Pain 2010—An Updated Review: Refresher Course Syllabus IASP Refresher Courses on Pain Management held in conjunction with the 13th World Congress on Pain August 29–September 2, 2010 Montreal, Quebec, Canada IASP Scientific Program Committee Jeffrey S. Mogil, PhD, Canada, Chair Nadine Attal, MD, PhD, France Rafael Benoliel, BDS, Israel Phyllis Berger, BSc, South Africa Mary Cardosa, MB BS, Malaysia José Castro-Lopes, MD, PhD, Portugal, ex officio Michael Caterina, MD, PhD, USA Jun Chen, MD, PhD, China Joyce De Leo, PhD, USA Fernando de Queiróz Cunha, PhD, Brazil Gerald Gebhart, PhD, USA, ex officio Kathy Kreiter, USA, ex officio Lance McCracken, PhD, United Kingdom Karin Petersen, MD, USA Srinivasa Raja, MD, USA Martin Schmelz, MD, Germany Michele Sterling, PhD, Australia Bonnie Stevens, RN, PhD, Canada Audun Stubhaug, MD, Norway Victor Tortorici, PhD, Venezuela Irene Tracey, PhD, United Kingdom Hiroshi Ueda, PhD, Japan Johannes Vlaeyen, PhD, Belgium
IASP PRESS® • SEATTLE
© 2010 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 Pain 2010—An Updated Review: Refresher Course Syllabus do not necessarily reflect those of IASP or of the Officers and Councilors 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 Available from the publisher.
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
Contents Preface
vii
Part 1: Neurobiology of Acute and Persistent Pain 1. Nociceptors, the Spinal Dorsal Horn, and Descending Modulation Frank Porreca 2. Dorsal Horn Plasticity and Neuron-Microglia Interactions Michael W. Salter Part 2: Cancer Pain: From Mechanisms to Treatment 3. Mechanisms of Cancer Pain: Experimental Data Sital Patel and Anthony H. Dickenson
3 13
27
4. Pharmacological Management of Cancer Pain Sebastiano Mercadante
37
5. Interventional Procedures in the Treatment of Refractory Cancer Pain Allen W. Burton
43
Part 3: The Basics of Brain Imaging 6. Functional MRI Studies of Pain Processing Irene Tracey
51
7. The Basics of Positron Emission Tomography Petra Schweinhardt
57
8. Electrocortical Responses to Nociceptive Stimulation in Humans Giandomenico Iannetti
63
Part 4: From Basic Science to Management of Chronic Musculoskeletal Pain 9. From Basic Science to Management of Chronic Musculoskeletal Pain Lars Arendt-Nielsen, Thomas Graven-Nielsen, Bruce L. Kidd, and César Fernández-de-las-Peñas
73
Part 5: Utility and Development of Pain Models: Animals to Humans 10. Utility and Development of Pain Models: Animals to Humans Martin Schmelz, Gary J. Bennett, and Karin L. Petersen
87
11. The Logic of Animal Models Gary J. Bennett
99
Part 6: Basics, Management, and Treatment of Complex Regional Pain Syndrome 12. Complex Regional Pain Syndrome: A Neuropathic Disorder? Ralf Baron, Dennis Naleschinski, Philipp Hüllemann, and Friederike Mahn
109
13. Movement Disorders in Complex Regional Pain Syndrome Jacobus J. van Hilten
119
14. Rehabilitation of People with Chronic Complex Regional Pain Syndrome G. Lorimer Moseley
125
iii
iv
Contents
Part 7: Orofacial Pain and Headache 15. Trigeminal Neuropathic Pain Joanna M. Zakrzewska
137
16. Pain Associated with Temporomandibular Disorders and with Burning Mouth Syndrome Antoon De Laat
147
17. Primary Headache Disorders Presenting as Orofacial Pain Peter J. Goadsby
153
Part 8: Pain Psychology for Non-Psychologists 18. Pain Psychology for Non-Psychologists Amanda C. de C. Williams, Francis J. Keefe, and Johan W.S. Vlaeyen
161
Part 9: Persistent Postoperative Pain: Pathogenic Mechanisms and Preventive Strategies 19. Persistent Postoperative Pain: Pathogenic Mechanisms and Preventive Strategies Henrik Kehlet, William A. Macrae, and Audun Stubhaug
181
Part 10: Clinical Pharmacology: Evidence-Based Guidelines and Defining the Proper Outcome 20. Clinical Pharmacology of Antidepressants and Anticonvulsants for the Management of Pain Ian Gilron
193
21. Clinical Pharmacology of Opioids in the Treatment of Pain Eija Kalso
207
22. Clinical Pharmacology of Nonsteroidal Anti-Inflammatory Drugs Raymond A. Dionne, Sharon M. Gordon, and May Hamza
217
Part 11: Pain Genes for Unraveling Pain: A Course for Non-Geneticists 23. What Are “Pain Genes,” and Why Are They Interesting? Marshall Devor 24. Pain-Related Mutations in the Human Genome M. Florencia Gosso, Curtis F. Barrett, Arn M.J.M. van den Maagdenberg, and Michel D. Ferrari
227 239
25. The Search for Human Pain Genes Using Whole-Genome Approaches: Achievements, Failures, and Promises Shad B. Smith, Inna E. Tchivileva, William Maixner, and Luda Diatchenko
255
Part 12: Neuropathic Pain: From Basic Mechanisms to Clinical Management 26. Clinical Manifestations of Neuropathic Pain and Distinguishing Features from Other Types of Pain Per Hansson
265
27. Neurobiological Mechanisms of Neuropathic Pain and Its Treatment Anthony H. Dickenson and Lucy A. Bee
271
