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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Emerging Strategies for the Treatment of Neuropathic Pain Editors
James N. Campbell, MD Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Allan I. Basbaum, PhD Department of Anatomy, W.M. Keck Foundation Center for Integrative Neuroscience, School of Medicine, University of California, San Francisco, California, USA
André Dray, PhD AstraZeneca Research and Development Montreal, Montreal, Quebec, Canada
Ronald Dubner, DDS, PhD Department of Oral and Craniofacial Biomedical Sciences, Dental School, University of Maryland, Baltimore, Maryland, USA
Robert H. Dworkin, PhD Anesthesiology Clinical Research Center, Department of Anesthesiology, School of Medicine, University of Rochester, Rochester, New York, USA
Christine N. Sang, MD, MPH Translational Pain Research, Department of Anesthesiology, Pain, and Perioperative Medicine, Brigham and Women’s Hospital, School of Medicine, Harvard University, Boston, Massachusetts, USA
IASP PRESS® • SEATTLE
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息 2006 IASP Press速 International Association for the Study of Pain速 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速. Thus, opinions expressed in Emerging Strategies for the Treatment of Neuropathic Pain 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 Emerging strategies for the treatment of neuropathic pain / editor, James N. Campbell ... [et al.]. p. ; cm. Includes bibliographical references and index. ISBN 0-931092-61-2 (alk. paper) 1. Pain--Chemotherapy--Congresses. 2. Neuralgia--Chemotherapy--Congresses. 3. Central pain--Chemotherapy--Congresses. I. Campbell, James N., 1948- II. International Association for the Study of Pain. [DNLM: 1. Pain--therapy--Congresses. 2. Nervous System Diseases--therapy--Congresses. WL 704 E53 2006] RB127.E52 2006 616'.0472--dc22 2005055225
Published by: IASP Press International Association for the Study of Pain 111 Queen Anne Ave N, Suite 501 Seattle, WA 98109-4955, USA Fax: 206-283-9403 www.iasp-pain.org www.painbooks.org Printed in the United States of America
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Contents List of Contributing Authors Acknowledgments Preface
vii x xi
Part I: Peripheral Nervous System Targets 1.
2. 3. 4.
Peripheral Nervous System Targets: Rapporteur Report Michael S. Gold, Iain Chessell, Marshall Devor, Andy Dray, Robert W. Gereau IV, Stefanie A. Kane, Martin Koltzenburg, Jean Claude Louis, Matthias Ringkamp, and Rolf-Detlef Treede
3
Peripheral Nerve Generators of Neuropathic Pain Marshall Devor
37
Peripheral Receptors in Neuropathic Pain Robert W. Gereau IV
69
Does Peripheral Sensitization of Primary Afferents Play a Role in Neuropathic Pain? Matthias Ringkamp and Richard A. Meyer
87
Part II: Central Nervous System Targets 5.
6.
7. 8.
9.
Central Nervous System Targets: Rapporteur Report William D. Willis, Jr., Donna L. Hammond, Ronald Dubner, Michael Merzenich, James C. Eisenach, Michael W. Salter, Smriti Iyengar, and Toni Shippenberg
105
Descending Modulatory Circuitry in the Initiation and Maintenance of Neuropathic Pain Ronald Dubner
123
Opioids and Neuropathic Pain Donna L. Hammond
139
The Role of Neuroimmune Activation in Chronic Neuropathic Pain and New Targets for Therapeutic Intervention Donald C. Manning
161
Signaling Pathways in Pain Neuroplasticity in the Spinal Dorsal Horn Michael W. Salter
193
10. Ascending and Descending Facilitatory Circuits in Neuropathic Pain States Michael H. Ossipov and Frank Porreca
v
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CONTENTS
Part III: Disease-Specific Targets 11. Disease-Specific Targets: Rapporteur Report Ralf Baron, John W. Griffin, Robert H. Dworkin, Ahmet Hรถke, Donald C. Manning, Mitchell B. Max, Karin L. Petersen, Christine Nai-Mei Sang, and William K. Schmidt 12. The Roles of Growth Factors in Painful Length-Dependent Axonal Neuropathies John W. Griffin 13. Pain Related to Inflammatory, Infectious and Toxic Neuropathies: Mechanisms and Perspectives on Treatment Ahmet Hรถke 14. The Depression-Pain Complex: Overlap between the Two Problems and Implications for Neuropathic Pain M. Dolores Ferrer-Garcia, Joachim F. Wernicke, Michael J. Detke, and Smriti Iyengar 15. Dissecting Molecular Causes of the Components of Chronic Neuropathic Pain Syndromes Mitchell B. Max and Beata Buzas 16. Tailoring Pharmacotherapy to Diagnostic Subgroups in the Treatment of Neuropathic Pain William K. Schmidt and Randall W. Moreadith
241
271
291
307
327
351
