Adjuvant Analgesics This Material Is Not Intended to Be, and Should Not Be Considered, a Sub- Stitute for Medical Or Other Professional Advice

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Adjuvant Analgesics This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. While this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues are constantly evolving, and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. Oxford University Press and the authors make no representations or warranties to readers, express or implied, as to the accuracy or com- pleteness of this material, including without limitation that they make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publishers do not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material. The Publisher is responsible for author selection and the Publisher and the Author(s) make all editorial decisions, including decisions regarding content. The Publisher and the Author(s) are not responsible for any product information added to this publication by companies purchasing copies of it for distribution to clinicians. OAPL OXFORD AMERICAN PAIN LIBRARY

Adjuvant Analgesics

Edited by

David Lussier, MD Assistant Professor of Medicine Institut universitaire de gériatrie de Montréal University of Montréal Division of Geriatric Medicine and Alan-Edwards Centre for Research in Pain McGill University Montréal, Quebec, Canada

Pierre Beaulieu, MD, PhD Associate Professor of Anesthesiology and Pharmacology Faculty of Medicine University of Montréal Centre hospitalier de l’Université de Montréal Montréal, Quebec, Canada

1 1

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Library of Congress Cataloging-in-Publication Data Adjuvant analgesics / volume editors, David Lussier and Pierre Beaulieu. p. ; cm. —(Oxford American Pain Library) Includes bibliographical references. ISBN 978–0–9–9898–8 (alk. paper) I. Lussier, David, editor. II. Beaulieu, Pierre, 958– , editor. III. Series: Oxford American Pain Library. [DNLM: . Analgesics. 2. Chronic Pain—drug therapy. QV 95] RM39 65.7′83—dc23 204036646

9 8 7 6 5 4 3 2  Printed in the United States of America on acid-free paper this Oxford Pain series, for his guidance throughout the process. the throughout guidance his for series, Pain Oxford this of Editor K. Portenoy, Dr. Russell thank we Finally, process. publication the during help and patience their for staff, Press University Oxford the all and such rapidly evolving fields.Our alsogratitude goes toAndreaKnobloch of review state-of-the-art this providing of challenge the up take to agreed who those all to gratitude our extend We therefore book. this in pain of pharmacology the on experts world-renowned many so include to able were we that fortunate very We are covered. topic the on experts leading by authored were chapters all because mainly challenges, both meeting in succeeded have we that confident are We field. this in knowledge of tion evolu rapid the given published, was book the after timely be still would that reviews provide to was encountered we challenge second The pages. of number areasonable exceeding without physician practicing the for topic each on information detailed provide still but area broad avery cover developments on that topic. future considering for framework a offers and topic aspecific on edge such as neuropathic pain, cancer pain, postoperative pain, and fibromyalgia. entities clinical on chapters included also we purposes, clinical for use itate To facil professionals. health other or physicians either researchers, clinical and clinicians for useful be would that analgesics adjuvant of pharmacology the of review comprehensive a offer would that book literature—a the in gap a fill to needed was book anew that felt We therefore hyperalgesics. sants, duloxetine), cannabinoids, topical analgesics, local anti anesthetics, first-linetherapy forneuropathic pain (gabapentinoids,tricyclic antidepres analgesic antidepressants and anticonvulsants that are recommended as other analgesics, the so-called “adjuvant analgesics.” These drugs include worldwide. patients of millions in life of quality improved and management pain better for the development of analgesics acting on providing new targets, new hope allowed has levels synaptic and molecular, cellular, at pain of mechanisms the of understanding improved Indeed, years. few past the in occurred has knowledge improved this of Most considerably. evolved has pain of ogy pharmacol the of knowledge our analgesics, novel of development the to ago millennia sativa cannabis and extracts poppy opium of use the From In preparing this book, we faced two main challenges. The first was to was first The challenges. main two faced we book, this preparing In knowl of state current the of review adetailed provides chapter Each on few but opioids to devoted textbooks and chapters many are There Preface ------

Contents

Contributorsâ ix

 Overview of Pain Management  David Lussier and Pierre Beaulieu 2 Classification of Analgesics 5 David Lussier and Pierre Beaulieu 3 Antidepressants  C. Peter N. Watson 4 Anticonvulsants 2 David Lussier 5 Cannabinoids 33 Julie Desroches and Pierre Beaulieu 6 Local Anesthetics 47 Patrick Friederich

7 N-Methyl-D-aspartate Antagonists 59 Philippe Richebé, Laurent Bollag, and Cyril Rivat 8 Topical Adjuvant Analgesics 7 Jana Sawynok 9. Neuropathic Pain 79 Nadine Attal 9.2 Cancer-related Pain 95 Paul N. Luong and Russell K. Portenoy 9.3 Rheumatic Pain and Fibromyalgia 07 Mary-Ann Fitzcharles 9.4 Acute Postoperative Pain 9 Pierre Beaulieu 0 Drug-Drug Interactions of Adjuvant Analgesics 3 David R. P. Guay