28. Management of Neuropathic Pain Troels Staehelin Jensen and Nanna Brix Finnerup
283
Part 13: Interventional Therapies for Acute and Chronic Pain 29. Interventional Therapies for Chronic Pain: Indications and Efficacy James P. Rathmell and Mark Wallace
293
30. Continuous Peripheral Nerve Blocks for Treating Acute Pain in the Hospital and the Ambulatory Environment Brian M. Ilfeld
303
Contents Part 14: Pain and Addiction: Optimizing Outcome, Reducing Risk 31. Pain and Addiction: Prevalence, Neurobiology, Definitions Roman D. Jovey
v
315
32. Identifying and Addressing Risks for Opioid Misuse in Opioid Therapy of Pain Seddon R. Savage
323
33. Balancing Safety with Pain Relief When Prescribing Opioids Jonathan Bannister
331
Part 15: Pathophysiology, Diagnosis, and Treatment of Persistent Abdominal/Pelvic Pain 34. Pathophysiology of Persistent Abdominal and Pelvic Pain Emeran A. Mayer
337
35. Diagnosis and Treatment of Persistent Pelvic Pain Fred M. Howard
345
36. Diagnosis and Treatment of Persistent Abdominal Pain Kirsten Tillisch
353
Part 16: Basics, Management, and Treatment of Low Back Pain 37. Basics, Management, and Treatment of Low Back Pain Paul J. Watson, Chris J. Main, and Rob J.E.M. Smeets
361
Part 17: Basics, Management, and Treatment of Pain in Children 38. The Development of Pain Mechanisms, Pain Effects, and Pain Experiences in Infants and Children Maria Fitzgerald
383
39. Management and Treatment of Pain in Infants Denise Harrison
391
40. Psychological Interventions for Chronic Pediatric Pain Christiane Hermann
399
Part 18: Preclinical and Clinical Challenges in Drug Development 41. Overview of the Drug Development Process and Regulatory Approval for New Drugs Steve Quessy
409
42. Predicting Analgesic Efficacy from Animal Models of Peripheral Neuropathy and Nerve Injury: A Critical View from the Clinic Andrew S.C. Rice
415
43. From “First-in-Human” Trials to Efficacy in Patients: Identifying Tomorrow’s Analgesics in a Sea of Failed Optimism John P. Huggins
427
44. Issues Relating to the Clinical Development Process of New Analgesics Steve Quessy
437
Index
447
Preface The chapters in this volume were written by the contributors to the Refresher Courses offered in conjunction with the 13th World Congress on Pain, held on August 29–September 2, 2010, in Montreal, Quebec, Canada. Refresher Courses are among the most popular components of World Congresses, and this year saw the addition of several new courses and many new speakers. The courses, and by extension this book, truly cover the gamut of modern pain research and treatment, with topics ranging from state-of-the-art techniques (e.g., brain imaging, genetics, and animal and volunteer models) and treatments (e.g., interventional therapies, psychological therapies, and pharmacotherapies) to the state of the art in our understanding of pain disorders (e.g., cancer pain, neuropathic pain, musculoskeletal pain, complex regional pain syndrome, orofacial pain and headache, persistent postoperative pain, abdominal/pelvic pain, low back pain, and pediatric pain) and comorbidities (pain and addiction). I draw your attention especially to a few completely new courses, on pediatric pain, orofacial pain, and challenges in drug development. Whether you are new to pain research or a clinician looking to
brush up your skills or thinking of delving into a new technique or treatment strategy, you’ll find this book a valuable resource—a snapshot in time of the field of pain. I wish to thank the speakers, both the many returning speakers and the “new blood,” for their hard work and talents in writing these excellent chapters and preparing what are sure to be dynamic and effective presentations at the meeting. It has been genuinely useful and enjoyable for me personally to have read these contributions at the editing stage. I also wish to express my deep gratitude to the Scientific Program Committee (especially Drs. Irene Tracey, Srinivasa Raja, and Johannes Vlaeyen, the Refresher Course Subcommittee), Dr. Jerry Gebhart (IASP President), Kathy Kreiter (IASP Executive Director), Terry Onustack (Meetings and Education Manager), and Elizabeth Endres and Irena Zlatanovic for their highly effective editorial assistance. Jeffrey S. Mogil, PhD Chair, Scientific Program Committee 13th World Congress on Pain
vii