Part IV: Measurement and New Technologies 17. Measurement and New Technologies: Rapporteur Report Allan I. Basbaum, M. Catherine Bushnell, James N. Campbell, Sandra R. Chaplan, Patrick W. Mantyh, Frank Porreca, Donald D. Price, Laszlo Urban, Charles J. Vierck, and Jon-Kar Zubieta 18. Brain Imaging as a Surrogate Measure of Pain: Human and Animal Studies M. Catherine Bushnell 19. Microarray Studies and Pain Fredrik Kamme and Sandra R. Chaplan 20. Psychophysical Models for Neuropathic Pain Rolf-Detlef Treede 21. Psychophysical Tests that Characterize Pathological Mechanisms of Pain in Humans and Animals Donald D. Price, Charles J. Vierck, and Roland Staud 22. Biomarkers in Pain Laszlo Urban, Istvan Nagy, Katalin Lukacs, and Peter Santha 23. Animal Studies of Pain: Lessons for Drug Development Charles J. Vierck Index
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383 407 427
443 457 475 497
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Contributing Authors Ralf Baron, Dr med Department of Neurological Pain Research and Therapy, Christian-Albrechts University, Kiel, Germany Allan I. Basbaum, PhD Department of Anatomy, W.M. Keck Foundation Center for Integrative Neuroscience, San Francisco, California, USA M. Catherine Bushnell, PhD McGill Centre for Research on Pain, Montreal, Quebec, Canada Beata Buzas, PhD Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA James N. Campbell, MD Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Sandra R. Chaplan, MD Johnson & Johnson Pharmaceutical R&D, San Diego, California, USA Iain Chessell, PhD Neurology CEDD, GlaxoSmithKline, Harlow, United Kingdom Michael J. Detke, MD, PhD Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; Indiana University School of Medicine, Indianapolis, Indiana; McLean Hospital and Harvard Medical School, Belmont, Massachusetts, USA Marshall Devor, PhD Department of Cell and Animal Biology, Institute of Life Sciences and Center for Research on Pain, Hebrew University of Jerusalem, Jerusalem, Israel AndrĂŠ Dray, PhD AstraZeneca Research and Development Montreal, Montreal, Quebec, Canada Ronald Dubner, DDS, PhD Department of Biomedical Sciences, University of Maryland Dental School, Baltimore, Maryland, USA Robert H. Dworkin, PhD Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA James C. Eisenach, MS, MD Department of Anesthesia, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA M. Dolores Ferrer-Garcia, MD, PhD Department of Anesthesiology, IMAS Hospitals, Barcelona, Spain vii
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CONTRIBUTING AUTHORS
Robert W. Gereau IV, PhD Washington University Pain Center, Departments of Anesthesiology and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA John W. Griffin, MD Department of Neurology, Johns Hopkins University School of Medicine, 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 Donna L. Hammond, PhD Department of Anesthesia, The University of Iowa, Iowa City, Iowa, USA Ahmet Hรถke, MD, PhD, FRCP Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland, USA Smriti Iyengar, PhD Neuroscience Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA Fredrik Kamme, PhD Johnson & Johnson Pharmaceutical R&D, LLC, San Diego, California, USA Stefanie A. Kane, PhD Pain Research Department, Merck & Co. Inc., West Point, Pennsylvania, USA Martin Koltzenburg, Dr med Institute of Child Health, University College London, London, United Kingdom Jean Claude Louis, MD, PhD AMGEN, Thousand Oaks, California, USA Katalin Lukacs, MD, PhD School of Medicine, Chelsea and Westminster Hospital, London, United Kingdom Donald C. Manning, MD, PhD Celgene Corporation, Summit, New Jersey, USA Patrick W. Mantyh, PhD NeuroSystems Laboratory, University of Minnesota, Minneapolis, Minnesota, USA Mitchell B. Max, MD Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA Michael Merzenich, PhD Department of Otolaryngology, University of California San Francisco, San Francisco, California, USA Richard A. Meyer, MS Departments of Neurosurgery and Biomedical Engineering and Applied Physics Laboratory, Johns Hopkins University, Baltimore, Maryland, USA Randall W. Moreadith, MD, PhD Renovis, Inc., South San Francisco, California, USA
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CONTRIBUTING AUTHORS
ix
Istvan Nagy, MD, PhD Department of Anaesthesiology and Intensive Care, Imperial College London; School of Medicine, Chelsea and Westminster Hospital, London, United Kingdom Michael H. Ossipov, PhD Health Sciences Center, University of Arizona, Tucson, Arizona, USA Karin L. Petersen, MD UCSF Pain Clinical Research, San Francisco, California, USA Frank Porreca, PhD Department of Pharmacology, Health Sciences Center, University of Arizona, Tucson, Arizona, USA Donald D. Price, PhD Departments of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, Gainesville, Florida, USA Matthias Ringkamp, MD Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Michael W. Salter, MD, PhD The Hospital for Sick Children, Toronto, Ontario, Canada Christine N. Sang, MD, MPH Translational Pain Research, Brigham and Women's Hospital, School of Medicine, Harvard University, Boston, Massachusetts, USA Peter Santha, MD, PhD Department of Physiology, University of