Indexâ 47

Munich, Germany Universität München Technische of Hospital Academic Hospital Bogenhausen Critical Care Medicine, Pain Therapy of Anaesthesiology, Department Anesthesiology of Chairman and Professor Friederich, MD Patrick Montréal, Quebec, Canada McGill University Health Center Pain Management Unit Edwards Alan University; McGill Division of Rheumatology Associate Professor of Medicine ChB, FRCPC MB, Fitzcharles, Mary-Ann Montréal, Canada University of Montreal Medicine of Faculty of Pharmacology Department Desroches, PhD Julie Washington Seattle, of Washington University and Pain Medicine Anesthesiology of Professor Associate Bollag, MD Laurent Versailles, France Saint-Quentin-en-Yvelines Versailles of University France Boulogne-Billancourt, Paré, APH Ambroise Hôpital of Pain Treatment and Evaluation for Center INSERM U 987 MD, PhD Attal, Nadine Contributors Palliative Care in Innovation for Institute MJHS Executive Director K. Portenoy, MD Russell Modesto, California Valley Area Kaiser Permanente Central Lead Palliative Medicine Physician N. Luong, MD Paul Minneapolis, Minnesota HealthPartners Inc. HealthPartners Geriatrics Consultant Staff University of Minnesota Pharmacy of College and Clinical Pharmacology Experimental of Emeritus Professor FCP, FCCP, FASCP R. P. PharmD, Guay, David Montréal, Quebec, Canada Hospital Maisonneuve-Rosemont University of Montreal of Anesthesiology Department Professor of Anesthesiology MD, PhD Richebé, Philippe New YorkBronx, College Einstein ofAlbert Medicine Professor of Neurology York New York, New Palliative Care and Hospice MJHS Officer Medical Chief

ix x CONTRIBUTORS Halifax, NovaHalifax, Scotia, Canada Dalhousie University of Pharmacology Department Sawynok, PhD Jana Montpellier, France Saint Eloi Hospital U05 (INM)-INSERM Montpellier of Neurosciences of Institute Montpellier of University Associate Professor Cyril Rivat, PhD Toronto, Ontario, Canada of TorontoUniversity Medicine of Professor Assistant MD, FRCPC N. Watson, Peter C.

aimed at reducing pain depending on the location and type of painsuch aimed atreducing of paindependingonthelocation andtype approachesInterventional topain managementinclude varioustechniques response to other treatments. thepatient’spain,comorbidities, traits, personality andprevious acteristics of basedonthenature patientcan bedetermined andchar agiven for strategy [3]‌ (eg,yoga, interventions mindfulness) mind-body therapy,cognitive-behavioral strategiesbasedonemotional disclosure, and thepain-managementstrategy. Psychological approaches include ponent of involved in the therapeutic plan. rolethat the patient and has is an fully active bilitation practices. betoensure Whenmanagingpain,thegoal shouldalways such asexercises (aimedatincreasing strength, and tone,orflexibility) reha therapiesare betterandmore used, response sustainedwhenactive isusually providepies. relief, Althoughthesetherapiescanusually someshort-term stimulation,ultrasounds,electrical nerve massage,andshock-wave thera psychological approaches. and Nonpharmacological approaches categorized asphysical are traditionally cological, and specific interventional, approaches to pain management [2]. psychological),ment shouldcombine pharma nonpharmacological(physical, To life. achieve thesegoals, of treat andquality impact onmood,function, noxious stimulibutalsoaddress themultipledimensionsandaimtominimize approach. Pain ondecreasingplinary focus the managementshouldnot only []‌ such damage” actual orpotential of tissuedamage,or described interms defined as andemotional experience associated“An unpleasantsensory with Pain, chronic especially persistentpain,isamultidimensionalexperience LussierDavid Beaulieu andPierre Management Overview of Pain Chapter  Interventional approaches to painmanagement Nonpharmacological approaches To achieve thisgoal, psychological approaches are usedasanessential com approaches therapiessuch astranscutaneous includePhysical passive . Assuch, itresponds bettertoamultimodal,multidimensional,interdisci

. Themostappropriate ------

2 CHAPTER  Overview of Pain Management Figure . with trigeminal neuralgia. patients apatientwithspinalstenosis,ablationfor for andgammaknife fusion treat pain: joint replacement inapatientwithosteoarthritis,laminectomy and to possible.Forever surgeriesmay example,thefollowing beperformed the pain, when than treating pain, it is preferable to treatRather the cause of respond to routes.conventional oral or transdermal analgesics, such as intrathecal, can also be used in patients who do not of delivery blocks, routes coeliac of block, orsympathetic block. Invasive as spinal blocks intra-articular (epidural blocks, or facet), peripheral nerve in recent years, due to developing scientific evidence. Eisenberg et al [5] in recent years,evidence. scientific Eisenberget al duetodeveloping soon extrapolated to chronic nonmalignant pain. cancer-related pain,theWHOpainladderwas thetreatmentposed for of pain(seeChapter 2).Althoughitwasfirstpro depending onthenature of any severity, painof can becombinedthetreatment withanalgesicsfor of opioids, andsevere painshouldbetreated with“strong” opioids. Adjuvants drugs),moderatepainshouldbetreated with“weak” dal anti-inflammatory should betreated withnonopioidanalgesics(acetaminophen ornonsteroi 2006, recommends treating [4]‌ painbasedonseverity The World HealthOrganization(WHO) AnalgesicLadder, firstpublished in Pharmacological approaches Specific approaches Several authors have proposed authorshave Several modificationsto the WHO pain ladder