Jeffrey S. Mogil, PhD, was born in Toronto, Ontario, Canada, in 1966. He received a BSc (Honours) in Psychology from the University of Toronto in 1988, and a PhD in Neuroscience from UCLA in 1993. After a postdoctoral fellowship in Portland, Oregon, from 1993 to 1996, he joined the faculty of the Department of Psychology at the University of Illinois at Urbana-Champaign. He moved to McGill University in 2001, and is currently the E.P. Taylor Professor of Pain Studies (a Chair previously occupied by Dr. Ronald Melzack) and the Canada Research Chair in the Genetics of Pain (Tier I). Dr. Mogil has made seminal contributions to the field of pain genetics and is the author of most major reviews of the subject, and the editor of the book, The Genetics of Pain (IASP Press, 2004). He is also a recognized authority in sex differences in pain and analgesia, and paintesting methods in the laboratory mouse. Dr. Mogil is the author of over 150 journal articles and book chapters since 1992, and has given over 190 invited lectures in that same period. He holds or has held funding from the U.S. National Institutes of Health, the Canadian Institutes for Health Research, the Canada Foundation for Innovation, Genome Canada, Neuroscience Canada, the Louise and Alan Edwards Foundation, the Krembil Foundation, and the pharmaceutical and biotechnology industry. He is the recipient of numerous awards, including the Neal E. Miller New Investigator Award from the Academy of Behavioral Medicine Research (1998), the John C. Liebeskind Early Career Scholar Award from the American Pain Society (1998), the Patrick D. Wall Young Investigator Award from the International Association for the Study of Pain (2002), the Early Career Award from the Canadian Pain Society (2004), and a Neuropathic Pain Award from Pfizer Canada (2010). He currently serves as a Section Editor (Neurobiology) at the journal PAIN and is Chair of the Scientific Program Committee of the 13th World Congress on Pain.
x
Dorsal Horn Plasticity and Neuron-Microglia Interactions
17
excitatory synaptic transmission in nociceptive neurons (see Fig. 1). The facilitation may occur through the enhanced NMDAR currents per se (Fig. 1, middle) or through triggering enhancement of AMPA receptor currents (Fig. 1, right). Importantly, the basal sensory thresholds and acute nociceptive behavior are not dependent upon Src phosphorylation-mediated upregulation of NMDAR function (Fig. 1, left), indicating that the kinase is not essential for acute pain but rather is important in chronic pain hypersensitivity [29]. Src-dependent phosphorylation of NMDARs is involved in both inflammatory pain and neuropathic pain, as inferred from the effects of a 10-amino-acid peptide derived from Src unique domain fused with the protein transduction domain of HIV Tat protein (Src40-49Tat), rendering the peptide membrane permeant [29]. Src40-49Tat uncouples Src from the NMDAR complex, thereby inhibiting Src-mediated upregulation of NMDARs [14]. Administering Src40-49Tat reverses mechanical, thermal, and cold pain hypersensitivity induced by inflammation and peripheral nerve injury (PNI), without changing basal sensory thresholds and
Basal
Microglia-Neuron Signaling Mediates Enhanced Transmission after Peripheral Nerve Injury The dominant theme in research on pain, as in all of neurobiology, for most of the past 100 years has been to understand the role of neurons. Until recently, glial cells were generally considered to serve primarily housekeeping roles in the nervous system. However, this view has changed radically in the last half-decade, in particular for the role of microglia in pain resulting from PNI. In the healthy CNS microglia are not dormant [7,37] as thought until recently, but instead engage in continuous
Sensitized
Sensitized
Glu
Glu
Intense Peripheral Nociceptive Stimulation
Glu
acute nociception. Furthermore, no confounding sedation, motor deficit, or learning and memory impairment was observed at doses that suppress pain hypersensitivity. Thus, uncoupling Src from the NMDAR complex prevents phosphorylation-mediated enhancement of these receptors and thereby inhibits pain hypersensitivity while avoiding the deleterious consequence of directly blocking NMDARs [24].
Mg2+ NMDAR
AMPAR KAIR
-
ND2
Na+
-
STEP
Csk CAKE E
ND2
P
Src
PTPĮ
GPCR, EphB and other signaling
P
Src
P
ND2
Src
+ CAKE
Ca2+
CAKE
AMPAR KAIR
Fig. 1. A model for the role of sensitization of nociceptive dorsal horn neuron in pain hypersensitivity. Left: under basal conditions, NMDAreceptor (NMDAR) activity is suppressed by partial blockade of the channel by Mg2+ and by the activity of the protein tyrosine phosphatase, STEP, and the kinase, Csk. AMPAR, AMPA receptor; KAIR, kainate receptor. Middle: nociceptive input increases NMDAR-mediated currents (1) by relief of Mg2+ inhibition; (2) by activation of Src (Src∗) via the actions of PTPα and activated CAKβ (CAKβ-P), which overcomes the suppression by STEP; and (3) by sensitizing the NMDARs to raised intracellular [Na+]. GPCR, G-protein-coupled receptor. Right: upregulation of NMDAR function allows a large boost in entry of Ca2+, which binds to calmodulin (CaM), causing activation of CaMKII (not illustrated). The enhancement of glutamatergic transmission is ultimately expressed through increased number of AMPARs/KAIRs in the postsynaptic membrane and/or through enhanced AMPA/KAIR activity.
