Pain 2012RefResheR CouRses

14th World Congress on Pain

InternatIonal assoCIatIon for the study of PaIn

Pain 2012 R

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sIrene tracey, Editor

Irene tracey, Editor

International Association for the Study of Pain

Every two years, the International Association for the Study of Pain (IASP) creates a benchmark publication of articles summarizing the status of pain research and management throughout the world. IASP has brought together many of the foremost authorities on pain to write about the latest thinking in their specific fields.

The resulting book, Pain 2012, gathers the presentations that these experts gave at the refresher courses preceding the World Congress on Pain in Milan, Italy, in August 2012. IASP Press published all of these articles in one book for use at the refresher courses themselves, as well as for pain researchers and clinicians everywhere who are unable to come to the Congress.

IASP website: http://www.iasp-pain.org/books

IasP scientific Program Committee

9 780931 092930

9 0 0 0 0ISBN 978-0-931092-93-0

IASP PRESS® • SEATTLE

Pain 2012Refresher Courses

14th World Congress on Pain

Edited by Irene Tracey, PhD

Chair, Scientifi c Program Committee

© 2012 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 2012: Refresher Courses, 14th World Congress on Pain do not necessarily refl ect those of IASP or of the Offi cers 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 verifi cation of diagnoses and drug dosages.

Library of Congress Cataloging-in-Publication Data

IASP Refresher Courses on Pain Management (2012 : Milan, Italy) Pain 2012 : refresher courses : 14th World Congress on Pain : IASP Refresher Courses held in conjunction with the 14th World Con-gress on Pain, August 27-31, 2012 Milan, Italy / IASP Scientifi c Program Committee, Irene Tracey ... [et al.]. p. ; cm. Includes bibliographical references and index. ISBN 978-0-931092-93-0 I. Tracey, Irene. II. IASP Scientifi c Program Committee. III. World Congress on Pain (14th : 2012 : Milan, Italy) IV. Title. [DNLM: 1. Pain Management--Congresses. WL 704.6]

616’.0472--dc23

2012026464

Published by:IASP PressInternational Association for the Study of Pain111 Queen Anne Ave N, Suite 501Seattle, WA 98109-4955, USAFax: 206-283-9403www.iasp-pain.orgPrinted in Italy

iii

Contents

Preface vii

Part 1: An Update on the Neurobiology of Acute and Persistent Pain

1. Nociceptors, the Spinal Dorsal Horn, and Descending Modulation 3 Frank Porreca

2. Dorsal Horn Plasticity and Neuron-Microglia Interactions 15 Michael W. Salter

Part 2: Pain Genes for Unraveling Pain: A Course for Non-Geneticists

3. What Are “Pain Genes,” and Why Are Th ey Interesting? 29 Marshall Devor

4. Progress and Challenges in Genome-wide Association Studies of Pain 41 Shad B. Smith, Inna E. Tchivileva, William Maixner, and Luda Diatchenko

5. Genetic Studies in Migraine with Relevance to Other Pain Disorders 51 Else Eising, Boukje de Vries, Arn M.J.M. van den Maagdenberg, and Michel D. Ferrari

Part 3: Pain Psychology for Non-Psychologists

6. Pain Psychology for Non-Psychologists 67 Amanda C. de C. Williams, Lance M. McCracken, and Johan W.S. Vlaeyen

Part 4: Neuropathic Pain Update: From Basic Mechanisms to Clinical Management

7. Neuropathic Pain Update: From Basic Mechanisms to Clinical Management 85 Nadine Attal, David Bennett, and Rolf-Detlef Treede

Part 5: Fundamentals of Neuropathic Pain Assessment and Diagnosis

8. Diagnosing Neuropathic Pain: Clinical Examination, Neurophysiology, and Neuroimaging 111 Maija Haanpää and Michael Rowbotham

9. Neuropathic Pain Screening Tools 123 Didier Bouhassira

Part 6: Persistent Postoperative Pain: Pathogenic Mechanisms and Preventive Strategies

10. Persistent Postoperative Pain: Pathogenic Mechanisms and Preventive Strategies 133 Henrik Kehlet, Robert R. Edwards, and Asokumar Buvanendran

Part 7: Chronic Musculoskeletal Pain Update: From Basic Science to Management

11. Musculoskeletal Pain Mechanisms and Quantitative Assessment 147 Th omas Graven-Nielsen and Lars Arendt-Nielsen

12. Diagnosing and Treating Chronic Pain on the Basis of the Underlying Mechanisms: Are We Th ere Yet? 157 Daniel J. Clauw

13. Nonpharmacological Treatment of Chronic Musculoskeletal Pain 169 Kim Bennell

iv Contents

Part 8: Update on the Management and Treatment of Complex Regional Pain Syndrome

14. Treatment of Complex Regional Pain Syndrome: Where Are We At, and Where To Now? 179 Frank Birklein, Frank J. Huygen, G. Lorimer Moseley, Candy McCabe, and Marlies den Hollander

Part 9: Low Back Pain: Basic Mechanisms, Treatment, and Management

15. Low Back Pain: Basic Mechanisms, Treatment, and Management 195 Steven J. Linton, Chris G. Maher, and Jan van Zundert

Part 10: Pathophysiology, Diagnosis, and Treatment of Persistent Abdominal/Pelvic Pain

16. Chronic Abdominopelvic Pain in Women 209 Fred M. Howard and Karen Berkley

17. Gastrointestinal Tract Pain: Basic Science and Clinical Implications 225 Emeran A. Mayer and Kirsten Tillisch

Part 11: Orofacial Pain for Physicians

18. Neurovascular Craniofacial and Orofacial Pain 239 Rafael Benoliel

19. Pain Associated with Temporomandibular Disorders 251 Antoon De Laat

20. Neuropathic Orofacial Pain 257 Eli Eliav

Part 12: Headache Update: Diagnosis and Th erapy

21. Trigeminal Autonomic Cephalalgias 271 Peter J. Goadsby

22. Tension-Type Headache 279 Rigmor Jensen and Lars Bendtsen

23. Migraine: An Update 287 Zaza Katsarava

Part 13: Cancer Pain Update: From Mechanisms to Treatment

24. Mechanisms of Cancer Pain 293 Sital Patel and Anthony H. Dickenson

25. Classifi cation and Assessment of Cancer Pain 297 Anne Kari Knudsen, Pål Klepstad, Cinzia Brunelli, Nina Aass, Augusto Caraceni, and Stein Kaasa