WHO analgesic ladder [4]‌ +/– Adjuvant Non opioid or increasing Pain persisting +/– Adjuvant +/– Nonopioid Opioid formildtomoderatepain or increasing Pain persisting +/– Adjuvant +/– Nonopioid Opioid formoderatetoseverepain . cancer pain Freedom from (Figure .).Mildpain 2 3 - - - ‌

low doses of strong beenshown opioidshave toprovide betterandfaster low dosesof cancer pain,because proposed thetreatment toeliminateweak opioidsfor of Responses to various opioids can vary depending on the patient and type of of dependingonthepatientandtype Responses tovariousopioidscanvary based onanalgesicresponse andtolerability.and increased progressively moderate orsevere intensity. Treatment shouldbeinitiatedwithalow dose pain of As indicated earlier, the treatment opioids should be used for of effects. adverse of comorbidities orpolypharmacy, withfrequent theoccurrence monitoring for inolderpatientsorthosewithseveral should beusedwithcaution,especially increased therefore, cardiac they andpossibly mortality; failure, heart tive injury,ing acute kidney gastrictoxicity, hyperkalemia, fluid retention, conges drugsareeffects,adverse associated withsignificantinclud anti-inflammatory acute pain.Nonsteroidal thetreatment orfor of (eg, rheumatoidarthritis) diseases inflammatory inhibitors arethetreatment indicatedfor of toxicity. tests should be done to liver avoid function liver of When acetaminophen isadministered onachronic basis, frequent monitoring dosecanbe used. than 0-day duration,thetraditional4000mgmaximaldaily less Whenusedtotreat impairment). acuteage, alcohol painof abuse,liver (polypharmacy, advanced and2600 mginpatientswithothericity riskfactors more toxaminophen isusedfor than0 days for inpatientswithriskfactors 3200mgwhenacet most guidelinesrecommenddoseof amaximaldaily whenusedattherapeuticdoses. effects and adverse evidenceRecent and toxicity of therarity musculoskeletal origin,becauseof of ate pain,especially Acetaminophen isrecommended asfirst-line therapy totreat mildtomoder for a better pain action relief. gesics with different mechanisms of patient,they shouldcombineappropriate agiven variousanal analgesicsfor fromence clinical derived practice. Therefore, whenclinicians selectthemost analgesics[8]‌ classes of diverse effects,whenusinga adverse trolled,combination of withfewer chronic pain. without control, and acute crises of pain, andcancer painanda“stepdown” approach acute pain,chronic for pain pain,usinga“stepup” approach chronic for pain,nonmalignant acuteness of spinal stimulators. Thetreatment shouldalsobeadapted tothenature and epidurals, patient-controlled analgesiapump, block therapy, neurolytic and chronic pain,comprising block, nerve managingthecrises of stepfor fourth considered or an adjunct to pharmacotherapy. at any stage, as an alternative procedures [6].Invasive shouldbe patientsatisfaction pain relief,withgreater Opioids Nonopioid analgesics Nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 drugsandselective Nonsteroidal anti-inflammatory thatpainisbettercon isstilllimited, thereAlthough evidence isproof Vargas-Schaffer [7]‌ proposed to keep steps –3 unchanged and add a (see Chapter 4 for examples).Itisclinical experi (seeChapter 4for ------

3 Chapter  Overview of Pain Management

4 CHAPTER  Overview of Pain Management approaches. Pharmacotherapy should also include various classes of analge approaches. Pharmacotherapy shouldalsoinclude variousclasses of andspecificbining nonpharmacological,pharmacological,interventional, should beused,withamultimodalandinterprofessionalapproach, com strategies variouspainrelief optimal painmanagement,acombination of painmanagement.To of ensure overview This chapter provides brief avery issues. reassess andthenfrequently these medicationabuseanddiversion the risk of evaluate tofirst opioid. Whenprescribing important anopioid,itisalways pain. Opioidrotation canbedonewhenpaindoesnot respond toaspecific 8. 7. 6. 5. 4. 3. 2. . References andtolerability. for betterpain action,relief sics withdifferentmechanisms of Conclusion

202; 7:CD008943. neuropathic pain in adults. Cochrane Database Syst Rev the treatmentfor of PJ,MooreChaparro LE,Wiffen RA,Gilron I. Combinationpharmacotherapy 200; 56:54–57. experience. Can Fam Physician Vargas-Schaffer G.IstheWHOanalgesicladderstillvalid? Twenty-four years of cancer pain: a randomized trial. J Pain Symptom Manage 2004; 27:409–46. Marinangeli F, strong opioidsinadvanced Ciccozzi A, Leonardis M,et al. Useof ladder? Pain Clin Update 2005; 3:–4. Eisenberg E, Marinangeli F, Birkhahm J, et al. Time to modify the WHO analgesic cancer/palliative/painladder/en/ World HealthOrganization.WHO’s painladder. Available at: :89–94. and clinical implications.pain in older Br adults: outcomes J Anaesth 203; Keefe FJ, Porter L, Somer T, Psychosocial managing for interventions et al. 2:80–833. Regional AnesthesiaandPain 200; Medicine. Anesthesiology of Society Anesthesiologists Task Force onChronic Pain ManagementandtheAmerican updatedreportby of theAmericanSociety chronicfor painmanagement: an Regional AnesthesiaandPain Medicine. Practice guidelines of American Society AnesthesiologistsTask Force of American Society onChronic Pain Management, WA: IASP Press; 994. Merskey H, Bogduk N, eds. lsiiaino Chronic Pain,Second Edition Classification of . Accessed 9 September 204. www.who.int/ . Seattle, - -