3
Mechanisms of Cancer Pain: Experimental Data Sital Patel, BSc, and Anthony H. Dickenson, PhD, FmedSci
Department of Neuropharmacology, University College London, London, United Kingdom
Improvements in the detection and treatment of cancers have resulted in patients surviving longer, but at a high cost of decreased quality of life, and severe pain is often a major contributor [36]. Bone metastases are frequently predictive of pain, and bone cancer pain is in fact the most common cancer-related pain; approximately 90% of cancer patients experience bone pain, and only about half of these have even temporary relief from conventional therapies [31]. Patients experience a triad of pain states consisting of background pain, spontaneous pain, or incident pain. The intermittent nature of spontaneous and incident pains makes them hard to treat, and it is very difficult for patients with bone metastases to attain freedom from pain on movement [30]. Currently, treatment of bone cancer involves a number of approaches including radiotherapy, chemotherapy, surgical intervention, pharmacotherapy, or a combination of these treatments. However, several novel compounds are currently under investigation, including denosumab, osteoprotegerin analogues, and anti-angiogenic agents [35]. In terms of pharmacotherapy for the pain associated with bone metastases, the main classes of drugs used are bisphosphonates, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Nonpharmacological treatments for the palliation of bone cancer include radiopharmaceuticals, of which the newer beta-emitting isotopes display better pharmacokinetic and decay properties [33]. Pain 2010—An Updated Review: Refresher Course Syllabus edited by Jeffrey S. Mogil IASP Press, Seattle, © 2010
Animal models of human diseases represent an area with a proven track record for value to translational research, particularly in the field of chronic pain; we have greater knowledge of nociceptive processing at the peripheral, spinal, and supraspinal level thanks to investigation in animal models of inflammatory and neuropathic pain. Until recently, cancer pain has been studied much less than other pains, but things are starting to change. Understanding the mechanisms of cancer pain was revolutionized by the development of animal models by Patrick Mantyh and colleagues [44]. Cancer-induced bone pain (CIBP) is a unique pain state but with some mechanisms overlapping those of chronic inflammatory and neuropathic pain. This chapter is an overview of current preclinical knowledge of mechanisms and treatments of cancer pain. Cancer pain can be considered to be a mixedmechanism pain, and not a single neuropathic, visceral, or somatic pain state. It is a complex syndrome where inflammatory, neuropathic, and ischemic mechanisms are often involved, and at more than a single site. Inflammation-induced changes will be caused by direct tissue damage resulting from tumor growth as well as by the release of pain mediators by the cancer cells themselves. The neuropathic pain component can be due to preexisting cancer-induced damage to sensory nerves such as infiltration or compression, as well as subsequent interventions such as chemotherapy and surgery that in turn may cause neuropathy. Although the effectiveness 27
52
Irene Tracey
metabolic response electrical activity - excitatory - inhibitory - soma action potential electrophysiology
- ↑ glucose consumption - ↑ oxygen consumption
FDG PET autoradiography H215O PET
hemodynamic response - ↑ blood flow - ↑ blood volume - ↑ blood oxygenation
EEG
NIRS optical imaging fMRI
MEG Fig. 1. The main imaging modalities in use today and the physiological correlate of brain activity they measure. EEG, electroencephalography; FDG, fluorodeoxyglucose; fMRI, functional magnetic resonance imaging; MEG, magnetoencephalography; NIRS, near-infrared spectroscopy; PET, positron emission tomography.
PET and fMRI thus measure brain activity indirectly, by imaging changes in blood flow, blood oxygenation, or local metabolic changes. Currently, PET and fMRI are the most extensively used tools in neuroimaging research in humans. The temporal resolution of PET is on the order of tens of seconds, while for fMRI it is shorter, which has significant advantages, as discussed later. Furthermore, fMRI is a completely noninvasive tool, unlike PET, which requires injection of a radioligand, and this feature provides added flexibility in terms of paradigm designs and patient studies. However, as discussed more extensively in the chapter by Schweinhardt in this volume, PET provides the additional opportunity for examining specific neurotransmitters or receptors and therefore, unlike fMRI,
has increased biological specificity. PET and MRI can therefore be employed to provide information on the anatomical structure and the neurochemical composition of the central nervous system (CNS), which along with functional information, yields a systems view of pain processing within the CNS. Advances in our ability to “label” receptors, neurotransmitters, or even intracellular substrates allow techniques based on PET (and to lesser extent MRI) to image their function and distribution within the CNS. These “labels” provide a “visual report” from the scene of cellular events. Molecular imaging has thus been defined as the measurement and imaging of biological processes in vivo at the molecular and cellular level.
Table I Comparison of fMRI and PET imaging techniques Modality
BOLD fMRI
15
Working principle
Detects changes in the magnetic field due to variations in the oxyhemoglobin : deoxyhemoglobin ratio
Detects the radioactive isotopes that are tagged onto the molecule of interest
Availability
Most tertiary medical centers
Isotopes are short-lived and must be generated by a nearby cyclotron
Invasiveness
Completely noninvasive
Employs radioisotopes; requires intravenous access as minimum
Spatial resolution
1–2 mm
5 mm at best
Temporal resolution
Hundreds of milliseconds
Minutes
Experimental design
Flexible; limited mainly by noise and magnetic environment
Limited by tracer half-life and radiation dose
Derived data
Unable to quantify the physiological baseline
Able to quantify the physiological baseline
O-Water PET
Abbreviations: BOLD fMRI, blood-oxygenation-level-dependent functional magnetic resonance imaging; PET, positron emission tomography.