26. Treatment of Cancer Pain 301 Michael I. Bennett

Part 14: Rational Opioid Th erapy for Cancer and Noncancer Pain

27. Is Chronic Opioid Th erapy Comfort Care? 307 Jane Ballantyne and Mark Sullivan

28. Role and Management of Opioids in Chronic Pain 313 Seddon R. Savage

29. Opioid Th erapy for Cancer Pain 319 Mary Lynn McPherson

vContents

Part 15: Clinical Pharmacology: Evidence-Based Guidelines and Defi ning the Proper Outcome

30. Clinical Pharmacology of Antidepressants and Anticonvulsants for the Management of Pain 327 Ian Gilron

31. Clinical Pharmacology of Opioids in the Treatment of Pain 345 Eija Kalso

32. Clinical Pharmacology of Nonsteroidal Anti-Infl ammatory Drugs 355 Stephan A. Schug

Part 16: Interventional Th erapies for Chronic Pain: Indications and Effi cacy

33. Interventional Th erapies for Chronic Spinal Pain 363 Maarten van Kleef

34. Interventional Pain Techniques in Cancer Patients 369 Richard L. Rauck

35. Spinal Cord Stimulation and Evidence-Based Medicine 379 Richard B. North and Jane Shipley

Part 17: Treating Pain in Children: An Update

36. Th e Biological Basis of Pain in Infants and Children 391 Maria Fitzgerald

37. Treating Pain in Infants and Young Children: Current Practice, Recent Advances, 401 and Ongoing Debates Denise M. Harrison

38. Psychological and Nonpsychological Interventions for Chronic Pediatric Pain 411 Christiane Hermann

Part 18: Th e Basics of Neuroimaging and Brain Interference Techniques

39. Functional and Structural MRI Techniques for the Investigation of Pain 425 Petra Schweinhardt

40. Electrocortical Responses to Nociceptive Stimulation in Humans 431 Giandomenico D. Iannetti

41. Advances in the Use of Noninvasive Brain Stimulation for the Management of Pain 439 Gabriela Bravo and Felipe Fregni

Part 19: Emergent Alternative Th erapies for Chronic Pain

42. Emergent Integrative Th erapies for Chronic Pain 449 Vitaly Napadow, Karen Sherman, and Ted Kaptchuk

Index 461

Acknowledgments 472

vi

Irene Tracey, PhD, FRCA, holds the Nuffi eld Chair in Anaesthetic Sci-

ence, is Director of the Oxford Centre for Functional Magnetic Resonance

Imaging of the Brain (FMRIB), and is Head of the Nuffield Division of

Anaesthetics at the University of Oxford, England. Over the past 10 years

her multidisciplinary research team has contributed to a better understand-

ing of pain perception, pain relief, and nociceptive processing within the

injured and non-injured human central nervous system using neuroimaging

techniques. Th e FMRIB Centre is recognized as one of the world’s leading

neuroimaging laboratories that integrates research into key neurological and

neuroscientifi c problems with cutting-edge developments in magnetic reso-

nance physics and image analysis (http://www.fmrib.ox.ac.uk). Th e Centre

has approximately 100 scientists and clinicians from a range of backgrounds,

and Professor Tracey has been their Director for the past seven years.

Irene Tracey was born in 1966 and performed her undergraduate and graduate studies in Biochemistry at the

University of Oxford, where she graduated with First Class Honours, winning the Gibbs Prize for joint top-First.

She held a postdoctoral position at Harvard Medical School before returning to the United Kingdom in 1996 to

help establish the FMRIB Centre. She is an elected Councilor to the International Association for the Study of

Pain (IASP). In 2008, she was awarded the triennial Patrick Wall Medal from the Royal College of Anaesthetists,

and in 2009 she was made an FRCA for her contributions to the discipline. She is Deputy Chair of the UK’s Med-

ical Research Council’s Neuroscience and Mental Health Board.

She is married to Professor Myles Allen, a climate physicist, and they have three wonderful yet irrepressible chil-

dren: a daughter, Colette, and two sons, John and Jim.

vii

Preface

Every two years the world’s leading pain scientists and clinicians gather for the International Association for

the Study of Pain (IASP) World Congress to discuss the latest research and best clinical practice for the under-

standing and treatment of acute and chronic pain. Such is the pace of new discoveries in this fi eld that we be-

lieve there is value in providing refresher courses on core topics at the congress. Th is enables new and seasoned

pain researchers and clinician to be introduced to and updated on specifi c aspects of this multidisciplinary fi eld.

Th e course spans a wide range of topics from basic nociception through to clinical diagnosis and treatment; cer-

tain conditions are highlighted at each congress alongside the more commonly treated ones. Each authoritative

speaker at the refresher course prepares a written narrative of their topic, and these documents are collected and

edited into this volume. Th e material in each chapter is written such that a beginner can quickly get up to speed

on the topic, while a more experienced pain researcher is quickly updated on the latest fi ndings and practice,

with helpful references for further reading.

I wish to thank all the speakers for their professionalism and the care taken in preparing their material, and I

trust that you, like me, will fi nd the chapters both interesting and informative. I want to thank all members of

the Scientifi c Program Committee for their tireless eff orts in producing an excellent scientifi c program for Milan

2012. Finally, I wish to acknowledge and thank Elizabeth Endres for her excellent editorial work and Ivar Nelson

for such careful general production.

Irene Tracey

Oxford, June 28, 2012

viii

IASP Scientifi c Program Committee

Irene Tracey, PhD, FRCA, UK, Chair

Qasim Aziz, PhD, FRCP, UK

Rafael Benoliel, BDS, Israel

Mary Cardosa, MBBS, Malaysia

Daniel Clauw, MD, USA

Roger Fillingim, PhD, USA

Maria Fitzgerald, PhD, UK

Michael Gold, PhD, USA

Kazuhide Inoue, PhD, Japan

Satu Jääskeläinen, MD, PhD, Finland

Eija Kalso, MD, PhD, Finland, ex offi cio

Kathy Kreiter, USA, ex offi cio

Jeff rey Mogil, PhD, Canada, ex offi cio

Lorimer Moseley, PhD, Australia

Noriyuki Ozaki, MD, PhD, Japan

Barbara Przewlocka, PhD, Poland

Srinivasa Raja, MD, USA

Andrew Rice, MBBS, MD, FRCA, FFPMRCA, UK

Juergen Sandkühler, MD, PhD, Austria

Claudia Sommer, MD, Germany

Audun Stubhaug, MD, Norway

Manoel Teixeira, MD, PhD, Brazil

Jose Tesseroli de Siqueira, DDS, PhD, Brazil

Johannes Vlaeyen, PhD, Belgium

Pain 2012: Refresher Courses, 14th World Congress on PainEdited by Irene TraceyIASP Press, Seattle, © 2012

3

1Frank Porreca, PhD

Department of Pharmacology, University of Arizona Health Sciences Center,

Tucson, Arizona, USA

Nociceptors, the Spinal Dorsal Horn,

and Descending Modulation

Educational Objectives

1) Describe the normal function and pathobiology of

primary aff erent nociceptors.