Several classifications been proposedSeveral have (Table 2.). different criteria. action,ora combination of anticonvulsants), mechanisms of analgesics(eg,antidepressants, pain,therapeuticclasses of of pain,type of Analgesics can be categorized based on different criteria, including severity shown to possess analgesic properties. they been have consider themasanalgesics if adjuvant analgesicsandsimply lication [4]‌ pain), andpainisanapproved some(eg,pregabalin, indicationfor duloxetine). an analgesic(eg,gabapentinoidsortricyclic antidepressantsneuropathic for to thesedefinitions. They are oftenusedaloneratherthan combined with considereddrugs thatare currently asadjuvantanalgesicsdonot correspond prescription practices. Most accumulatingevolutionevidence scientific of and both become adjuvantanalgesicandcoanalgesichave obsoletewith terms conditions”tion other thanpain,butisanalgesicinsomepainful [3]‌ changeably, indica andthey been defined as“any have drugthathas aprimary Nowadays, “adjuvantanalgesic” terms andcoanalgesic are oftenusedinter muscle relaxants were used to treat muscle spasms. example,steroids to pain; for were usedtotreating factor inflammationand considered asanalgesicsbutwere usedtotreat eitheracauseorcontribut to aiditsaction.”Afterthisdefinitionwasestablished,“adjuvants” were not an“adjuvantdrug”as“asubstance addedtoadrug accepted definitionof relaxants, corresponds tothe andbisphophonates)[2].Thislattercategory convulsants andantidepressants) and“adjuvantmedicines” (steroids, muscle distinguishing“coanalgesics” anadjuvant analgesic, (anti the definitionof ing symptoms, ratherthanasanalgesicsperse.TheWHOlatermodified were recommended andanxiety,” “tocalmfears thatis, totreat accompany In the initial World Health Organization (WHO) pain ladder [] evolved adjuvantanalgesicshave considerably. The definitionand concept of LussierDavid Beaulieu andPierre ofAnalgesics Classification Chapter 2 Existing classification ofanalgesics Definition ofadjuvant analgesics This findinghasleadsomeauthors, including ourselves inaprevious pub evolved adjuvantanalgesics have with time. The definition and use of , to propose to completely abandon the terms and concept of and concept, to propose abandon the terms to completely of . However, ‌, adjuvants ------

6 Chapter 2 Classification of Analgesics anesthetics), or adjuvants (steroids, muscle relaxants, bisphosphonates) [2]. oids, opioids, coanalgesics (antidepressants, anticonvulsants, ketamine, local recent butlessknown WHOclassification categorizes analgesicsasnonopi pain. Adjuvantdrugsare recommended andanxiety. tocalmfears A more morphone, high-doseoxycodone, methadone)aresevere fentanyl, usedfor done) are moderate usedpain for and “strong” opioids (morphine, hydro mild pain,whereas “weak” opioids(hydrocodone, codeine, low-dose oxyco drugs[NSAIDs])arefor aminophen ornonsteroidal used anti-inflammatory ladder, thetreatment isbasedonpainseverity. Nonopioidanalgesics(acet cancer pain(Table 2.2)[]‌ non cancer painandwaslaterextrapolated for thetreatmentWHO for of of analgesics, which was remains classic, presented by The first classification World Organizationclassification Health Analgesics for Mild Analgesics for Table 2.2 Adjuvant Analgesics Severe Analgesics for Moderate Analgesics for Based on pain mechanisms (mechanistic approaches) Based on therapeutic class Based on clinical efficacy Based on pain severity Table 2. “Strong opioids” “Weak opioids” Nonopioids Lussier and Beaulieu [4]‌ [6]‌ Costigan and Woolf Marchand [5]‌ Lussier and WHO pain ladder []‌ Methadone Fentanyl High-dose oxycodone Hydromorphone Morphine Low-dose oxycodone Codeine Hydrocodone drugs (NSAIDs) Nonsteroidal anti-inflammatory Acetaminophen

World OrganizationPain Health Ladder []‌ Categories ofClassificationsAnalgesics P ortenoy [3]‌ P ain P ain P ain . Inthisclassification, known astheWHOpain - - - - -

Classification based onclinicalefficacy class, theseclassifications, called“mechanistic approaches”, analgesics divide R Classifications based onpainmechanisms prescribed an antidepressant to treat depression. which istrue.Itcanalsobemisleadingtopatients, whomay they believe are action,neitherof all drugsfrom thesameclasssimilarmechanisms have of that either all drugs from the class analgesic properties or it have might imply Thiscategorizationrelaxants, canoftenbemisleadingbecause antiarrythmics. example,antidepressants,class andindication,for anticonvulsants, muscle Adjuvant analgesicsare thencategorized basedontheiroriginaltherapeutic Classification based ontherapeutic class drugs, which would require frequent modifications to the classification. ofvarious evolving classification knowledge isthe onanalgesic efficacy of type pain, boneandmusculoskeletal pain[3]‌ analgesics isbasedonclinical efficacy, forexample,multipurpose, neuropathic adjuvant relevantclassification of usedandclinically The mostcommonly and Portenoy [3]‌ Table 2.3 Adjuvant Analgesics Used for MusculoskeletalAdjuvant Analgesics Used for BowelAdjuvant Analgesics Used for Obstruction Bone Adjuvant Analgesics Used for NeuropathicAdjuvant Analgesics Used for Multipurpose Adjuvant Analgesics ather than classifying analgesics based on their clinical efficacy or therapeutic ortherapeutic ather thanclassifying analgesicsbasedontheirclinical efficacy Other drugs: First Line: Corticosteroids Octreotide Anticholinergics Corticosteroids R Calcitonin and bisphosphonates Baclofen Cannabinoids N Oral and parenteral sodium channel blockers Corticosteroids Antidepressants Gabapentinoid anticonvulsants α Corticosteroids Antidepressants 2 adiopharmaceuticals -methyl- -Adrenergic agonists