Szeged, Szeged, Hungary William K. Schmidt, PhD Renovis, Inc., South San Francisco, California, USA Toni Shippenberg, PhD Integrative Neuroscience Section, National Institute of Drug Abuse, National Institutes of Health, Bethesda, Maryland, USA Roland Staud, MD McKnight Brain Institute, Gainesville, Florida, USA Rolf-Detlef Treede, Dr med Institute of Physiology and Pathophysiology, Johannes Gutenberg-University, Mainz, Germany Laszlo Urban, MD, PhD Preclinical Compound Profiling, Lead Discovery Center, Discovery Technologies, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, USA Charles J. Vierck, PhD Department of Neuroscience and McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida, USA Joachim F. Wernicke, MD Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA William D. Willis, Jr., MD, PhD Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA Jon-Kar Zubieta, MD, PhD Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan, USA
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Preface On April 13, 2005, we began a five-day meeting in Scottsdale, Arizona, with the express purpose of furthering the development of new ways to treat the problem of neuropathic pain and to produce this book. This book provides the background for our deliberations and also summarizes the discussions themselves. This intensive effort involved 40 participants from academia and the pharmaceutical industry, all regarded internationally as leading experts in the field. Pain is a major health care problem for which current treatments are often inadequate. The tangible costs economically are in the many tens of billions of dollars, and the costs in terms of human suffering, while difficult to measure in dollars, are known only too well to practitioners who seek to help these patients. Demographics indicate that with the aging population these problems will only grow. Moreover, we see setbacks. One innovation of the past decade was the introduction of selective COX-2 inhibitors. Now use of this therapy has been sharply curtailed because of the emerging evidence for cardiovascular risks. The problem of neuropathic pain has always intrigued scientists and clinicians, but only in recent years has this particular form of pain been appreciated for its overall magnitude as a clinical problem. Gabapentin deserves much of the credit. Although developed to treat epilepsy, gabapentin was soon shown by clinicians to help many patients with neuropathic pain. Peak annual sales of the drug for pain have exceeded a billion dollars. This staggering growth in sales reveals the true magnitude of the problem of neuropathic pain. The pharmaceutical industry has made definite strides in bringing new therapies to bear on the problem of neuropathic pain, but to the suffering patient this progress must seem glacially slow. In an age of medical miracles, why should people still suffer from severe chronic pain? Many would say that the best therapy for serious pain remains one of the oldest treatments— morphine. However, opioid therapy remains entangled in the morass of the pervasive problem of drug abuse. Policy makers strive for a balance between patient access to legitimate care and the fight against addiction. One might think that by now we would have found a way to deliver opioids in a way that obviates the abuse problem, but we have not. Of course, for all drug treatments we strive to maximize benefit and minimize adverse effects. For new and old therapies, this ratio is often unfavorable. For too many patients, xi
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PREFACE
the current choice is between barely tolerable side effects versus pain relief, if indeed pain relief is to be had at all. There is hope, however, and this book, the outcome of a novel thinktank conference among industry leaders and researchers from the academic sector, addresses this hope. There has been a rapid acceleration in the discovery of new molecular targets, and opportunities are abundant. The choices for industry in terms of selecting these targets for drug development are, however, formidable. Costs for drug development are daunting, particularly when it comes to clinical trials. We need to pick targets accurately and have methods that will establish clinical “proof of concept� as expeditiously as possible. We still see a mismatch between animal model outcomes and limitations of clinical information and modeling. New therapeutic concepts have progressed slowly because of weaknesses in translational methods that bridge animal and human pain research. By way of a seed grant from Novartis Pharmaceuticals, we convened a series of strategy meetings to determine how to confront these issues. Many traditional conferences offer conventional lectures, with only minutes left for discussion. These meetings are important and useful, but they do not offer the opportunity to delve in