2) Discuss nociceptive processing and neuroplasticity

in the spinal dorsal horn.

3) Describe current understanding and concepts in

neuron-glia and neuron-immune cell interactions in

acute and chronic experimental pain models.

4) List the brain neural networks involved in noci-

ceptive processing, and describe how these networks

change in chronic pain.

5) Discuss descending inhibitory and excitatory con-

trol mechanisms and their role in chronic pain

Introduction

Pain is defi ned by the International Association for the

Study of Pain (IASP) as: “An unpleasant sensory and

emotional experience associated with actual or po-

tential tissue damage, or described in terms of such

damage” [74]. Whereas pain is considered to be an ex-

perience with sensory, cognitive, and emotional com-

ponents, nociception refers to the neural process by

which stimuli that can elicit pain are detected by the

nervous system. Specialized primary aff erent sensory

neurons, termed “nociceptors,” are normally activated

by high-threshold stimuli and transmit excitatory sig-

nals to the dorsal spinal cord. Sensory neurons have

their cell bodies in the dorsal root ganglion (DRG) or

the trigeminal ganglion. Th e peripheral sensory neu-

rons are pseudounipolar, with an axonal stalk that bi-

furcates and sends axonal projections to peripheral

sites and a central projection to the dorsal horn of the

spinal cord or to the medullary dorsal horn. Conse-

quently, excitation of these sensory fi bers can result in

release of transmitters at both central and peripheral

sites, the latter eliciting “neurogenic infl ammation.”

High-intensity heat or mechanical stimuli or chemi-

cals that can produce damage to tissues are termed

“noxious” and are selectively detected by specifi c

transducers localized at the peripheral terminals of

nociceptors. Nociceptors are capable of encoding nox-

ious stimuli, and, critically, stimulation of nociceptors

reliably elicits sensations of pain in humans.

While most sensations are aff ectively neu-

tral, pain is unpleasant at threshold. It is this unpleas-

antness that serves as the teaching signal that allows

avoidance of stimuli that can damage tissues [32,33].

Th us, pain is an important physiological mechanism

that increases chances of survival.

Anatomical Characterization of Nociceptors

Primary aff erent sensory neurons can be classifi ed

by many criteria. Generally, however, classifi cation

has been based on the anatomical and electrophysi-

ological characteristics of these neurons. Th e Aβ fi -

bers are large-diameter myelinated fi bers with fast

Dorsal Horn Plasticity and Neuron-Microglia Interactions 19

nerve injury (PNI) [19,34,35], with the non-receptor

tyrosine kinase, Src, and the phosphatase, striatal-en-

riched tyrosine phosphatase (STEP), having major roles

[48]. Src and STEP are themselves subject to regulation,

and they provide a point of convergence through which

sustained enhancement of NMDARs may facilitate ex-

citatory synaptic transmission in nociceptive neurons

(see Fig. 1). Th e facilitation may occur through the en-

hanced NMDAR currents per se (Fig. 1, middle) or by

triggering enhancement of AMPA-receptor currents

(Fig. 1, right). Importantly, the basal sensory thresh-

olds and acute nociceptive behavior are not dependent

upon Src phosphorylation-mediated upregulation of

NMDAR function (Fig. 1, left), indicating that the ki-

nase is not essential for acute pain but rather is impor-

tant in chronic pain hypersensitivity [34].

Src-dependent phosphorylation of NMDARs

is involved in both infl ammatory pain and neuropath-

ic pain, as inferred from the eff ects 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 mem-

brane permeant [34]. Src40-49Tat uncouples Src from

the NMDAR complex, thereby inhibiting Src-medi-

ated upregulation of NMDARs [18]. Administering

Src40-49Tat reverses infl ammation- and PNI-induced

mechanical, thermal and cold pain hypersensitivity,

without changing basal sensory thresholds or acute

nociception. Furthermore, no confounding sedation,

motor defi cit, or learning and memory impairment

was observed at doses that suppress pain hypersensi-

tivity. Th us, uncoupling Src from the NMDAR com-

plex prevents phosphorylation-mediated enhance-

ment of these receptors, and thereby inhibits pain

hypersensitivity while avoiding the deleterious conse-

quence of directly blocking NMDARs [28].

Microglia-Neuron Signaling Mediates Enhanced Transmission after Peripheral Nerve Injury

Th e 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 re-

cently, 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, mi-

croglia are not dormant [11,42], as was thought until

recently, but instead are in continuous surveillance of

Basal SensitizedSensitized

GluIntense

PeripheralNociceptiveStimulation

Glu Glu

STEP

NMDAR

Mg2+

Na+

PND2Src

ND2Src

ND2Src�

+-- P �

AMPARKAIR

CAK��CAK�

CAK�P Ca2+

PTP�Csk GPCR, EphB and

other signaling

AMPARKAIR

Fig. 1. A model for the role of sensitization of nociceptive dorsal horn neurons in pain hypersensitivity. Left: Under basal conditions, NMDA-receptor (NMDAR) activity is suppressed by partial blockade of the channel by Mg2+ and by the activity of striatal-enriched pro-tein tyrosine phosphatase (STEP) and the kinase, Csk. AMPAR, AMPA receptor; KAIR, kainate receptor. Middle: Nociceptive input in-creases NMDAR-mediated currents (1) by relief of Mg2+ inhibition; (2) by activation of Src (Src*) via the actions of PTPα (protein tyro-sine phosphatase-α) and activated cell adhesion kinase-β (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. Th e enhancement of glutamater-gic transmission is ultimately expressed through an increased number of AMPA/KAIRs in the postsynaptic membrane and/or enhanced AMPA/KAIR activity.