Classification Based onClinicalEfficacy, FromLussier D -aspartate (NMDA)-aspartate receptor blockers P ain P ain P ain (Table 2.3). The pitfall of this (Table of 2.3).Thepitfall

7 Chapter 2 Classification of Analgesics 8 Chapter 2 Classification of Analgesics analgesics inspired by previously existing classifications and based mainly existingclassificationsanalgesics inspired andbasedmainly by previously analgesics. ous molecular targets of transmission (Table 2.5).Moreover, invari divided each mechanism isfurther maintained pain, central sensitization, and reduced inhibition or increased mechanisms intoperipheralsensitization,ectopicdischarge, sympathetically cord injury, pain) (Table 2.4). functional plex regional painsyndrome, peripheralandcentral neuropathic pain,spinal orneuropathic visceral, (comexample, nociceptive inflammatory) (somatic, the patient’sfor pain, basedbe determined on the specific mechanism of targets. According toMarchand [5]‌ depending on which pain mechanism they acton theon ormolecular even knowledge. frequentnate theneedfor modificationstotaxonomyevolving with action, which should elimi the classification based on their mechanism of added to as nonopioids and opioids.level drugs can be easily Investigational “adjuvantanalgesic”term andconsiders themasanalgesics, onthesame analgesia [4]‌ on mechanisms of Abbreviations: CNS, central system; nervous Abbreviations: CNS, NSAIDs, nonsteroidal anti-inflammatory drugs. Marchand [5]‌ Table 2.4 Neurogenic Nociceptive Type ofPain Finally, inapreviouspublication,we proposed have ataxonomy of In contrast toMarchand [5]‌

Mechanistic Classificationof Pain, From lesions) radiculopathy, CNS (neuralgia, Causalgia (musculoskeletal) Inflammatory cystitis) bowel, (irritable Visceral (tissue injury) Somatic irritable bowel)irritable thalamic syndromes, (fibromyalgia, Functional , Costigan and Woolf [6] have divided pain divided [6]have , CostiganandWoolf (Table eliminates the 2.6). It completely , themostappropriate analgesiccanthen chemical stimuli or thermal, Mechanical, Mechanisms CNS mechanisms in or inhibitory excitatory of Dysregulation CNS lesions P inflammation with localized Associated distension Visceral eripheral or blockers Sodium channel Acetaminophen Treatments Pharmacologic Example of Cannabinoids Opioids Anticonvulsants Antidepressants Antidepressants Opioids Anticonvulsants Steroids NSAIDs Antispasmodics NSAIDs Opioids Steroids NSAIDs - - - maintained pain Sympathetically E sensitization P Mechanism Molecular Targets, From CostiganandWoolf [6]‌ Table 2.5 ouaoso Descending InhibitionorExcitation Modulators of Antihyperalgesics Cannabinoids Opioids Nonopioids Antinociceptive Analgesics Beaulieu andLussier [4]‌ Table 2.6 Na TTXs Na TTXr NMDA, GABA, subtype 2; Abbreviations: transmission Increased R Central sensitization eripheral ctopic discharge educed inhibition SNRIs Tricyclic Antidepressants Coxibs Nitrous oxide Nefopam Lamotrigine Levetiracetam pregabalin) Gabapentinoids (gabapentin, NMDA antagonists NSAIDs Acetaminophen N + + -methyl- -VGSC, tetrodotoxin-resistant-voltage-gated sodiumchannel; -VGSC, tetrodotoxin-sensitive-voltage-gated sodiumchannel.

α Mechanistic Taxonomy ofAnalgesics, From Drug Treatment Based onPain Mechanism  / α γ D -aminobutyric acid; MOR,µ-opioidreceptor;-aminobutyric 2 -aspartate receptor;-aspartate TRPV,vanilloidreceptor ; subtype , adrenergic receptor COX-2, subtypes; cyclooxygenase Ca N-type MOR, R COX-2 NMDA receptor α Na TTXr Na TTXs TRPV Target  eceptors -receptor 2+ channels α 2 , GABA, + + -VGSC -VGSC tricyclic antidepressants gabapentin, clonidine, µ-opioid agonists, inhibitors COX-2 selective Dextromethorphan Ketamine NMDA antagonists Guanethidine block Phentolamine Lidocaine Mexiletine Lamotrigine Carbamazepine blockers Sodium channel Capsaicin Drug

( continued

)