Pain Models: Animals to Humans
93
Why Include a Pain Model in a Chronic Pain Clinical Trial? Correlating Study Drug Effects on Experimental Pain and Chronic Pain A matrix of possible correlations is presented in Table I. The first requirement is that the drug has been shown effective in experimental pain models in healthy volunteers using the same or a very similar pain model. If the treatment effects on experimental and chronic pain are correlated, the study shows that the study drug is effective and that experimental and chronic pain may share common mechanisms. This outcome would strongly support a “go-decision” for further development of the drug (Table IA). If the drug is effective only in experimental, but not clinical, pain (Table IB), the study confirms the healthy volunteer data but suggests that the drug will not be useful for that that particular type of chronic pain. The drug may still be effective, but it should not be developed for that disease indication. It is possible that the clinical pain has a different underlying mechanism than the experimental pain, or that the subjects included simply do not represent the disease. It becomes more difficult to interpret the results when the drug is effective in clinical, but not experimental, pain (Table IC). Possible interpretations include placebo response, expectations, or the possibility that the study drug is effective for the mechanisms underlying the chronic pain, but that these mechanisms were not simulated by the model (model failure). An example would be intravenous lidocaine, which is effective in chronic neuropathic pain, but not convincingly effective in human experimental pain models. The effect of lidocaine probably depends on neuronal injury that cannot be mimicked in human pain models. The effect of intravenous lidocaine on experimental and clinical pain has not been tested simultaneously in patients, however. Table I Interpretations of possible outcomes comparing drug effects on clinical pain and experimental pain (heat/capsaicin sensitization model) Clinical pain success
Clinical pain failure
Experimental pain success
(A) Efficacy validated
(B) Clinical failure
Experimental pain failure
(C) Expectations/placebo? Model failure?
(D) Study failure? Drug failure?
When the drug has no effect on experimental or clinical pain (Table ID), the reason may be true lack of drug effect or study failure. The results from Phase 1 studies can help guide interpretation. In this situation, no recommendation regarding further development can be made.
Analgesic Drug Development Once an analgesic effect of the study drug has been demonstrated in a human experimental pain model or in a preclinical or Phase 1 study, the model can be used again in later studies at each stage of development. This model could take the place of a standard positive comparator drug and thereby simplify the study design because an additional control session with the comparator drug might be eliminated. The effects of the study drug on experimental and clinical pain can be correlated as demonstrated in Table I, which will aid in study interpretation along with Phase 1 results. Models can also be useful as an additional means of gathering data on the time course of analgesic effect by repeating model measures at different time points after dosing has started, either in a single-dose, single-session format, or during a multiple-dose study. Dose-response data can be gathered by comparing the effect on model measures after administering various doses (Fig. 4). The stimulus applied with the model is standardized across all subjects, whereas the injuries leading to chronic pain vary across subjects and diseases, possibly contributing to variations in drug response. Day 1
Day 2
TITRATION
Day 3
Day 4
STEADY STATE
Fig. 4. Example of an experimental protocol combining assessment of clinical and experimental pain. Analgesic effects of cannabis are assessed in neuropathic pain patients by daily visual analogue scale (VAS) pain ratings (upper panel). In addition, experimental pain models (Heat/Capsaicin with 4 rekindling periods [RK1–RK4]) are employed repetitively for 4 days (lower panel). Medication is started after the first test. Systemic levels of the drug can then be correlated to clinical analgesic effects and to analgesia in the models.
Investigating Drug Mechanism of Action and Pain Mechanisms The mechanisms underlying the sensory phenomena observed in the cutaneous sensitization models have been extensively studied. The addition of models in
Is CRPS Neuropathic?
115
catecholamines by a presynaptic action, may be helpful when small areas of hyperalgesia are present.
functional restoration [39,40]. The pain specialists should include neurologists, anesthesiologists, orthopedic surgeons, physiotherapists, psychologists, and the general practitioner. The severity of the disease determines the therapeutic regime (Fig. 1). The reduction of pain is the precondition with which all other interventions have to comply. All therapeutic approaches must not cause any pain themselves. At the acute stage of CRPS, when patients still have severe pain at rest and
Therapy Guidelines for CRPS Treatment of CRPS should be immediate and, most importantly, should be directed toward restoration of full function of the extremity. This objective is best attained in a comprehensive interdisciplinary setting with particular emphasis on pain management and
Diagnosis
CRPS Start treatment as early as possible SMP ?