Genetic Studies in Migraine 53

function upon activation is to mediate Ca2+ entry

at the nerve terminal, triggering the release of neu-

rotransmitters [7]. CACNA1A has been associated

with a wide range of clinical phenotypes, includ-

ing, besides FHM, episodic ataxia type 2 (EA2) and

spinocerebellar ataxia type 6 (SCA6) [106]. To date,

some 20 CACNA1A mutations—all missense muta-

tions—have been reported in FHM1 patients exhib-

iting a wide clinical spectrum from pure hemiplegic

migraine (i.e., in patients with the R192Q mutation)

[72] to hemiplegic migraine with associated cerebel-

lar ataxia, epilepsy, and mild head-trauma-induced

edema that can lead to coma and may sometimes be

fatal (i.e., in patients with the S218L mutation) [46]

(for a review, see [14]).

Functional studies in various cellular model

systems revealed that FHM1 mutations manifest as a

gain-of-function by shifting voltage-dependence to-

ward more negative membrane potentials and by en-

hancing channel open probability (for a review, see

[75,76,97]). Th is situation would lead to increased neu-

ronal Ca2+ infl ux and increased neurotransmission,

predictions confi rmed by studies in transgenic knock-

in mice carrying either the human FHM1 R192Q or

S218L mutation in the orthologous Cacna1a gene

[94,98,99]. Neuronal Ca2+ infl ux and neurotransmis-

sion phenotypes in FHM1 mutant mice are more pro-

nounced in those with the S218L mutation than those

with the R192Q mutation, which coincides well with

the more severe phenotype in FHM1 patients with the

S218L mutation. Notably, the S218L mutant mice ex-

hibited also the migraine-associated phenotypes seen

in patients with this mutation.

Consistent with the increased central excit-

ability, the FHM1 mutant mice are highly susceptible

to the induction of CSDs upon topical cortical ap-

plication of KCl or current injection into the cortex

[20,98,99]. Experimental CSD also caused a tempo-

rary hemiparesis, but only in FHM1 mutant mice [20].

Pharmacological blocking of excess cortical glutamate

in slices was capable of preventing the increased sus-

ceptibility to CSD [94], indicating that it indeed was

the increased neurotransmission phenotype that un-

derlies the increased susceptibility of CSD in FHM1

mutant mice. In the same study, it was shown that

inhibitory neurotransmission was not aff ected by the

FHM1 mutation, and thus an imbalance of excitatory

and inhibitory neurotransmission appears to underlie

FHM. Notably, in line with the female preponderance

in migraine patients, CSD susceptibility was more

Effe

ct si

ze

Allele frequency

very rare rare low frequency common 0.1% 0.5% 5% 50%

1

1.5

3

5

10

50

Mendelian mutations

FHM CACNA1A ATP1A2 SCN1A Other SCN9A

Rare variants with small effects

Common variants

Migraine GWAS MTDH, TRPM8, PRDM16, LRP1

Candidate genes MTHFR, SLC6A4, TRPV1, SCN9A

High effect common variants influencing

common disease

- Linkage analysis - Next generation sequencing Only few examples known

Very hard to detect - Candidate gene association studies - Genome-wide association studies

Fig. 1. Th e frequency and eff ect size of genetic risk factors determine which genetic approach can be used for their identifi cation. Mende-lian mutations with low frequency and high eff ect size can be detected by linkage analysis, as well as by next generation sequencing (NGS). Susceptibility variants underlying common disorders, with high frequency and low eff ect sizes, can be detected by an association approach; either in candidate gene or genome-wide association studies. For both types of causal DNA variants, examples are given from studies on migraine and other pain disorders. DNA variants with low frequency and low eff ect size are hard to detect with current techniques.

78 Amanda C. de C. Williams, et al.

Exposure in Vivo with Behavioral Experiments

Graded exposure to back-stressing movements has

been tested as a treatment approach for back pain

patients reporting substantial fear of movement/(re)

injury. Such a cognitive-behavioral treatment usually

consists of at least four steps: (1) defi ning treatment

goals; (2) education about the paradoxical eff ects of

safety-seeking behaviors; (3) establishing a fear hier-

archy; and (4) exposure to activities with increasing

levels of perceived harmfulness, according to the fear

hierarchy. A detailed description of the treatment can

be found elsewhere [125]. A series of studies using

replicated single-case experimental designs revealed

that decreases in pain-related fear occurred during the

exposure module only. Additionally, these improve-

ments were related to decreases in pain disability, pain

vigilance, and an increase in physical activity [4]. In

one study, patients with complex regional pain syn-

drome were able to take up desired functional activi-

ties after pain-related fear went down, but before pain

levels decreased below 50%, suggesting that fear of

pain is more disabling than the pain itself [29].

So far, the published RCTs on the eff ective-

ness of exposure in chronic low back pain have found

mixed results. Woods and Asmundson [136] ran-

domly assigned 44 patients to graded exposure in

vivo, graded activity, or a wait-list condition. Th ey

found that, in comparison with the graded activity

condition, patients in the graded in vivo exposure

condition demonstrated signifi cantly greater im-

provements on measures of fear of pain/movement,

fear avoidance beliefs, and pain-related anxiety, but

only trend diff erences for pain-related disability and

pain self-effi cacy. When graded exposure in vivo

was compared to the waiting-list control group, ex-

posure showed signifi cantly greater improvements

on measures of fear-avoidance beliefs, fear of pain/

movement, pain-related anxiety, pain catastrophiz-

ing, pain experience, anxiety, and depression. Over

a 3-month follow up, the exposure condition main-

tained improvements. Leeuw et al. [68] conducted

a multicenter trial in which 85 participants were in-

cluded in either a graded exposure or a graded activ-

ity program, and reported similar fi ndings. Exposure

resulted in a signifi cantly decreased perceived harm-

fulness of activity, while the diff erence between both

treatments in improved function almost reached sta-

tistical signifi cance. A recent review on treatments

available to address fear-avoidance beliefs in patients

with chronic musculoskeletal pain suggests that

graded exposure in vivo and ACT result in the best

outcomes for treating pain-related fear [4].

Challenges and Future Directions

Depression and Persistent Pain

Th e subject of depression in pain has been extensively

described over several decades of pain research and

treatment, and the interested reader is directed to re-

views [13,115]. Rather than being characterized as a

comorbidity, depressed mood is closely linked to pain

on many levels [91], from experience and symptoms

to common neurotransmitters [13]. It is more helpfully

understood within a broader context that includes fears

and restricted activity; persistent pain implies losses of

role, of pleasant activities, and often of an anticipated

active future, to the extent that the patient describes a

changed identity [85]. Rehabilitation usually brings an

improvement in mood, with recovery of activities and

of hopes [86], emotional disengagement and accep-

tance, and less rumination and “stuckness” [128].