depth into the many issues that bar progress. Our approach was to put the lectures into written materials that could be digested before the meeting and use the meeting time to create, critique, and debate how best to develop new treatments for neuropathic pain. This effort had, in our opinion, to be a marriage of academia and industry. We needed to keep the group small. And we wanted an end product. Much of the book was written before the meeting. Nearly all of these chapters were then rewritten post-meeting. Finally, four of the chapters, which summarize the deliberations of the different groups that met in discussion, were written during the meeting. The contents of these rapporteurs’ reports were discussed on the final day of the meeting, revised after the meeting, and included in the book along with the chapters that were written in advance of the meeting. This meeting was modeled after the well-known Dahlem workshops held in Berlin. In most meetings, many participants come and go, but not in this Dahlem-styled meeting. Cell-phones, e-mail, and much of the rest of the world were shut out over the course of four and a half days. Meetings started early and went into the evening. There were four main groups. The groups met by themselves initially, but then met with each of the other groups, pursuing an agenda that was established on the first day. Rapporteurs, with the help of their colleagues, kept careful notes of the proceedings. Smaller groups engaged in intense writing sessions just before all four groups met together for a final summation.
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The topics for each group were chosen with great care and reflected themes for drug development.
PERIPHERAL NERVOUS SYSTEM TARGETS
Many neuropathic pain conditions stem from a lesion that affects primary afferent nociceptive fibers. Thus it is appealing to develop strategies of treatment that specifically focus on this group of patients. The concept that abnormal activity in nociceptive afferents triggers and maintains neuropathic pain remains a heuristic model. Nociceptive afferents express receptors, surface molecules, and channels and use a variety of biochemical processes that distinguish them from other sensory neurons, and from other cells in general. Attacking these targets provides promise, but the utility of targeting individual molecules is unclear. Nerve injury leads to events that promote nerve regeneration, some of which may be maladaptive, contributing to the phenotype of the neuropathic pain condition. In addition, some of the molecules and cellular processes concerned with regeneration may lead to abnormal discharges in nociceptive afferents.
CENTRAL NERVOUS SYSTEM TARGETS
Therapies directed at the CNS provide further opportunities for pain treatment. The CNS is important because maladaptive plasticity of function at several levels of the neuraxis almost certainly contributes to the development and persistence of neuropathic pain. Neurotransmitter modulators hold the promise of beneficially affecting nociceptive processing. Neuronal interactions with glial and other support cells may promote lasting pain. Attacking these interactions may be beneficial. Changes in neural processing brought about by neural injury may also lead to persistent pain. Clearly, injury to the spinal cord and brain, through trauma, vascular disease, and other pathological processes may lead to pain problems with very limited therapeutic options. The dorsal horn has been extensively studied, and many new directions for pain treatment should emerge from this knowledge. However, we ignore the rest of the CNS at our peril. How can drug development aimed at other central targets proceed in a practical way?
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DISEASE-SPECIFIC TARGETS
Certain diseases are notorious for producing neuropathic pain. Postherpetic neuralgia, diabetic neuropathy, compression neuropathies, and trigeminal neuralgia are but a few examples. The extent to which the pain in these diseases represents distinctive nervous system pathophysiology must be determined. It is entirely possible that advances in treatment for neuropathic pain must await the development of specific disease therapies. For example, the effects of a simple axotomy have often been used as a model for neuropathic pain. In actuality, traumatic axotomy in humans accounts for a small percentage of the cases of neuropathic pain. Understanding how diabetes affects nociceptive neurons may lead to therapies that address this underlying pathophysiology. How can molecules be screened better in early-stage clinical trials to determine the likelihood of correcting the effects on nociceptive processing? Will it be possible in the future to develop a signature of different diseases based on biomarkers, psychophysics, brain imaging, and genomic approaches?
