of Neurosurgery and Applied Physics Laboratory, Johns Hopkins University, Baltimore, Maryland, USA Bjรถrn A. Meyerson, MD, PhD Department of Clinical Neuroscience, Section of Neurosurgery, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden

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Jeffrey S. Mogil, PhD Department of Psychology and Centre for Research on Pain, McGill University, Montreal, Quebec, Canada Harvey Moldofsky, MD, FRCPC Professor Emeritus, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada Dwight E. Moulin, MD, FRCPC Departments of Oncology and Clinical Neurological Sciences, University of Western Ontario, and London Regional Cancer Centre, London, Ontario, Canada Paul M. Murphy, MB, MRCPI, FCARCSI Pain Management Research Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia. Michael H. Ossipov, PhD Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona, USA Frank Porreca, PhD Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona, USA Rebecca W. Pryor, BA Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA Dean Ricketts, MD Private Practice in Orthopedics, Bellevue, Washington, USA James P. Robinson, MD, PhD Department of Rehabilitation Medicine, University of Washington, Seattle, Washington, USA Barry J. Sessle, MDS, PhD, DSc, FRSC Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada Michael Von Korff, ScD Center for Health Studies, Group Health Cooperative, Seattle, Washington, USA Gordon Waddell, CBE, DSc, MD, FRCS Centre for Psychosocial and Disability Research, University of Cardiff, Cardiff, United Kingdom Linda R. Watkins, PhD Department of Psychology and Center for Neuroscience, University of Colorado at Boulder, Boulder, Colorado, USA C. Peter N. Watson, MD, FRCPC University of Toronto, Toronto, Ontario, Canada William D. Willis, Jr., MD, PhD Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA Tony L. Yaksh, PhD Department of Anesthesiology, University of California, San Diego, California, USA Manfred Zimmermann, Dr-Ing, Dr med Neuroscience and Pain Research Institute, Heidelberg, Germany

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Preface This volume is a commissioned work. The Council of the International Association for the Study of Pain (IASP) invited a group of editors to produce the volume to celebrate the 11th triennial World Congress on Pain, being held in Sydney 30 years after the 1st World Congress, held in Florence in 1975. This celebration was proposed because the IASP has flourished as an international institution, founded in unique circumstances as described in Chapter 2, evolving with advances in science and health care, and having an enormous influence, much greater than the number of its professional members might suggest. The association is a professional scientific, medical, and health care body that provides support for research, patient care, and education about pain throughout the world. In its chosen disciplines the IASP has become a beneficial influence in spreading knowledge about pain and encouraging research on pain in all its aspects. Such a claim should not be made lightly. It deserves or requires validation. We lack the temerity to claim that we have produced such validation in systematic social science and historical studies. That approach requires examination in depth of the state of pain medicine and other pain studies, including all the relevant sciences and clinical topics with their starting points and current end points. But there have been triumphs, as with the focus upon children’s pain (Chapter 30), that the association appears to have facilitated. Many other developments support a favorable view of what has happened over the past 30 years. We can, indeed, point to a number of indices of achievement between 1975 and 2005. First, there is the organization itself with its widespread membership and creation of chapters in 63 countries, only two or three of which had any sort of pain society, much less national chapters, before the start of the IASP. Notably, unlike most professional and scientific international organizations, the IASP was not founded by a group of existing societies from different countries, but came into being as an international body with specific purposes, thanks to the Herculean efforts of one individual, the late Dr. John J. Bonica, in raising the funds and persuading fellow scientists and clinicians to join his campaign. The widespread international presence is strongly sustained by the success of the association’s journal PAIN, which, by the usual criteria of early indexing, difficulty of access, number of papers, level of citation among its peers, and widespread recognition of the high standard of its contents, is xv