An Aff ective-Motivational Approach

A number of authors have recently called for an ex-

panded aff ective-motivational approach with a promi-

nent focus on behavior in the context of multiple goals

[23,117,124]. In their attempt to resume daily life ac-

tivities, pain patients engage in various goals, some of

which are directly related to dealing with pain, whereas

others are not pain-related. Th ese multiple goals may

facilitate each other, or they can be confl icting. For

example, the goal to satisfy others by resuming work-

related activities may confl ict with the goal to protect

bodily integrity by staying safely at home. Unfortunate-

ly, unresolved pain-related goal confl icts may fuel fear

[63]. An emerging and intriguing question is whether

cognitive-behavioral therapies aimed at the re-evalua-

tion of major life goals and at the resolution of enduring

goal confl icts help to counter fear-driven and disabling

avoidance behavior [117,124]. When patients are pur-

suing a goal that competes with the goal to reduce pain,

both attentional bias toward pain cues and pain behav-

ior are inhibited [97,118]. It would be worthwhile to ex-

amine whether the eff ects of fear-reduction treatments

can be enhanced by adding a motivational component

focused at the resolution of goal confl icts [98].

Persistence Versus Avoidance

Finally, it is diffi cult to apply fear-avoidance principles

to musculoskeletal pain syndromes associated with

116 Maija Haanpää and Michael Rowbotham

NCV and SEPs remains of considerable importance

in the evaluation of pain patients, for several rea-

sons. First, large and small peripheral fi bers are ana-

tomically mixed in nerves, plexuses, and spinal roots,

without spatial segregation up to the dorsal root entry

zone, and therefore peripheral lesions, in particular

traumatic or metabolic, tend to aff ect large and small

fi bers indiscriminately. NCV studies are readily avail-

able and can be easily obtained, and their abnormality

on stimulation of a painful territory provides objective

evidence of somatosensory involvement, thus giving

strong support to the diagnosis of neuropathic pain.

A standard neurophysiological assessment including

NCV and SEPs should remain the fi rst-line approach

in cases of suspected neuropathic pain, before or in

parallel to more selective examinations of the pain and

temperature pathways [16].

Clinical examination alone is less sensitive

than several complementary tests to document the

presence of a somatosensory lesion [11,13,14]. For

example, electroneuromyography (ENMG) has been

shown to be superior to clinical examination alone

for the diagnosis of peripheral neuropathy [14]. Th is

widely available method is the best way to verify a

Fig. 3. Pain-mapping procedure.

Identification�of�Pain�and�Allodynia�Area�Situate�patient� Ensure�patient�is�comfortable,�willing�

to�move�clothes�away�from�the�PHN�area,�or�change�into�a�gown.�

�

Photograph�PHN�area�

With�a�digital�camera,�photograph�the�PHN�areas�from�as�many�angles�as�required�to�obtain�clear�views�of�the�entire�painful�area.�

�

Ask�patient�to�draw�on�photograph�

Print�photographs�on�a�color�printer�and�ask�the�patient�to�outline�the�maximal�area�of�spontaneous�pain�on�the�photograph�using�a�BLACK�marker.�

�

� Ask�the�patient�to�outline�on�the�photographs�the�area�of�the�skin�that�feels�unpleasant�to�the�touch�(allodynic�skin)�using�a�RED�marker.�

Locating�PHN�pain�on�the�skin�

Using�the�photographs�as�a�guide�and�with�the�patient’s�help,�outline�the�most�painful�area�using�the�following�techniques:�

�

Use�the�foam�brush�

The�foam�brush�should�be�positioned�so�that�the�long�axis�of�the�brush�is�parallel�to�the�direction�of�stroking.���

�The�right�amount�of�pressure�

Apply�enough�pressure�on�the�brush�to�where�the�brush�is�slightly�bent�upon�contact�with�the�skin.�

� Start�brushing�outside�the�area�of�pain�as�indicated�on�the�patient’s�photograph.�If�the�brush�stroke�does�not�feel�normal�for�the�patient,�move�further�away�from�the�pain�area�until�an�area�of�the�skin�without�pain�is�found.�

�

Gentle�strokes� Using�approximately�10�cm�long�strokes,�start�brushing�parallel�to�the�perimeter�of�the�area�of�pain,�and�perpendicular�to�the�vector�until�the�patient�indicates�pain.�Move�along�the�vector�1�cm�at�a�time�towards�the�area�of�pain�at�a�rate�of�1�stroke�per�second.� �

Marking�areas�of�pain�onto�skin�

Mark�the�skin�at�the�point�where�the�patient�indicates�that�the�brushing�feels�painful.�

Be�as�accurate�as�you�can.�

� �

160 Daniel J. Clauw

As with most illnesses that may have a familial

or genetic underpinning, environmental factors may

play a prominent role in triggering the development

of FMS and other central pain states. Environmental

“stressors” temporally associated with the develop-

ment of either FMS or CFS include early life trauma;

physical trauma (especially involving the trunk); cer-

tain infections such as hepatitis C, Epstein Barr virus,

parvovirus, or Lyme disease; and emotional stress.

Th e disorder is also associated with other regional

pain conditions or autoimmune disorders [1,11,13].

Of note, each of these “stressors” only triggers the de-

velopment of fi bromyalgia and/or chronic fatigue syn-

drome in approximately 5–10% of individuals who are

exposed; the overwhelming majority of individuals

who experience these same infections or other stress-

ful events regain their baseline state of health.

In fact, emerging evidence from a number of

diff erent areas in the pain fi eld suggests that the same

characteristics that are often attributable to FMS pa-

tients, in fact more broadly represents a “pain-prone

phenotype.” Fig. 2 portrays the fact that factors includ-

ing female sex, early life trauma, a personal or fam-

ily history of chronic pain, a personal history of oth-

er centrally mediated symptoms (insomnia, fatigue,

memory problems, and mood disturbances), and cog-

nitions such as catastrophizing, are present in subsets

of individuals with any chronic pain state and predict

which individuals are more likely to transition from

acute to chronic pain.