DEVELOPMENT OF MEASUREMENT TOOLS AND APPLICATIONS OF NEW TECHNOLOGIES
Success will also involve the development of novel technologies. Among the approaches to be considered are downregulation of pronociceptive molecules, which might be achieved, for example, by delivery of RNAi by intrathecal injection. By contrast, viral delivery techniques may open doors to altering gene expression in dorsal root ganglion cells, for example, by upregulating expression of “pain” inhibitory molecules and receptors. Molecular “neurosurgery” may be accomplished with toxins, such as saporintagged ligands or antibodies that allow selective destruction of pain-signaling cells. The introduction of midline myelotomy to treat visceral pain and motor cortex stimulation to treat atypical facial and post-stroke pain suggests that ablative and stimulation strategies have yet to be fully exploited. A second charge for this group was to consider how improvements in measurement might facilitate drug development and treatment. At present, simple withdrawal measurements dominate animal psychophysical techniques. Advances in imaging, development of biological markers, and advances in psychophysical techniques should improve our chances to learn more about mechanisms and treatment. Finally, there are generic issues that crosscut all these considerations. What is neuropathic pain, and how do mechanisms of neuropathic pain differ from those that lead to persistent pain that is not neuropathic? What are the models that should be used in drug development? What proof-ofconcept models can be used in phase I/II human trials that will expedite
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better decision making about whether to pursue phase II/III testing? Success in finding new therapies depends on finding capital-efficient techniques to order to make the cost manageable.
THE END PRODUCT
We intend for this book to represent not only the state of the art, but also a blueprint for what is to come. Neuropathic pain is a daunting and important problem. We need new approaches, new understandings of mechanisms, and finally new treatments. We will have achieved our goal if a reader coming into the field uses this book to frame the specific aims and the background and significance of a new NIH research proposal. Did we achieve our goal? We shall see. It is hard to represent the intensity and intellectual vigor that permeated this meeting in a book. It is also hard to write by committee. On the other hand, it is a thing of beauty to watch colleagues working together in small groups, debating the course of our young field. This is our best shot for the moment. Clearly there is momentum, but many challenges and opportunities await us. The editors recognize the great effort put forward by the attendees from both academia and the pharmaceutical industry. To them we offer our heartfelt thanks for an unforgettable meeting and, we hope, an unforgettable book. We also thank the talented staff of IASP Press, who worked faithfully to make this book a reality. This book and the meeting would simply not have happened except for the masterful stewardship of Paul Lambiase. We all owe him heartfelt gratitude. This meeting was financed entirely by the pharmaceutical industry. The grants were made without strings attached. The sponsors have the vision that the community of science is the engine of new ideas. Finally, we extend our thoughts to the many patients who suffer the ravages of neurological diseases that lead to pain and suffering. We dedicate this book to them. JAMES N. CAMPBELL, MD ALLAN I. Basbaum, PhD ANDRÉ DRAY, PhD RONALD DUBNER, DDS, PhD ROBERT H. DWORKIN, PhD CHRISTINE N. SANG, MD, MPH
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M.S. GOLD ET AL. heat cold
capsaicin mustard oil formalin
8) Neuron-glial/immune interactions Cytokines Trophic factors Inflammatory mediators
1) transduction 2) transformation
3) impulse conduction 6) Axonal transport
5) Integration of activity within ganglia Ectopic activity Cross talk Phenotypic changes
7) Access to key sites along peripheral nerve
4) Neurotransmitter release glutamate, neuropeptides, trophic factors
Fig. 1. The primary sensory neuron. Primary nociceptive afferents terminate as free nerve endings of Aδ or C fibers in the skin and other tissues. Their principal sensory functions consist of (1) transduction of external or internal chemical or physical stimuli into generator potentials, (2) transformation of generator potentials into trains of action potentials, (3) action potential propagation toward the central nervous system, and (4) presynaptic release of neurotransmitters and neuromodulators. The sensory neuron cell body (5) appears to be a site critical for the integration of neural activity in nociceptive afferents under normal conditions and may become a site of aberrant activity under pathological conditions. Axonal transport (6) of proteins in both anterograde and retrograde directions appears be critical for maintaining afferent phenotype under normal conditions, and for initiating changes in phenotype under pathological conditions. Axonal transport may also be a mechanism of shuttling critical mediators such as cytokines from the periphery to central targets. Blood- and tissue-nerve barriers (7) limit drug access to potential therapeutic targets in peripheral nerves. However, both the cell body and peripheral terminals are relatively accessible under normal conditions, and their accessibility may increase at critical points following nerve injury. Neuroimmune interactions have been depicted in the peripheral tissue, where they play an important role in inflammatory pain. In neuropathic pain, neuron-glial and neuroimmune interactions (8) may occur along the entire length of the primary sensory neuron. These nerve fibers are axons of neurons situated in the dorsal root ganglion or trigeminal ganglion.