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unquestionably the leading journal in this field. It is also in the forefront among anesthesiology and neuroscience journals. In addition, the publications of IASP Press rank high in the world of medical science on pain. Other significant advances in knowledge and practice include the establishment of clinical definitions for clinicians that have largely proved acceptable. Thus, the IASP functions as a body that has developed a classification of pain disorders, has provided criteria for education and training in numerous disciplines, and has published valuable appraisals of the state of knowledge, as in the series Pain: Clinical Updates. The aim of this book is to show, within a limited space, how matters stood concerning knowledge of the many fields in which pain is important, in basic science, in clinical knowledge, and in health care, when the IASP started and where matters stand now. One book of the present size cannot adequately accommodate enough individual chapters to exhaustively appraise the changes that have occurred and the influence the IASP may have had in bringing about these changes. But what has happened in those 30 years is exciting in the history of knowledge and the progress of medicine, and to be able to provide a chronicle of those changes is a wonderful opportunity that allows us to display at least a portion of the progress, the arguments and the advances, the efforts and their outcome that we have witnessed in the life of the IASP. Accordingly, the editors and the editorial committee agreed upon a series of chapters, each of limited length, with some economy of references but precision of report, that would display the evolution of ideas and information for these 30 years. Hard choices had to be made about topics that were left out, which ideally would have better rounded out the accounts now offered. Some of the editors’ own favorite themes have been omitted because we strove to give a representative account without hoping unrealistically for an amply comprehensive statement. We offer sympathy to those who feel justice was not done to their particular focus of interest and seek a little sympathy in return for our efforts at self-restraint. The editors also want to acknowledge on behalf of the authors of chapters that many of them were obliged to omit material and references that they clearly took to be important. The first chapter provides a highly focused historical account from the early modern period to the second half of the 20th century. The second chapter outlines the development, growth, success, and challenges of the IASP. Most other chapters start with an attempt to characterize the state of knowledge in 1975 and then move at varying speeds to the evolution of knowledge and our current situation. As editors we have not thought it practicable to set quotas on what proportion of each chapter should be devoted respectively to past, present, and future. We would like to believe that most readers will find this approach appropriate and interesting. Should

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we comment more often on how things did develop or where they are going? As we are historians here, we will avoid prediction. The benefit of historical study is well understood to be as a guide for the student to avoid, if possible, repetition of the errors of the past, and not to pretend to be wise enough to prevent new cases of error, which must be frequent in prophecy. Difficulty in forecasting is particularly strong when it comes not so much to specific remedies as to organizational and social change. The final chapter of this volume looks ahead to see where the developments of knowledge to date may lead the world in biological knowledge and remedies for pain. We will not expand on this comment, but we should note as well the importance of psychological skills, not just in helping to explain pain, nor in curing it, but rather in helping to ease and support the patients and families who suffer through the maze of problems and the prolonged and often intense distress of severe chronic pain. We think it fair to claim that the international movement to help patients with pain, and to better understand the sources and causes of pain, has contributed to the atmosphere of respect for patients’ pain, some reduction in the denigration or disparagement of pain, and a better recognition in many countries with which we are acquainted, and that have chapters of the IASP, that pain can be relieved. To avoid the appearance of complacency, we emphasize that much more remains to be done for the relief of pain than has so far been accomplished from all sources, but that the association has, by its very existence, recognized and supported the dignity of the patient with pain. It is evident that that is not enough. No one expects to complete this task, but the principle of the association is that everyone should continue to contribute to it. We thank the Council of the IASP for the wonderful opportunity to organize and display something of the state of knowledge on pain as it has existed and changed over the last 30 years. In so far as the association has been influential, so do we in turn feel privileged at the opportunity to edit the present volume. We thank all the authors who provided chapters under strict conditions, agreeing to sacrifice some of their most attractive material in order to allow everyone else to have a fair opportunity to present their topics. We are grateful to Pfizer Limited for their generosity in funding this volume with an unrestricted grant, which meant that we were free to deal with any topic that we thought appropriate without reference to any of the interests of the donor. We thank as well the other members of the editorial committee who joined us in the planning of this work and the staff of IASP Press, in particular the production editor, Elizabeth Endres, for outstanding assistance. HAROLD MERSKEY JOHN D. LOESER RONALD DUBNER

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The Paths of Pain 1975–2005, edited by Harold Merskey, John D. Loeser, and Ronald Dubner, IASP Press, Seattle, © 2005.