9 Chapter 2 Classification of Analgesics

10 Chapter 2 Classification of Analgesics 5. 3. 2. . References 4. 6.

Costigan M, Woolf CJ. P Costigan M,Woolf brain. tothe theperiphery painmechanisms: from of Marchand Thephysiology S. Press, 200; pp. 27–40. Lussier D, P Lussier D, Beaulieu P 4th edition. Oxford, eds. N,et al, N,Christakis G, Cherny Lussier D, P November, 204. Scoping_WHOGuide_non-malignant_pain_adults.pdf Available at: Adopted inWHOSteeringGroup onP cancer, life-threateningillnessesinadults. HIVandother progressive World Health Organization. Treatment guidelines on pain related to cancer/palliative/painladder/en/ World HealthOrganization.WHO’s painladder. Available at: Table 2.6 Abbreviations: Coxibs, cyclooxygenase-2-inhibitors; selective NMDA, Other or Excitation Descending Inhibition Mixed: Antinociceptive Analgesics andModulators of Peripheral Transmission orSensitization Modulators of inhibitors. serotonin-norepinephrine reuptake serotonin inhibitors;SSRIs, selective reuptake N -methyl- Bisphosphonates Calcitonin Tapentadol Tramadol Capsaicin Topiramate Oxcarbazepine Carbamazepine Local anesthetics α SSRIs heum Dis Clin North Am 2008; 34:285–309. Rheum Dis Clin North 2 -adrenergic agonists orreca F, Dickenson AH,eds. D K. Adjuvant analgesics in pain management. In: Hanks ortenoy RK.Adjuvantanalgesicsinpainmanagement.In: Hanks -aspartate; NSAIDs, drugs;SNRIs,-aspartate; nonsteroidal anti-inflammatory Continued http://www.who.int/medicines/areas/quality_safety/ . Toward P analgesics. In: Beaulieu a rational taxonomy of ngland: Oxford University England: Oxford University ain: molecular mechanisms. JP . Accessed 29 August 204. xodTxbo fPalliative Medicine Oxford Textbook of hraooyo Pain of Pharmacology ain Guidelines, October4,2008. Press, 200; pp. 707–734. ain 2000;(Suppl):35–44. . Seattle,WA: IASP . Accessed 8 www.who.int/

, , ,

jabbing, and evoked pain (allodynia). Other analgesicscannowjabbing, andevoked beregarded pain(allodynia). thatis,pain, steady NPinparticular; different components of of the relief theantidepressants by RCTs someof and ananalgesic actionof of evidence 3.2). The TCAs, SSRIs, and combined SNRIs are considered here. There is neuropathicmiscellaneous chronicpain[NP]) (Table pain,andparticularly inCNCP(arthritis,fibromyalgiaand safety [FM],headache, low back pain, regarding dataconcerningevidence-based clinical efficacy meaningfulness these drugs (Table of 3.)and(2)themacodynamics, effects) adverse analgesia. andbetter effects adverse fewer tonin andnoradrenaline withthehopeof onbothand milnacipran, sero which,aneffect have similartoamitriptyline, serotonin noradrenaline re-uptake duloxetine, inhibitors(SNRIs)venlafaxine, N TCA [6]),recent nortriptyline research hasexploreddrugssuch asthe new thesemore specific antidepressants (except themore mostof of superiority disappointingresults regarding More recently,nortriptyline. the becauseof and themore noradrenergic (N)agentssuch asmaprotiline, desipramine, and serotoninselective re-uptake inhibitors(SSRIs)such asfluoxetine and others effects,turned tothe adverse and attention more about in efficacy concern limitations mechanisms serotonininvolving and noradrenaline. Because of actiononpotentiating pain-inhibitory theirputative data andbecauseof depressants (TCAs) such basedonpublishedobservational asamitriptyline non-cancer pain [–5]. Historically, these RCTs first examined tricyclic anti RCTs quality Thischapter of isbasedonsystematictopic. inchronic reviews literature onthis hasresulted investigation inalargeamountof of century trials (RCTs) chronic for noncancer pain(CNCP)[]‌ chronic pain, andthey been subjected to many have randomized controlled theoldest pharmacological treatments for sants. Antidepressants are oneof some antidepres monoaminergic neurotransmittersaction on inhibitory of The quotation referstoboth theindependentanalgesicactionanddual PeterC. N. Watson Antidepressants Chapter 3 Introduction This chapter () pharmacological reviews aspects (dose, duration, phar “I do believe,” said Alice“I do believe,” in the same house!” at last, “that they live LEWIS CARROLL, Through theLooking Glass . More thanaquarter - - - -