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M. DEVOR
WHAT NEEDS EXPLAINING? SENSORY DYSFUNCTION DUE TO NEUROPATHY
Nerve injury and disease may precipitate abnormalities of sensation including pain, motor disturbances, autonomic signs and symptoms, and trophic tissue changes. The focus here, naturally, is on sensory changes. Three categories of pain need to be distinguished. (1) Spontaneous pain (ongoing pain) is present at rest when no (intentional) stimulus is applied. Whether the pain is truly independent of any stimulus, or whether it is associated with internal physiological factors such as blood chemistry, autonomic nervous system activity, or hormones, is often unknown. It is a bad habit to refer to ongoing pain simply as “pain.” (2) Evoked pain is pain on stimulation of the skin or other accessible tissues such as the oral or nasal mucosa. According to current IASP usage, pain evoked by stimuli that are normally painless (touch, warm or cool stimuli, or dilute chemicals) is called “allodynia” (tactile allodynia, heat allodynia, etc.). When a normally painful stimulus evokes more intense pain than expected, this pain is termed “hyperalgesia.” (3) Pain evoked by movement and weight bearing, or by focal pressure to deep tissues (muscle, tendon, or visceral “tender points” or “trigger points”), might simply be mechanical allodynia due to deep tissue inflammation. Alternatively, it may reflect neuropathology, perhaps at sites where small nerve branches are pinched as they cross fascial planes (microneuroma). When the source of pain is not at the surface, it is inherently difficult to analyze. THE SENSORY QUALITY OF NEUROPATHIC PAIN
The words that people with neural damage or disease use to describe their sensory experience can be informative. Some of these terms are generic, but some are characteristic of neuropathy in general, or even of particular neuropathic pain diagnoses (Bouhassira et al. 2004). For example, spontaneous burning pain occurs in postherpetic neuralgia (PHN) as well as after acute burns, but shooting pain and electric shock-like paroxysms are uncommon except in neuropathy. “Hyperpathia” is a constellation of pain descriptors essentially exclusive to neuropathy. In hyperpathia, sensation shows odd temporal and spatial characteristics. A gentle tap on the back of the hand may feel dull (hypoesthetic), as if felt through a boxing glove. However, with repeated tapping (say, once or twice a second for 10–20 seconds) the sensation “winds up,” becoming stronger and stronger until it reaches a painful crescendo. Hyperpathic sensations also spread in space; localized touch may trigger a stinging sensation that spreads up the arm.
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PERIPHERAL NERVE GENERATORS
41
Even though distinctive sensory peculiarities like electric shock-like paroxysms and hyperpathia are rare compared to ongoing burning pain, they are important objects for theoretical analysis because they get to the heart of what makes a pain neuropathic. PHANTOM LIMB PAIN AND ANESTHESIA DOLOROSA
Special mention needs to be made of neuropathic sensory experience felt in parts of the body that no longer exist or that are completely numb due to major nerve injury or traumatic avulsion of sensory roots from the spinal cord (Wynn-Parry 1980; Nikolajsen and Jensen 2001). The limb continues to be felt as a “phantom” and is painful some of the time in most patients, and most of the time in some patients. Many amputees report factors that exacerbate phantom pain (e.g., urination, emotional upset, or cold weather), or that provide temporary relief (e.g., massage or warming). What is the source of the impulses that are interpreted by the conscious brain of the amputee as phantom limb sensation and phantom limb pain? In principle, they could arise in the peripheral nerve and ganglion, in the cerebral cortex, or anywhere in between. Beyond the sensory quality of phantom limb sensation (tingling, burning pain, etc.), amputees also report changes in the spatial aspects of phantom limb representations. There may be willed or unwilled movement of the phantom, for example, and its size and location are subject to distortion. Most amputees, for example, describe “telescoping,” where over a period of months or years a full-length phantom arm draws in toward the body until only a hand is felt protruding from the stump. Sensation may also be referred to (i.e., felt in) the phantom arm upon stroking the cheek or the chest wall. As in phantom limb pain itself, there is uncertainty as to what extent these body schema distortions are due to PNS activity as opposed to plastic changes that originate in spinal and supraspinal body surface representations. DIVERSITY OF DIAGNOSES