3 The Gate Theory, Then and Now Fernando Cervero Anaesthesia Research Unit, McGill University, Montreal, Quebec, Canada THE GATE CONTROL THEORY

The gate control theory of pain mechanisms (Melzack and Wall 1965) has had a profound influence in the field of pain research and in the development of many pain therapies. In this chapter, presented on the 40th anniversary of the publication of that paper, I would like to give a historical perspective of the gate theory, discuss its basis and its modifications, and offer insight into its current state and its future. The account includes a few personal notes that give details of my involvement in some of the issues and debates. The starting point is the recognition that afferent inputs interact in the spinal dorsal horn and that this interaction can play a key role in the processing of pain-related information. My first contact with the gate theory happened in 1968, three years after its publication, when I was finishing preclinical medical studies at Madrid University. This was a momentous time for my generation, and I have many memories from that year about events unrelated to pain research, including an enforced visit to the lugubrious headquarters of Franco’s political police. I first read the gate theory when I was asked, as part of physiology coursework, to write an essay on the organization of presynaptic inhibition in the spinal cord. My interest in neuroscience was already high, but I became fascinated by the mechanism of presynaptic inhibition, which remains a neurobiological process that I find truly astonishing. When I first read the Melzack and Wall paper I concentrated almost exclusively on the model that they proposed for the control of incoming sensory input into the spinal cord, and therefore I did not pay much attention to the discussion about specificity versus pattern interpretations of pain mechanisms. The specificity theory was presented in a very extreme way, and the existence of specific nociceptors was given a swift dismissal. The most 33



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innovative aspect of the theory was the idea of the “gating” of sensory inputs at the first synaptic relay, which by itself does not necessarily support or deny a specificity interpretation of the peripheral input. In fact, the division of the afferent input to the cord into “large” and “small” afferents, with the former being mainly tactile and the latter nociceptive, implies a considerable amount of peripheral specificity. What remained in my mind was the proposal of a presynaptic inhibitory mechanism responsible for pain-related interactions between sensory afferents in the substantia gelatinosa of the superficial dorsal horn. However, the original description of the gate theory also focused on the conflict between specificity and pattern interpretations of pain mechanisms, and this topic needs to be addressed here.


One of the most enduring legacies of the gate theory has been an “antiDescartes” movement, blaming Descartes, not very accurately, for being the founding father of the specificity theory. The original Melzack and Wall paper used Descartes’ now-famous picture of a boy with his foot close to a fire to criticize the labeled-line mechanism of pain transmission. Yet, Descartes’ writings (1664) and the picture in question address scientific questions far beyond those related to pain mechanisms. Descartes was a dualist, probably more by fear of the Catholic Church than by conviction, and so his book is about how the human body, as opposed to the soul, works. He proposed that the human body was a machine, and he used the technology of his time—mostly clockwork, optics, and mechanics—to illustrate some bodily functions, including how the brain deals with external stimuli. He suggested that such stimuli activate nerves in the periphery of the body, which transmit their signals to the brain, where, after being “reflected” by the pineal gland, they activate motor nerves that in turn move the appropriate muscles away from the stimulus. What Descartes was describing is the “reflex arc,” so named as an acknowledgment of his idea of sensory signals being “reflected” in a mirror-like brain that directs them to motor nerves. This was quite revolutionary thinking at a time when all brain activity was though to be centrifugal and mediated by “animal spirits,” and his idea of a “reflex arc” is a lasting interpretation of the way the brain reacts to external stimuli. Descartes’ picture also holds a lot of truth as an example of strict pain specificity. It implies the existence of sensors in the periphery capable of detecting noxious stimuli. His diagram suggests the presence of distributed sensory and motor pathways in the spinal cord and brain and implies a