1111 12 Chapter 3 Antidepressants

Table 3. Analgesic Antidepressants (Dose, Duration, Pharmacodynamics, Adverse Effects) Drug Therapeutic Half-life (h) Neurotransmitter Most Common Side Effects (%) Range for Profile Pain (mg/24 h) NA 5-HT Sedation Orthostatic Weight Dry Constipation GI hypotension gain mouth distress, nausea, diarrhea Tricyclics Amitriptyline 0–50* 0–46 +++ +++ >30 >0 >30 >30 >0 >2 Doxepin 0–50* 8–36 +++ ++ >30 >0 >0 >30 >0 <2 Trimipramine 0–50* 7–30 ++ + >30 >0 >0 >0 >0 <2 Imipramine 0–50* 4–34 +++ +++ >0 >30 >0 >30 >0 >0 Clomipramine 0–50* 7–37 +++ ++++ >2 >0 >0 >30 >0 >0 Desipramine 0–50* 2–76 +++++ ++ >2 >2 >2 >0 >2 >2 Nortriptyline 0–00* 3–88 ++++ ++ >2 >2 >2 >0 >0 <2 Serotonin/Noradrenaline Reuptake Inhibitors Venlafaxine Effexor 37.5–225 3–7 (parent) ++ ++++ >0 >0 <2 >0 >0 >30 9–3 (metabolite) Duloxetine Cymbalta 60–20 0 ++++ +++++ >0 <0 <2 >0 >0 >0 Abbreviations: GI, gastrointestinal; NA, not applicable; 5-HT, 5-hydroxytryptamine. *The therapeutic range for depression is up to 200 mg/24 h for nortriptyline and to 300 mg/24 h for the remaining tricyclic antidepressants; in general, these doses are not required for an analgesic effect, and the usual dose will consist of 75 mg/24 h or less. Adapted from Reference 5 with permission. the dorsal horn of thespinalcord [8].This modelinvolves anendorphin of the dorsalhorn occurred viapain-inhibiting systems thatdescend from thebrainstemon to antidepressant analgesia was that this analgesia the mechanism of cept of con theanalgesicandantidepressant[6, 7]. Anearly effects separation of demonstratedthe controlled andclearly Randomized repeatedly trialshave sants in chronic pain. antidepres patients. Finally, we provide theuseof practicalguidelinesfor antidepressants withanticonvulsantsandopioidsinmany combinations of forof drugsoftenleadtotheneed these drugsandthelimitedefficacies practice) toordinary [5]of (generalizability validity The limitedexternal (Canada, UnitedStates, andEurope) reasonable [9–4]have concordance. figures [3] (Table 3.2).Evidence-based guidelinesfrom different countries on number-needed-to-treat(NNH) (NNT)andnumber-needed-to-harm head-to-headRCTsfew dataarebased [8],and comparative predominantly serotonergic more selective (S)andNagentsSNRIs[7]‌ of ity abandoning TCAs asaninitialchoice. Evidence isprovided thelesserutil for as first-line therapy (thegabapentinoids),buttherefor evidence isno good Examining TCAs, andSerotonin andNoradrenaline Reuptake Table 3.2 Adapted from Reference 5withpermission. trials. Thus, theNNTdataare arough guide only. selectionthatgoes into may trials,validity comparative bepoorbecauseof andtheexternal few ofpatients. There are different methodologies, withdifferentnumbers differentdataanalyses, which tocalculate NNT. anaverage Pleasenote from thatthesefigures studiesusing derive + effects. fromduetoadverse withdrawal thestudy consists**Major harm of NNTfigures arefoundin Reference 5. *References sources several for of TCA, tricyclic antidepressants. Abbreviations: NNT, numbersneededtotreat; serotonin SSRIs, selective re-uptake inhibitors; SSRIs Venlafaxine Average TCAs Clomipramine Nortriptyline Desipramine Imipramine Amitriptyline Agent* (50% orMore Reduction ofPain), andMinorMajor Harm Inhibitor Antidepressants for Neuropathic Pain for Benefit Mechanism of action This column refers to the number of studies for which there was adequate information with which there studiesfor wasadequateinformation This column referstothenumberof

Average NNTAmong Placebo-Controlled Trials “Benefit” NNT 6.7 4.0 2.3 2. 2.6 2.4 2. 2.4 data available No dichotomous 2.4 20.4 Harm” NNT “Minor 8.9 .4 .4 7 5.2 3.7 30.5 Harm”** NNT “Major 8.7 – Studies of Number 3 2  3 3 4 6 . There are + - - -

13 Chapter 3 Antidepressants

14 Chapter 3 Antidepressants anticholinergic effect, an antihistaminic effect, an anti-inflammatory effectdue ananti-inflammatory anantihistaminiceffect, anticholinergic effect, on multiple receptors (dopamine potentiation, the multiple effects and have drugs” “dirty Antidepressantsthatact aremetabolite nortriptyline. relatively chronicsants for painseemtobetheTCAs andits desipramine,amitriptyline a mixed onSandN effect (TCAs, antidepres SNRIs).Themore effective thanNagentsandthosewith [20]orlesseffective are eithernot effective controlled Sdrugs Randomized demonstratedthattheselective trialshave S drugs such as the SSRIs.of selective efficacy explain the lesser or lack of bydescending anSmechanism hasbeendescribed facilitation [9].Thismay which involveslateral ponstothedorsalhorn, noradrenalin. More recently, However, system extendsfrom another thelocus inhibitory coeruleus inthe thespinalcord. then anSconnection fromof theraphetodorsalhorn raphenucleus andlink fromarea theperiaqueductalgray tomedullary skin pain (allodynia or pain on touch). Randomized controlled or painontouch). Randomized trialsresults pain(allodynia in skin the differentpain qualitiesseeninNP, pain,jabbing pain,and including steady of on depression aneffect andthe relief independentof an analgesiceffect significant effectcompared with placebo. These RCTs shownhave repeatedly (3 RCTs), andtheN/dopaminergicbupropion (oneRCT) shown alsohave a with paroxetine, citalopram, Nmaprotiline andescitalopram. Thetetracyclic, serotoninSelective re-uptake results over inhibitorsyieldedfavorable placebo andduloxetine SNRIs, venlafaxine were superiortoplacebo. Of nortriptyline. favorably, desipramine,and including imipramine,nortriptyline, amitriptyline, pressants in36RCTs showed With asignificanteffect. TCAs, sixdrugs tested oraldrugs, 3antide thetrialsof limb pain,andchronic lumbarroot pain.Of thy, spinalcord injury, cisplatin neuropathy, polyneuropathy, painful phantom cer, central poststroke pain, human immunodeficiency virus (HIV) neuropa PHN, and33inother NPconditions, pain,NPwithcan which included facial sants inNPwere identified[]‌ RCTs(PDN) andpostherpeticneuralgia(PHN).Sixty-one 20antidepres of in NP, NPRCTs diabeticneuropathy and80%of beendoneinpainful have provided inChapter 9.1.Mostantidepressant research out hasbeen carried NPare The definition,assessmentmethods, andmost common etiologies of Neuropathic pain and 9.2, respectively, as well as in Reference []‌ antidepressantsacute andcancer for painisdiscussed inChapters 9.4 Use of Acute andcancer pain however, this assertion [7] base the does evidence not‌ support clinicians thatthose are thefirst-line pharmacotherapyfor theseindications; SNRI antidepressantsboth NPandFMhascreated for animpression among newer marketing pharmaceutical the analgesicantidepressants. of Aggressive of inhibition modelandusethistocategorize andexplaintheefficacy channel blockers. Inthischapter, we onthemonoaminedescending willfocus are that these drugs may be current thinking, channel action).Recentideas, blocking inlightof attractive GABA channel activation, K prostaglandin synthetase, anopioid-mediatedeffect, to theinhibitionof B potentiation, substance Preduction, oracalcium N . Seventeen were. Seventeen conducted inPDN, -methyl- D -aspartate antagonists-aspartate or sodium . . + - - - - -