Neuropathic pain is fundamentally a paradox. Like cutting a telephone cable, injuring a nerve ought to make the line go dead (negative symptoms). Why, then, does neuropathy trigger paresthesias, dysesthesias, and pain (positive symptoms)? A related question concerns diversity. Many authors presume that, since different diagnoses are triggered by different precipitating events and present with different clinical pictures and natural histories, each has its own pain mechanism. Does “peripheral neuropathic pain” represent a
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ASCENDING AND DESCENDING FACILITATORY CIRCUITS 221
Cortex
Thalamus
PAG
RVM
DLF
Aβ
N Gr DC
STT
C
Fig. 1. Large-diameter primary afferent (Aβ) fibers project directly through the dorsal columns (DC) to the nucleus gracilis (N Gr). These primary afferents may also terminate in the intermediate laminae of the spinal dorsal horn and synapse with second-order neurons that might include postsynaptic dorsal column (PSDC) cells that project along the DC to the n. gracilis. The n. gracilis communicates with thalamic nuclei via the medial lemniscus. The unmyelinated C-fiber nociceptors transmit nociceptive inputs to the outer laminae of the spinal dorsal horn, where they may synapse with neurons of the spinothalamic tract (STT), which projects to supraspinal sites, including the thalamus, and to the periaqueductal gray (PAG). Descending projections from the PAG mediate nociception by activating spinopetal inhibitory projections from the rostral ventromedial medulla (RVM). These projections course along the dorsal lateral funiculus (DLF) and inhibit nociceptive inputs either by inhibiting release of excitatory transmitters from afferent terminals or by inhibiting the response of ascending second-order neurons to noxious inputs.
conditions (Ossipov et al. 2000a; Porreca et al. 2002). Early observations indicated that electrical stimulation of the DLF elicits an excitation of dorsal horn units in lamina I through activation of descending fibers, and not through antidromic activation of ascending fibers (McMahon and Wall 1983, 1988). Considerable evidence now exists to show that the activation of descending facilitation from the RVM is essential to maintain the behavioral features of the neuropathic pain state (Ossipov et al. 2001; Porreca et al.
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Emerging Strategies for the Treatment of Neuropathic Pain, edited by James N. Campbell, Allan I. Basbaum, André Dray, Ronald Dubner, Robert H. Dworkin, and Christine N. Sang, IASP Press, Seattle, © 2006.
18 Brain Imaging as a Surrogate Measure of Pain: Human and Animal Studies M. Catherine Bushnell Department of Anesthesia, Faculty of Medicine, and Faculty of Dentistry, McGill University, Montreal, Quebec, Canada
Most neuropathic conditions are dominated by ongoing pain. Our major means of assessing clinical pain is to communicate with language. This chapter will consider whether it is feasible to use brain and spinal cord imaging to measure nociceptive processing and, by implication, pain in animals and humans. Measurement of ongoing pain in animals may afford an impetus to development of new treatments. The health care industry has much at stake in the question as to whether we can use brain imaging as a surrogate measure of pain. Insurance companies want to know if brain imaging can tell them whether a person on disability really has low back pain or is just malingering. Pharmaceutical companies want to know if brain imaging can provide objective evidence of their drugs’ effectiveness. Can it provide a more sensitive and reliable measure than self-report in patients? Marketing executives want to show pictures to consumers and say: “This is pain in your brain before and after taking our drug.” As brain imaging evolves, many of these questions can be answered in the affirmative. Nevertheless, as will be discussed below, brainimaging data must always be interpreted with caution.