Psychological pathway Pain coping skills Biofeedback Relaxation training Cognitive-behavioral therapy
Rehabilitation pathway Respect pain threshold. The therapy must not hurt! Pain management (anticonvulsants, antidepressants, opioids, topicals)
Physiotherapy Occupational therapy
Interventional pain management (sympathetic blocks)
Acute stages with inflammatory component (edema) Corticosteroids
Treatment adapted to degree of severity Severity of CRPS Severe Intense pain at rest and during movements
Intense pain management Immobilization Contralateral physiotherapy If SMP: sympathetic blocks
Moderate No pain at rest, but pain during movement
Pain management Physiotherapy and occupational therapy up to pain threshold
Mild No pain at rest and no pain during movement
Intense physiotherapy and occupational therapy
Inadequate or partial
Increase frequency and intensity of psychotherapy
Therapeutic consequence
Relapse
Repeat pathway Neurostimulation (e.g., spinal cord stimulation) Epidural clonidine Severe dystonia Intrathecal baclofen
Fig. 1. Therapeutic regime for complex regional pain syndrome (CRPS), based on disease severity. SMP, sympathetically maintained pain.
Pain-Related Mutations
247
A
B
Fig. 4. (A) Cartoon depicting a glutamatergic synapse in the central nervous system and the functional roles of proteins encoded by the FHM1, FHM2, and FHM3 genes. CaV2.1 calcium channels are located in the presynaptic terminal of excitatory and inhibitory neurons. In response to an invading action potential, these channels gate, allowing Ca2+ to enter and triggering vesicle fusion and glutamate release into the synaptic cleft. K+ in the synaptic cleft is removed in part by the action of the Na+/K+-ATPase located at the surface of glial cells (astrocytes). Removing extracellular K+ serves to dampen neuronal excitability and maintains a Na+ gradient, which drives uptake of glutamate from the cleft by transporters (e.g., EAAT1). Lastly, the NaV1.1 voltage-gated sodium channel is expressed in inhibitory interneurons, where it serves to initiate and propagate action potentials. Gain-of-function mutations in CaV2.1 and loss-of-function mutations in ATP1A2 and NaV1.1 will each lead to a net eect of increased general excitability (reproduced from [4]). (B) Representation of the cell membrane of dorsal root ganglion (DRG) and superior cervical ganglion (SCG) nerve terminals showing the respective complements of voltage-gated sodium channels that are present in these neurons. The NaV1.8 and NaV1.9 sodium channels require stronger depolarization to activate relative to NaV1.1, NaV1.3, NaV1.6, and NaV1.7. In addition, NaV1.8 and NaV1.9 channels contribute to persistent and slowly inactivating currents, respectively.
Management of Neuropathic Pain
287
Table I Number needed to treat using various analgesics for different neuropathies Number Needed to Treat (95% CI)
Drug
No. Trials/ No. Positive Trials
Tricyclic antidepressants
23/20
Central Pain
Painful Polyneuropathy
Postherpetic Neuralgia
Peripheral Nerve Injury
Mixed Neuropathic Pain
2.7 (1.7–6.1)
2.1 (1.9–2.6)
2.8 (2.2–3.8)
2.5 (1.4–11)
NA
SNRIs
7/5
ND
5.0 (3.9–6.8)
ND
NA
ND
SSRIs
4/3
ND
6.8 (3.9–27)
ND
ND
ND
Gabapentin
14/8
NA
6.4 (4.3–12)
4.3 (3.3–6.1)
NA
8.0 (5.9–32)
Pregabalin
14/13
5.6 (3.5–14)
4.5 (3.6–5.9)
4.2 (3.4–5.4)
ns
3.8 (2.6–7.3)
Opioids
9/8
ND
2.6 (1.7–6.0)
2.6 (2.0–3.8)
5.1 (2.7–3.6)
2.1 (1.5–3.3)
Tramadol
6/6
ns
4.9 (2.1–9.0)
4.8 (2.6–27)
NA
ND
NMDA antagonists
13/2
ND
3.4 (1.8–6.6)
ns
ns
ns
Lidocaine patch
3/2
ND
ND
NA
NA
4.4 (2.5–17)
Cannabinoids
6/5
3.4 (1.8–23)
ns
ND
ns
ns
Capsaicin
11/6
ND
11 (5.5–316)
3.2 (2.2–5.9)
ns
NA
NGX capsaicin
3/3
ND
ND
ns
ND
ND
Botulinum toxin A
2/2
2.3 (1.5–4.7)
ND
ND
ND
3.0 (1.6–22)
Nitrate spray
3/3
NA
ND
ND
ND
ND
Source: N.B. Finnerup et al., unpublished observations. Abbreviations: NA, dichotomized data are not available for calculating number needed to treat (NNT); ND, studies not done; NMDA, N-methyl-D-aspartate; ns, absolute risk difference not significant; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.
doses of morphine and gabapentin. They showed a higher pain reduction with gabapentin and morphine at lower doses than when either compound was given alone [14]. In a recent study, a similar beneficial effect was shown for the combination of gabapentin and a tricyclic antidepressant [15].
Novel Therapeutic Approaches Botulinum toxin, which has been shown to inhibit vanilloid receptors and to inhibit release of glutamate and substance P, has also been shown to have a pain-relieving effect in patients with focal peripheral neuropathic pain and allodynia [34] and in diabetic neuropathic pain [43]. Other substances such as glycine antagonists, cyclooxygenase-2 inhibitors, acetylcarnitine, and neurotrophic factors have failed in clinical trials [10].