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Progress in our mechanistic understanding of nociception was dependent on major technological advances that occurred in three main areas: electrophysiology, biochemistry, and molecular biology. The work of Hodgkin and Huxley in the early 1950s had established the ionic basis of fundamental electrophysiological properties of neural tissue such as the resting membrane potential, the action potential and action potential conduction. Throughout the first half of the century, investigators perfected the use of glass microelectrodes to enable intracellular recording from excitable tissues. When used in combination with the operational amplifier, first developed in the 1950s, these electrodes made it possible to record the relatively small ionic currents in mammalian neurons. Application of these recording techniques to primary afferent neurons in vivo enabled characterization of the electrophysiological and histological properties of damage-sensing primary afferents, and this work began in earnest at the end of the 1970s. The seminal work of Sakmann and Nehrer in the early 1980s (Hamill et al. 1981) led to a major advance in the realm of electrophysiology with the discovery of the patch-clamp recording configuration. With this approach, it was possible to study the behavior of a single molecule in real time, and therefore to characterize many of the critical properties of ion channels that serve as receptors in primary afferent neurons. Of course, it would have been impossible to deal with the vast amounts of data generated with these approaches had there not been simultaneous advances in computing. Prior to developments that occurred in the 1980s, advances in the areas of biochemistry and molecular biology were largely the result of “brute force” approaches to isolating, purifying, and sequencing cellular proteins. During the late 1970s and early 1980s, techniques were developed that enabled the isolation of cellular mRNA, which could then be used as a template with which to synthesize complementary DNA (cDNA) in a test tube. Transcripts originally encoded by the mRNA could be inserted into the DNA of a plasmid used to transform bacteria, resulting in a cDNA “library” with each bacterial colony containing a “clone” of an mRNA transcript. Techniques were also developed that enabled transfection of cDNA into different cell types. These transfection approaches enabled researchers to take advantage of the host cells’ transcriptional and translational “machinery” so that these cells would generate the proteins encoded by the foreign cDNA. This method of inducing cells to express foreign proteins is called heterologous expression, and it enabled researchers to study the function of the proteins expressed in this way in relative isolation. If, for example,



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researchers were interested in identifying the receptor encoding a specific inflammatory mediator, they could screen transfected cells for a response to the inflammatory mediator of interest. This screening process, called expression cloning, would enable identification of genes encoding many of the receptors present in sensory neurons. Once a gene was identified, it was possible to deduce the amino acid sequence of the encoded protein. Knowledge of protein sequence enabled the generation of antibodies that were used in conjunction with physiological approaches to further establish structure-function relationships for specific proteins and more importantly, the localization of proteins at a cellular and subcellular level. A major advance occurred in 1985 with the discovery of a process that enabled the rapid amplification of small fragments of DNA: polymerase chain reaction (PCR; Mullis et al. 1986). This technique fueled an explosion in the rate at which the genes encoding specific proteins were identified. It also enabled researchers to manipulate, or mutate, the genes encoding specific proteins, which, when used with heterologous expression, enabled researchers to identify the function of specific sequences and even single amino acids of the protein of interest.


Prior to 1975, traditional pharmacological approaches employed well into the second half of the 20th century not only had established the concept of a receptor as a specialized structure that enabled specific chemicals to produce biological effects, but had enabled the classification of receptor subtypes. The ability of specific classes of molecules (i.e., agonists) to produce the same or similar effects (such as muscle contraction or an increase in heart rate) and more importantly, the ability of other classes of molecules (i.e., antagonists) to block the actions of agonists made it clear that there were several distinct classes of receptors subserving specific biological functions. Furthermore, biochemical and electrophysiological approaches had established the distinction between ionotropic receptors (those coupled to ion channels) and metabotropic receptors (those coupled to second-messenger pathways). The importance of second-messenger pathways to nociception had been recently underscored by the discovery in the early 1970s that aspirin-like compounds worked by blocking an enzyme, cyclooxygenase. Thus, one important mechanism whereby inflammatory mediators like bradykinin produce hyperalgesia is via activation of a receptor that initiates the activation of a second-messenger cascade, resulting in the liberation of arachidonic acid, the substrate for cyclooxygenase. Within this framework, and