BRAIN IMAGING TO MEASURE NOCICEPTIVE PROCESSES
The use of brain imaging in humans to study nociceptive processes dates back to the 1970s, when Lassen and colleagues (1978) injected the radioisotope Xenon133 into human volunteers and produced the first images of cerebral hemodynamic changes related to pain. Although this technique provided only crude spatial resolution and no temporal resolution, the results 383
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suggested that presentation of a noxious stimulus led to increased blood flow to the frontal lobes. Although these were exciting results, researchers using these techniques did not continue to study pain, partly because of the prolonged stimulation periods that were required. Nevertheless, when new radiotracers with short half-lives were developed in the late 1980s, imaging of pain in the human brain came into its own. Today, there are numerous imaging techniques for studying pain in the human brain, including positron emission tomography (PET), single photon emission computed tomography (SPECT), functional magnetic resonance imaging (fMRI), electroencephalographic (EEG) dipole source analysis, and magnetoencephalographic analysis (MEG). Each technique has advantages and disadvantages in terms of spatial and temporal resolution, sensitivity, and cost. However, all of these techniques provide measures that can be used as indirect indices of neural activity, and some can be used as measures of neurochemical activity. This chapter will concentrate on data obtained using PET and MRI methodology, which provide better spatial information than other techniques and thus are particularly important for determining pain pathways and pain-modulatory systems. There have now been scores of brain-imaging studies of pain processing, using both PET and fMRI (see (Apkarian et al. 2004 for an in-depth review]. Although there are many differences in activation patterns across studies, a consistent cortical and subcortical network has emerged that includes sensory, limbic, associative, and motor areas. The most commonly activated brain regions include parts of the primary and secondary somatosensory cortices (S1 and S2), the anterior cingulate cortex (ACC), insular cortex (IC), prefrontal cortex (PFC), thalamus (Th), and cerebellum (CB).
BRAIN IMAGING TO MEASURE PAIN PERCEPTION
The earliest human brain-imaging studies used a block design in which stimuli were turned on and off, and hemodynamic measures were compared during different stimulus conditions. For example, Talbot et al. (1991) measured regional cerebral blood flow (rCBF) when painful heat stimuli as compared to nonpainful warm stimuli were applied to the arm. Similar techniques were used by many investigators in both PET and fMRI scanning protocols. Although the investigators usually confirmed that the subjects were or were not experiencing pain, depending on the condition, they did not factor the intensity of pain into the analysis. Analytical techniques now allow us to correlate the imaging signal with the individual’s perception. Different aspects of perception, such as perceived pain intensity and pain
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L. URBAN, I. NAGY, K. LUKACS, AND P. SANTHA
BIOMARKERS IN OSTEOARTHRITIS
Because the etiology of osteoarthritis is far from clear and the progress of the disease is difficult to predict (it is often episodic and erratic), many teams are attempting to determine biomarkers that would shed light on the pathophysiological mechanisms of this disease, provide a reliable prognosis, and be useful in monitoring the effects of treatment. The major changes are associated with the cartilage, the synovium, and the subarthritic bone, and so successful markers would be likely to reflect changes in bone or cartilage tissue (Garnero and Delmas 2003). Although all clinical trials of osteoarthritis measure pain among other symptoms, a correlation between pain and serum or urine biomarkers has not been satisfactorily studied. Thus, biomarkers described in this chapter are more closely linked to cartilage, synovial, and bone pathology and only correlate to a certain extent with associated pain. Bruyere et al. (2003) describe these correlations in a well-designed 3year study in patients with knee osteoarthritis. The investigators compared data from an extensive list of biomarkers to the pain, stiffness, and physical function subscales of the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index at baseline and after 1 year. In addition, mean and minimal joint space width of the femorotibial joint was measured after 3 years. The aim was to investigate the relationship between the biomarkers and bone and cartilage remodeling and progression of the disease. Biomarkers under investigation were serum keratan sulfate, serum hyaluronic acid, urine Table I Biomarkers for osteoarthritis degradation products Bone
Cartilage
Synovium
Pyridinoline
Pyridinoline
Deoxypyridinoline, collagen telopeptides (CTX-I, NTX-I, ICTP) Bone sialoprotein
CTX-II, collagen Îą-chain fragments: COL2-3/4 (long) and COL2-3/4C (short) Core protein fragments, keratan 1 sulfate (epitopes 5D4, ANP9 ) Cartilage oligomeric matrix protein
Pyridinoline, CTX-I, NTX-I Glucosyl galactosyl pyridinoline
Tartrate-resistant acid phosphatase (5b isoenzyme)
Source: Modified from Garnero et al. (2003). Abbreviations: CTX-I = carboxy-terminal crosslinking telopeptide of type I collagen; CTX-II = carboxy-terminal cross-linking telopeptide of type II collagen; ICTP = pyridinoline cross-linking carboxy-terminal telopeptide of type I collagen; NTX-I = N-terminal cross-linking telopeptide of type I collagen.
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