Practical Guidelines for Pharmacological Therapy Before choosing a neuropathic pain treatment, clinicians need to consider the benefits and hazards of a specific treatment. Table I presents a list of the numberneeded-to-treat (NNT) values for various drug classes against different groups of neuropathic pain conditions. In general, the simpler and less harmful treatments
should be chosen, and the efficacy of one compound should always be compared with its adverse effects. It is mandatory that clinicians be familiar with contraindications; this is particularly important in the elderly. Cardiac conduction abnormalities (e.g., AV block), congestive heart failure, and convulsive disorders are contraindications for treatment with TCAs. For anticonvulsants the contraindications are fewer, but side effects such as sedation, dizziness, tremor, and skin rashes are not uncommon. Adverse effects are important in the decision of any treatment for pain. The calculation of adverse effects, usually as the number needed to harm (NNH), is rarely done in a systematic way that permits an analysis of the specific harm caused by one agent. In most cases, the only harmful effect that can be calculated in a systematic fashion is the number of patients who drop out of a trial [10], and in these cases it is assumed that dropouts are due to side effects. Before starting a pharmacological treatment, the clinician must consider the patient’s age, concomitant medical conditions, depression, sleep disturbances, and other psychosocial factors. Realistic expectations for the outcome of a given treatment should be discussed with the patient, and it should be explained that often only partial pain relief can be expected.
Interventional Therapies for Chronic Pain
295 chronic radiculopathy [73]. This patient group has characteristics similar to those with other nerve injuries, and initial management should consist of pharmacological treatment for neuropathic pain [18].
Acute Lumbosacral Pain Most patients presenting with acute onset of lumbosacral pain without radicular symptoms have no obvious abnormal physical findings [29], and radiologic imaging is unlikely to be helpful [39]. Traumatic sprain of the muscles and ligaments of the lumbar spine or the zygapophyseal joints, and early internal disk disruption, are significant causes of acute lumbosacral pain. Similar to patients with acute radicular pain, this group is best managed symptomatically.
Chronic Lumbosacral Pain
Fig. 1. The definition of low back pain. (A) “Low back pain” is more precisely termed “lumbosacral spinal pain,” which encompasses both lumbar spinal pain (L) and sacral spinal pain (S). (B) Radicular pain describes pain that is referred to the lower extremity and is caused by stimulation of a spinal nerve.
There are many causes of chronic lumbosacral pain, and the anatomical cause cannot be identified with certainty in up to 90% of cases [40]. The structures most
Acute Radicular Pain Herniated nucleus pulposus typically causes acute radicular pain, with or without radiculopathy (signs of dysfunction including numbness, weakness, or loss of deep tendon reflexes referable to a specific spinal nerve). In elderly patients and those with extensive lumbar spondylosis, acute radicular symptoms caused by narrowing of one or more intervertebral foramina can occur [16]. Initial treatment is symptomatic, and symptoms resolve without specific treatment in about 90% of patients [59]. For those with persistent pain after HNP, lumbar diskectomy may be indicated. A controlled trial of surgical versus nonoperative treatment showed significant improvement in both groups over 2 years, but it was inconclusive about the superiority of either approach [72].
Chronic Radicular Pain Persistent leg pain in the distribution of a spinal nerve may occur in patients with a disk herniation with or without subsequent surgery. In those with persistent pain, a search for a reversible cause of nerve root compression is warranted. In many individuals, scarring around the nerve root at the operative site can be seen with magnetic resonance imaging (MRI) [7], and electrodiagnostic studies show a pattern suggesting
Fig. 2. The functional spinal unit and the degenerative changes that lead to lumbosacral and radicular pain. (A) The normal functional spinal unit. (B) The degenerative changes leading to lumbosacral pain (disk disruption, facet joint arthropathy) and radicular pain (herniated nucleus pulposus). (C) The degenerative changes of lumbar spondylosis leading to lumbosacral (facet joint) pain, radicular (foraminal stenosis) pain, and neurogenic claudication (central canal stenosis).
Persistent Abdominal and Pelvic Pain pain disorders, including IBS [37]. IBS was associated with decreased gray matter density in widespread areas of the brain, including medial and lateral prefrontal regions. Compared with healthy controls, increased gray matter density in IBS patients was observed in the pregenual anterior cingulate cortex and the orbitofrontal cortex, both regions involved in the stress and arousal circuit. Analogous structural changes have been reported in other persistent pain disorders, including vulvodynia [35].