In addition to the study of central pain states,

we have made signifi cant advances in our broader un-

derstanding of chronic pain pathogenesis. Data from

experimental sensory testing and functional neuro-

imaging studies suggest wide individual variation in

sensory sensitivity that adheres to a bell-shape dis-

tribution across a wide variety of chronic pain states,

with a subset of individuals displaying hyperalgesia or

augmented CNS activity across pain states [1,69,78].

Th e centralized pain states originally identifi ed as hav-

ing diff use hyperalgesia/allodynia include FMS, IBS,

TMJD, idiopathic low back pain, tension headache,

IC, and vulvodynia [28–30,33,43,45,51,52,55,67,72,74].

Functional neuroimaging studies, especially those us-

ing functional MRI (fMRI), corroborate these experi-

mental pain testing fi ndings, showing that individuals

with central pain states have increased neuronal activ-

ity in pain-processing regions of the brain when they

are exposed to stimuli that healthy individuals fi nd in-

nocuous [15,30,32,56].

Several meta-analyses of fMRI studies have

summarized the brain regions that show activation

when experimental pain is applied to human subjects,

and these fi ndings generally agree with those of single

photon emission computed tomography (SPECT) and

PET studies. Activation sites across studies vary to

some degree, depending on experimental paradigm

and pain stimulus (e.g., heat, cold pressure, electric

shock, or ischemia). However, the main components of

this “pain matrix” are the primary (S1) and secondary

“Central” Pain-Prone Phenotype� Female� Genetics� Early life trauma� Family history of chronic pain and mood disturbances� Personal history of chronic centrally mediated symptoms (multifocal pain with neuropathic descriptors, fatigue, sleep disturbances, psychological distress, memory difficulties) � Cognitions such as catastrophizing� Lower mechanical pain threshold and descending analgesic activity

Exposure to “stressors” or acute, peripheral nociceptive input

New or different region of chronic pain

Psychological and behavioral response to

pain or stressor

Fig. 2. Female sex, early life trauma, a personal or family history of chronic pain, a personal history of other centrally mediated symptoms (insomnia, fatigue, memory problems, mood disturbances), and cognitions such as catastrophizing can occur in subsets of individuals with any chronic pain state and predict which individuals are more likely to transition from acute to chronic pain.

Low Back Pain 199

activity that provoke pain and more rest (overactiv-

ity/underactivity cycle). Pacing involves breaking

down an activity into smaller parts and alternating

the activity with short breaks. Th e idea is to learn to

take the natural small pauses in an activity that might

otherwise normally occur to provide for a stable rate

of participation.

Cognitive-Behavioral Th erapy

Emotional distress is one of the most prevalent psy-

chological components in the development of chronic

pain, and cognitive-behavioral therapy off ers vari-

ous forms of emotional support. It also off ers specifi c

treatments for a variety of problems including fear of

movement. An important aspect is that while psy-

chological factors such as fear, distress, or depression

might be thought to dissipate when the pain is treated

properly, this is seldom the case [39]. Th erefore, it is

important to include a cognitive-behavioral program

for emotional problems such as distress, depression,

and anxiety problems [53].

Routines for Assessment and Treatment of Low Back Pain in Primary Care

All guidelines recommend a diagnostic triage when

assessing a patient with low back pain. Having fi rst ex-

cluded back pain that arises from a structure beyond

the back (for example, retroperitoneal structures or

the hips), the clinician needs to consider the possibil-

ity of serious pathology (such as cancer, infection, or

fracture) as the cause of the patient’s back pain. Seri-

ous disease is uncommon in patients with acute back

pain presenting to primary care, accounting for ap-

proximately 1% of cases [25]. Suspicion is raised by the

presence of red fl ags [9] such as unexplained weight

loss, fever, or recent infection. Recent evidence sug-

gests that the presence of a single red fl ag is common

in people without serious disease [25]. A cluster of red

fl ags may be a better indicator of serious pathology.

Patients with suspected serious pathology

should be sent for imaging and/or blood tests relevant

for the possible cause [2]. Th ey may need specialist re-

ferral to establish a defi nitive diagnosis. Radiculopathy

accounts for approximately 5% of cases seen in pri-

mary care. It is diagnosed by the presence of reduced

power, refl exes, and sensation in the distribution of

the involved spinal nerve.

Th e remaining 94% of patients presenting in

primary care are classed as having nonspecifi c low

back pain (NSLBP). Th is term simply means that the

pathoanatomical source of the pain has not been spec-

ifi ed. A pathoanatomical diagnosis is not pursued be-

cause there are no tests available to the general practi-

tioner that could establish a diagnosis, and in any case

a pathoanatomical diagnosis would not change man-

agement.

Patients with NSLBP should not routinely

be sent for imaging or pathology tests. International

clinical practice guidelines [30] uniformly recommend

that investigations should be reserved for patients

with suspected serious pathology or for those with ra-

diculopathy who are being considered for surgery. A

systematic review of trials revealed that routine imag-

ing does not improve clinical outcomes, compared to

imaging only when indicated,[12] and therefore it is

not recommended.

Primary Care Management of Acute Nonspecifi c Low Back Pain

First-Line Care

When managing acute NSLBP it is best to start sim-

ple, reserving more complex treatments for those

who do not respond. Patients should be given advice

[61] and education about self-care and should take a

full dose of paracetamol (acetaminophen) regularly

(1 g four times a day for adults). While nonsteroidal

anti-infl ammatory drugs (NSAIDs) also have a role in

this setting, they are not preferred as fi rst-line drugs

due to the risk of adverse eff ects. Patients should re-

main active and be scheduled for review within 1

week. If this simple approach is delivered well, pa-

tients can recover remarkably quickly. An Australian

study conducted in primary care showed that 50% of

patients who received this approach were pain-free

within 2 weeks [22].

Unfortunately, most people with acute back

pain do not get this care. A survey of Australians self-

managing their low back pain revealed that the ma-

jority were not taking adequate doses of the over-the-

counter medicines they were using. For example, 82%

of those taking paracetamol were underdosing [69].

Another Australian survey of patients managed in pri-

mary care revealed that only 21% received advice and

only 18% received paracetamol. Instead, the analgesics

provided were typically NSAIDs (37%) and opioids

(20%) [70].