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By the age of five, most children can differentiate a wide range of pain intensities, and many can use simple ratio and interval pain scales (e.g., visual analogue scales, numerical scales, faces scales, and verbal descriptor scales) to rate their pain intensity. Many scales have excellent psychometric properties, are convenient to administer, are easy for children to understand, are adaptable to many clinical situations, and help parents to monitor their children’s pain at home. Interviews, usually conducted independently with a child and his or her parents, are the cornerstone of assessment for children with persistent pain, enabling clinicians to identify relevant child, family, and situational factors that contribute to children’s pain and disability problems (Varni et al. 1987; Savedra et al. 1993; McGrath and Hillier 2001).


Anand and colleagues (1987) dramatically highlighted the adverse impact of untreated postoperative pain in 1987, when they revealed that premature infants undergoing surgery without adequate analgesic medication had significantly increased postsurgical morbidity and mortality in comparison to a group that had received fentanyl. The ensuing publicity as people learned that minimal anesthesia and analgesia represented “the norm in pediatric postoperative management,” rather than the exception, sparked a revolution (for review, see Schechter et al. 2003). Amidst increased pressure from health care providers, public advocates, and distressed parents, clinical practice started to change so that children began to receive more appropriate analgesics in adequate doses and at regular dosing intervals. New interest was directed toward the pharmacokinetics and pharmacodynamics of conventional analgesics in infants and children, the development of pain-free transdermal and transmucosal drug delivery methods, the design of improved sedation regimens for children undergoing painful or aversive therapies, the feasibility of “child- and parent-controlled” analgesia, the use of adjunct analgesics for neuropathic pain, and a broader use of regional anesthetic techniques in pediatric medicine. At the same time, increasing attention was focusing on the problem of undertreated procedural pain for children with cancer. Many children were incredibly anxious and distressed about scheduled lumbar punctures and bone marrow aspirations; despite receiving sedatives and local infiltrations, they experienced intense pain during these procedures. Clinicians designed versatile cognitive-behavioral programs, incorporating hypnosis, attention and distraction, and relaxation training, to help these children (Zeltzer and



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The Paths of Pain 1975–2005, edited by Harold Merskey, John D. Loeser, and Ronald Dubner, IASP Press, Seattle, © 2005.

32 Opioid Treatment for Cancer Pain and Chronic Noncancer Pain Dwight E. Moulin Departments of Oncology and Clinical Neurological Sciences, Universityof Western Ontario, and London Regional Cancer Centre, London, Ontario, Canada

Opium and its derivative, morphine, have been recognized for millennia as powerful analgesics. In 1680, Sydenham wrote, “Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.” Despite this awareness, Christian teaching saw pain as an expression of vitality and as a means of redemption. In the Victorian era, there was argument about the justification for using analgesia for childbirth and, to a lesser extent, for surgery, but the benefits of anesthesia quickly overwhelmed opposition. Popular use of opium preparations and derivatives was widespread in Victorian England, where the public was prone to self-medication, and concern arose over the indiscriminate and unregulated use of morphine and alcohol-based compounds (Holmes 2003). In the United States, the alarming spread of morphine use to the working class, coupled with a rising concern over iatrogenic addiction, led to the passage of the Harrison Narcotic Control Act in 1914. Opioid use came under such strict regulatory control that physicians were reluctant to prescribe narcotics at all, and, as a result, pain was grossly undertreated (Hill 1996). Even cancer pain did not escape the stigma attached to opioid use. An authoritative pronouncement in the Journal of the American Medical Association in 1941 had a major negative impact on a generation of physicians (Lee 1941). The article stated, “The use of narcotics in terminal cancer is to be condemned if it can possibly be avoided. Morphine and terminal cancer are in no way synonymous. Morphine use is an unpleasant experience to the majority of human subjects because of undesirable side effects. Dominant in the list of these unfortunate effects is addiction.” Fortunately, by the time of the 1st World Congress of the IASP in 1975, this 469