Summary and Conclusion Despite significant progress during the past two decades in the characterization of peripheral and central candidate mechanisms that may play a role in the pathophysiology of persistent abdominal and pelvic pain states, it is becoming obvious that no single pathophysiological mechanism can explain symptoms in all patients. Nevertheless, the similarities in peripheral and central mechanisms implicated in IBS and PBS/IC are remarkable. Based on currently available information, it is likely that different patterns of dysregulation
341 in the interactions between the central nervous system and the respective abdominal and pelvic end organs are involved in different subsets of patients. Gene-environment interactions are likely to shape the vulnerability of individuals to develop chronic abdominal and pelvic pain states by altering the specific components of these neurovisceral interactions [9,32]. Some of plausible components of these interactions are illustrated in Fig. 2. The brain receives interoceptive input from abdominal and pelvic viscera and responds to these inputs in a reflexive way, taking into account contextual factors and other needs of the organism. In the healthy individual, most of this interoceptive input is not consciously perceived. However, alterations in the modulation of interoceptive input by stress and arousal circuits, and cortical input to these circuits, can alter both perception and feedback to these organs. The brain responds to the interoceptive input through the emotional motor system (EMS) [15], which refers to a set of parallel motor pathways governing somatic, autonomic, neuroendocrine, and pain modulatory motor responses associated with different emotions, including those associated with the stress response and emotional
Fig. 2. Bidirectional brain-visceral interactions which may play a role in the pathophysiology of irritable bowel syndrome (IBS) and painful bladder syndrome/interstitial cystitis (PBS/IC). ACTH, adrenocorticotropic hormone; ECC, enterochromaffin cells; ICC, interstitial cells of Cajal; PSNS, parasympathetic nervous system; SNS, sympathetic nervous system.
442 can differ widely from values reported by the same subject in other instruments assessing pain, even though there is tendency for correlation of mean values across instruments [72]. Pain scores also fluctuate depending on whether pain is assessed in the morning or evening. The fact that individuals may report inconsistent responses to the different assessment instruments at the same time, together with the very strong placebo response in many pain trials, suggests that there is still room to explore whether analgesic trials are using too many instruments to assess pain, whether the patient’s interpretation of what is being reported is the intended one, and whether there is a best set of instruments or question construction that can distinguish signal from noise.
Challenges Beyond Phase 2: Meeting Standards for Regulatory Approval Generalizing outcome (either positive or negative) from one population to another is not a straightforward process, or even possible at the current level of understanding. For example, efficacy in osteoarthritis pain does not inform on the likelihood of efficacy in PDN, and vice versa. To add to the problem, efficacy in PDN does not inform on efficacy in other types of neuropathic pain, and efficacy in osteoarthritis of the knee may not be accepted as predictive of osteoarthritis in other locations. Many drugs have reached Phase 3 development based on efficacy in one population, only to fail in new populations. In some cases this outcome may have been due to a failure to conduct careful Phase 2 trials before launching into large Phase 3 trials, and in other cases it may have been lack of correspondence in efficacy between pain conditions. One example is lamotrigine, a drug established as an anticonvulsant, which appeared to be effective in a number of small trials in neuropathic pain (including diabetic neuropathy and HIV-associated neuropathy), but in two large Phase 3 diabetic neuropathy trials [75] and one large Phase 3 HIV-associated neuropathy trial [64], lamotrigine failed to separate from placebo. Topiramate, another established anticonvulsant, also failed in three large Phase 3 trials in diabetic neuropathy [72]. Pregabalin, which was originally approved as an anticonvulsant and for PHN and PDN, has subsequently shown mixed results in other types of neuropathic pain or chronic pain [47,65,76]. Bupropion, an established antidepressant with evidence of efficacy in a small mixed neuropathic pain trial, failed in a CLBP trial [34].
Steve Quessy There are many potential reasons for attrition in Phase 3, and while most are not unique to analgesics, the rate of attrition for analgesics does seem to be above average. By far the greatest challenge in Phase 3 analgesic trials is the placebo effect in long-term trials [33,50]. The combined interactions of a placebo response and analytic methods for handling missing data for dropouts is making it difficult to achieve positive results that meet regulatory evidentiary requirements using standard designs. The problem is compounded for drugs that are poorly tolerated initially, or that require a titration to effective dose [49]. Despite many attempts at analyzing factors that influence positive or negative outcomes in pain trials [9,14,16,24,32,33,35,36,44,49, 50,57,72,81], there is no clear convergence on the “best” way to design and conduct a trial to maximize success. A summary of identified issues thought to affect trial success is given in Table II. Table II Factors associated with study failure or high placebo response Study Factor
Ref.
Baseline pain scores too low (sensitivity) Too many treatment groups (anticipation) Forced fixed dose levels (flexible dosing regimen reduces dropouts) Unrealistic patient expectations (motivations) Influences/communications by site personnel Inability to identify and select out placebo responders (noise)
33
Selection of pain instrument different from primary endpoint instrument (sensitivity loss on primary endpoint) Pain questionnaire is not specific to painful location (sensitivity) Analgesic use allowed during washout period (confounded baseline) Analgesic washout period prior to randomization too short (unstable baseline) Long-term placebo response (sensitivity)
72
Impact of early dropouts during titration period (i.e., before achieving assigned target dose) Long-term placebo response (sensitivity)
75
Centers with rapid recruitment associated with greater placebo response
32
Source: Compilations from sources shown.
As development progresses to trial exposures of longer duration and in a broader range of populations, some of the following issues may arise that affect the probability of success or the timing of potential approval. • Tachyphylaxis may occur (a loss of effect over time) (this issue applies to opioids).