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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
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