A key aspect of fi rst-line care is an early re-

view of progress. If patients have followed the simple

management approach, there should be a marked im-

provement in their back pain when they are reviewed

Role and Management of Opioids in Chronic Pain 315

implemented in the absence of an optimum trial of

more resolution-oriented care and without a support-

ive context that might improve their effi cacy. Th ere

are probably subpopulations of patients who will ben-

efi t from the long-term use of opioids and others who

will not. In addition, there are subpopulations of pa-

tients with substance abuse or addiction problems

who are at increased risk for harm as a result of using

opioids. In the absence of clear prospective criteria to

identify positive responders, however, clinicians must

rely on judgment informed by available evidence and

clinical experience—the art of medicine—in consider-

ing the unique risks and potential benefi ts for each in-

dividual patient.

Strategies for Safe and Eff ective Opioid Th erapy

A number of clinical strategies are emerging that may

support safe and eff ective use of opioids when they are

indicated, while discouraging misuse and unfavorable

outcomes. Further research is needed to determine

the ultimate effi cacy of such approaches. Current pi-

loted strategies include providing opioids as one com-

ponent of multidimensional care (as described above);

comprehensive assessment that includes screening for

risk of opioid misuse; informed consent for treatment

and documentation of a written plan of care, includ-

ing a clear statement of goals (usually integrated into

an Opioid Treatment Agreement); careful monitor-

ing, including use of urine toxicology screens; limiting

doses to low or moderate doses of opioids; adjustment

of structure of care to match risk; and a plan for con-

tinuation or discontinuation of treatment depending

on progress toward goals.

Risk Screening

Research has begun to defi ne risk factors associated

with a greater likelihood of misuse of opioids pre-

scribed for pain treatment [8,12,28]. Among these

factors are a history of substance use disorder or un-

healthy substance use, a history of mental health con-

ditions, current smoking, an unstable social situation,

a history of incarceration, younger age, and male gen-

der. A family history of substance use disorder prob-

ably also infers higher risk because some of these dis-

orders are in part genetically mediated, although this

risk has not been documented in a pain context. A

number of approaches to risk screening may be help-

ful, including an interview of the patient and signifi -

cant others, a review of medical records, consultation

with the Prescription Drug Monitoring Program if

available, and the use of a risk-screening tool spe-

cifi cally developed to detect risk of opioid misuse. A

number of risk screening tools are in evolution. Most

widely used are the Screener and Opioid Assessment

for Patients with Pain (SOAPP) [4], the Opioid Risk

Tool (ORT) [31], and Pain Medication Questionnaire

(PMQ) [16]. Th e SOAPP is available in 5-, 14-, and

21-question versions. Th e ORT is a simple 5-question

tool, and the PMQ contains 26 questions, all related to

the patient’s experience and use of medication. Each

tool has a scoring system that indicates a level of risk

with a reasonable level of sensitivity and specifi city;

however, as evidence related to the clinical utility of

these screening tools is evolving, some experts prefer

a comprehensive clinical review to assess risk.

Opioid Treatment Agreement

Opioid treatment agreements usually include a pro-

cess of informed consent for opioid therapy and docu-

mentation of a mutually shared agreement on the plan

of care. Common items in informed consent include

the anticipated benefi ts or goals of treatment, as well

as the potential risks associated with the treatment.

Commonly cited goals or intended benefi ts of chronic

opioid therapy include reduced pain, improved func-

tion, and enhanced quality of life. It may be helpful to

elicit more specifi c goals, for example engagement in

activities valued by the patient such as ability to con-

centrate while reading, walk for a specifi ed period of

time, or sit through a church service or movie. Th ese

goals provide an important basis on which to continue

or discontinue care.

Commonly cited risks of opioid therapy in-

clude physical side eff ects (such as constipation, nau-

sea, or itching), tolerance, physical dependence, ad-

diction, hyperalgesia, sedation and cognitive blurring,

victimization by others seeking opioids, potential

overdose with misuse, and endocrine changes that

may result in osteopenia or hypogonadism. Th e plan

of care commonly documents the indication of a sin-

gle prescriber and pharmacy; intervals for renewal of

the prescription and clinic visits; medication dosing

and interval; and an agreement by the patient to un-

dergo periodic urine drug screens, to avoid illicit sub-

stances, to use the medication as prescribed, to store

safely and not to share or sell the medication, and to

permit communication with other care providers and

signifi cant others. Some evidence suggests that opioid

treatment agreements may help improve care of per-

sons receiving longer-term opioid therapy [25].

328 Ian Gilron

sodium channel blockade, and N-methyl-D-aspartate

receptor inhibition, among others [82].

Anticonvulsants

Drugs which suppress experimental and clinical sei-

zures, defi ned as anticonvulsant or antiepileptic drugs,

are classifi ed as “fi rst-generation” anticonvulsants (e.g.,

benzodiazepines, carbamazepine, ethosuximide, phe-

nobarbital, phenytoin, primidone, and valproic acid),

which were introduced between 1910 and 1970, and

“second-generation” anticonvulsants (e.g., felbamate,

gabapentin, lamotrigine, levetiracetam, oxcarbaze-

pine, pregabalin, tiagabine, topiramate, vigabatrin, and

zonisamide), which were introduced more recently

[69]. In addition to reduction in pain intensity, some

anticonvulsants have also been shown to improve sleep

[93] and reduce anxiety [90], eff ects that are of clinical

relevance to the management of chronic pain. Multiple

pharmacological mechanisms (see Table III and Fig.

1) have been elucidated for most anticonvulsant drugs

including sodium channel blockade, calcium channel

blockade, suppression of glutamatergic transmission,

and γ-aminobutyric acid (GABA)ergic modulation [21].

Trial-Based Evidence of Analgesic Effi cacy

Attempts to describe effi cacy of a given treatment of-

ten involve systematic review of published high-quality

clinical trials (randomized controlled trials; RCTs) and

meta-analysis in order to estimate the number-need-

ed-to-treat (NNT) to obtain at least 50% pain relief

in one patient (such that a lower NNT suggests bet-

ter effi cacy), or a mean diff erence between treatment

and placebo across multiple trials using a common

continuous outcome measure [79]. Several obstacles

as well as reduction of pain intensity [112]. A large

body of preclinical research has pointed to several pu-

tative analgesic mechanisms of antidepressant drugs

(see Table II). Th ese include increased supraspinal

availability of norepinephrine (thought to enhance

descending inhibitory bulbospinal control), activa-

tion of endogenous mu- and delta-opioid receptors,

NMDA-R

GLU

GABA

Ca ++

Na +

Na +

Ca++ channel blockadecarbamazepine, ethosuximide, valproic acid, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate,zonisamide

GABA potentiation barbiturates,

benzodiazepines,felbamate, levetiracetam, topiramate

Decreased glutamate transmission

valproic acid, gabapentin, lamotrigine, pregabalin,

phenytoin, carbamazepine, oxcarbazepine,

felbamate

Na+ channel blockadecarbamazepine, felbamate, lamotrigine, oxcarbazepine, phenytoin, topiramate, zonisamide

Fig. 1. Pharmacological mechanisms of anticonvulsants relevant to pain treatment. GABA, gamma-amino butyric acid; GLU, glu-tamate; NMDA-R: N-methyl-D-aspartate receptor. Modifi ed from Gilron [32].