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situation had changed due to advances on both sides of the Atlantic. Under the direction of Cicely Saunders in the United Kingdom in the early 1950s, the hospice movement was born. Saunders asserted that opioids were not addictive for patients with pain from advanced cancer, that opioids did not cause a major problem of tolerance, and that treatment of pain requires consideration of the whole person (Faull and Nicholson 2003). Concurrently, Beecher, Houde, and Rogers in the United States developed analgesic scales and testing methods using double-blind crossover trials to provide guidelines for the rational use of opioids in clinical practice (Meldrum 2003). Through this pioneering work, opioid therapy was re-established as accepted treatment for pain due to cancer and pain caused by any terminal disease. This chapter will outline some of the advances and controversies in opioid pharmacology and treatment over the past 30 years.


In 1975, clinicians appreciated that there was tremendous interindividual variability in opioid responsiveness, but very little was known about response mechanisms. The discovery of endogenous opioids or enkephalins in that year, coupled with the identification of the opiate receptor 2 years earlier, set the stage for an explosive increase in our knowledge of opioid pharmacology (Gutstein and Akil 2001). These advances explain some of the variability in opioid responsiveness and have provided important guidelines for the clinical use of opioid analgesics. PHARMACOGENOMICS

Three distinct opioid receptor types have been characterized (mu, delta, and kappa), and splice variants of the µ-opioid receptor have been identified (Pasternak 2001). Polymorphisms in the µ-opioid receptor may explain differential responses to opioids with high µ-opioid affinity such as fentanyl. Polymorphisms also exist in the cytochrome P450 enzyme system that metabolizes many opioids. Codeine serves as a pro-drug for morphine, and about 10% of the Caucasian population lacks the CYP2D6 isoenzyme responsible for this conversion, making codeine ineffective as an analgesic for this subpopulation (Gutstein and Akil 2001). METABOLISM

Metabolites play an important role in the analgesic and side-effect profiles of several opioids. Meperidine has a toxic metabolite, normeperidine,



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How then should the scientist and by extension, the pharmaceutical industry proceed? Should their efforts be directed at one or a few of the molecules that are differentially expressed in normal and injured nociceptors? If a subset of these nociceptors is altered by the drug, will that be sufficient to produce adequate pain relief? Or is there too large an escape route, via nociceptors that are injured but do not express the particular molecule, or because there are dozens of other critical molecules that are also dysregulated by injury? The P2X3 subtype of purinergic receptor provides a good illustration of the latter problem. The P2X3 receptor is almost exclusively expressed by a subset of the nonpeptide-containing, IB4-binding population of unmyelinated nociceptors (Snider and McMahon 1998; Vulchanova et al. 1998). Importantly, its elimination, through gene deletion (Cockayne et al. 2000; Souslova et al. 2000), antisense technology (Barclay et al. 2002), or siRNA technology (Dorn et al. 2004), can reduce persistent pain behavior in different animal models. Do these studies provide a sufficient body of evidence to spend the millions of dollars required to test for the effects of antagonizing this receptor in patients? The fact is that the subset of neurons that express the P2X3 receptor is very small. My bias is that targeting of molecules that are more ubiquitously expressed, such as the TTX-resistant Na+ channel or different Ca2+ channel subtypes, has advantages. The downside of that approach is that the adverse side-effect profile is probably directly related to the extent to which the molecule is expressed in a ubiquitous, or a highly distributed fashion.


There is no question that I have concentrated on the nociception component of the pain experience. For this reason it is not surprising that my predictions about future directions in pain therapy emphasize pharmacological targets that regulate nociceptive processing. These are concentrated in the periphery (at the nociceptor) and in the spinal cord, a critical locus for central sensitization. Of course, targets must also be present at higher levels of the neuraxis, but we have much less information about the neurochemical and molecular basis of nociceptive processing at these levels. This situation could change significantly in the next few years. Imaging techniques are opening a fascinating window into the thalamic and cortical mechanisms that contribute to the experience of pain. Of particular interest



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