Table I Pharmacological classification of

antidepressant drugs

Tricyclic Antidepressants

Tertiary Amine

Amitriptyline

Clomipramine

Doxepin

Imipramine

Trimipramine

Secondary Amine

Nortriptyline

Desipramine

Maprotiline

Protriptyline

Amoxapine

Serotonin-Norepinephrine Reuptake Inhibitors

Venlafaxine

Duloxetine

Milnacipran

Desvenlafaxine

Reboxetine

Sibutramine

Viloxazine

Bicifadine

Serotonin Selective Reuptake Inhibitors

Fluoxetine

Paroxetine

Fluvoxamine

Citalopram

Escitalopram

Sertraline

Lofepramine

Dapoxetine

Zimeldine

Monoamine Oxidase Inhibitors

Phenelzine

Tranylcypromine

Iproniazid

Isocarboxazid

Nialamide

Moclobemide

Selegiline

Pirlindole

Other Antidepressants

Trazodone

Nefazodone

Mirtazapine

Bupropion

Atomoxetine

Mianserin

Note: This list is not exhaustive. The above pharmacological classifications are not clearly delineated, and some compounds may also be considered members of another drug subclass.

442 Gabriela Bravo and Felipe Fregni

Long-Lasting Eff ects of Noninvasive Brain Stimulation Associated with Changes in Cortical Excitability

A recent study investigated the long-lasting eff ects of

rTMS in patients with fi bromyalgia, using neurophysi-

ological outcomes to measure these eff ects. Fibromyal-

gia syndrome is characterized by chronic widespread

pain on digital palpation in at least 11 of 18 tender

point sites; the pain can be accompanied by cogni-

tive problems, unrefreshing sleep, fatigue, and somatic

symptoms [53,54]. Although the underlying patho-

physiology remains unclear, disturbances in central

pain-modulating systems [36], abnormal cortical excit-

ability [37], and dysfunctional pain inhibition may be

implicated [25]. Patients with fi bromyalgia show a defi -

cit in intracortical modulation [37], and daily unilateral

rTMS of the motor cortex (M1) can transiently reduce

pain and improve quality of life for up to 2 weeks af-

ter treatment. However, no studies have been able to

show a sustained eff ect on analgesia. Mhalla et al. [37]

conducted the fi rst randomized controlled study to

assess the long-term maintenance of analgesia with

multiple series of daily rTMS in patients with chronic

pain. Th e 14 stimulation sessions were conducted over

a 21-week period in two phases: daily stimulations for

5 consecutive days for the induction phase and daily

stimulations in three series that took place weekly, fort-

nightly, and monthly for the maintenance phase. Th eir

results showed a signifi cant decrease in pain intensity

with active rTMS vs. sham. Although this eff ect was

sustained for 6 months, the magnitude decreased af-

ter the monthly sessions. Quality of life also improved

in these patients as they reported decreased interfer-

ence in daily activities such as walking, relations with

other people, enjoyment of life, and sleep. Interestingly,

long-lasting pain improvement was directly related to

changes in cortical excitability, as indexed by changes

in intracortical inhibition.

Th e recent fi ndings by Mhalla et al. [37] con-

fi rm the notion that maintenance treatment of TMS

may lead to long-lasting eff ects, as shown by several

trials in depression [13] and a case report from Za-

ghi et al. [55]. Further trials need to establish optimal

maintenance regimens and should have longer follow-

up periods to determine maximal duration of eff ects.

Combination of Noninvasive Brain Stimulation with Pharmacological Treatment

An important question not fully addressed in the pain

fi eld is whether combination of NIBS with pharmaco-

logical treatment may enhance its eff ects. Th is ques-

tion was initially addressed by a case report from An-

tal et al. [1]. Th e idea behind this case report is based

on previous fi ndings showing that tDCS can eff ec-

tively modulate cortical excitability and transiently de-

crease pain perception in patients with various chron-

ic pain conditions. Th ese eff ects can last from several

days to weeks depending on diff erent stimulation pa-

rameters [2,16,19,38]. Th ey may involve NMDA-re-

ceptor modulation in a similar mechanism to en-

hancement of synaptic transmission in learning and

memory via long-term potentiation [42]. Th erefore,

Nitsche et al. hypothesized that the combination of

presynaptic enhancement via pharmacological stimu-

lation of the NMDA receptor with postsynaptic mem-

brane depolarization by anodal tDCS might potentiate

the duration of cortical excitability and increase the

Fig. 3. In transcranial direct current stimulation (tDCS), a rubber band is placed around the patient’s head. Electrode pads soaked in saline solution are placed over the scalp. A battery-powered device delivers electrical current via two electrodes with opposite elec-trical charges. Anodal stimulation increases cortical excitability, while cathodal stimulation decreases cortical excitability.

Pain 2012RefResheR CouRses

14th World Congress on Pain

InternatIonal assoCIatIon for the study of PaIn

Pain 2012 R

ef

Re

sh

eR

Co

uR

se

sIrene tracey, Editor

Irene tracey, Editor

International Association for the Study of Pain

Every two years, the International Association for the Study of Pain (IASP) creates a benchmark publication of articles summarizing the status of pain research and management throughout the world. IASP has brought together many of the foremost authorities on pain to write about the latest thinking in their specific fields.

The resulting book, Pain 2012, gathers the presentations that these experts gave at the refresher courses preceding the World Congress on Pain in Milan, Italy, in August 2012. IASP Press published all of these articles in one book for use at the refresher courses themselves, as well as for pain researchers and clinicians everywhere who are unable to come to the Congress.

IASP website: http://www.iasp-pain.org/books

IasP scientific Program Committee

9 780931 092930

9 0 0 0 0ISBN 978-0-931092-93-0