as lumbarroot pain,HIVandcisplatin neuropathies, andspinalcord injury PDN andPHNaresimilar, reasonably trialsinsuch NPdisorders butnegative one RCT headache. The SSRIswere indrugwithdrawal tobenomore found and tension headache, wassuperiorinonly butamitriptyline both migraine were andmirtazapine) adrenaline superiorin venlafaxine, (ie,amitriptyline, drugs,commercially available those with a mixed on serotonin effect and nor the Of and medication-induced headache and chronic [, 4]. migraine, daily Four antidepressants in6 RCTs were favorable headache, intension-type these studies. of in several life sion, sleep, of and quality drugs, dualuptake inhibitorsimproved pain,depres milnacipran. Asaclass of theSNRIsduloxetine (20–20mg/day)RCTs andfour threefor trialsof of SNRIs (duloxetine, milnacipran). (fluoxetine,for SSRIs size dole), andasmalleffect citalopram, paroxetine) and for monoamine size effect oxidase (MAO) inhibitors(moclobemide, pirlin for sizes amedium amitriptyline), ysis alsoindicatedlargeeffect TCAs (mostly theanal inpatientswithFM.Results of life sleep, andhealth-related of quality depressants were associated withimprovements inpain,depression, fatigue, data weremilnacipran but that long-term were lacking. effective thatsomeSSRIsand theSNRIsduloxetine They alsofound life. and of quality mg/day) and reduceddepression in FM and improved pain, fatigue, sleep and [2] wasbasedon26RCTs. Theauthorsconcluded (0–50 thatamitriptyline antidepressants inFM2008 of theeffectiveness of A systematic review choice. places TCAs as a first choice along with gabapentinoids and SNRIs as a second inplacing thedifferentdrugs inatreatmentfor NP[9],which algorithm ful balin), theopioid-like drugtramadol,andcannabinoids. Thesedataare help morphine andoxycodone prega andsuperiortogabapentinoids(gabapentin, are superiortoSSRIs. Inaddition,TCA NNTs are aboutequaltotheopioids that balanced N/STCAs are superiortoNTCAs andSNRIs, which inturn sants and other analgesic classes [3] (Table 3.2). In NP, these data indicate for NP figuresfor withdrawal RCTs for both beencalculatedantidepres have To andNNH address thesedeficiencies, NNTfiguresfor50%ormore relief data(mostRCTs comparative of paucity are acomparison withplacebo) [8]‌ [5].Another issueisthe relief subjectswith satisfactory as thenumberof datainmoststudiessuch clinical meaningfulness One problem isthelack of many RCTs translationtoclinical practice for indeciding which drugtouse. these NP problems. maygreater of reflect intractability the Headache Fibromyalgia The literature review for thischapter []‌ The literaturefor review 8RCTs antidepressants concluded thatanti [22]of of A meta-analysis ofthese forthe clinician liesininterpretingA significantdifficulty the results found further favorable results favorable further found ------.

15 Chapter 3 Antidepressants

16 Chapter 3 Antidepressants triptyline, and triptyline, doxepin) [, 3]. Three low antidepressants back for nor pain(amitriptyline, were favorable severity. headache and, less commonly, of tion in duration and frequency of headaches. andtension-type MostRCTs both migraine tion of reportareduc headache preven for allseemuseful andtheSNRIvenlafaxine mirtazapine, Thus, theTCA headaches [, 4]. tension-type thetetracyclic amitriptyline, than andlesseffective TCAsin thanplacebochronic inmigraine effective ate choice of agent because there head-to-head are comparative trials few ate choice of astotheappropri confusion These trialsmay theclinician leave inastateof antidepressants are superiortoplacebo inmany conditions. of that avariety There areplacebo-controlled numerous largely RCTs inCNCP, indicating most antidepressants in pregnancy and lactation has not been established. of Drug interactionsare aconsideration withallantidepressants, and thesafety sea, anorexia, weakness, drowsiness, nervousness, mouth. dizziness, anddry exacerbate seizures, andtriggermania.Morehypertension, common are nau been reported.Serotonin norepinephrine re-uptake inhibitorsmay aggravate gastrointestinal bleedinghave SsyndromeA central andan increased riskof ness, sweating, anxiety, andtremor. agitation, headache, sexualdysfunction, may causegastrointestinal mouth,drowsi upset(commonest), insomnia,dry histaminic side effects,hypotension, severe sedation, and weight gain. They Most SNRIsaretocausesevere adrenergic,andanti anticholinergic, unlikely than other drugchoices CNCPsuch asgabapentinoids(Table for 3.2)[3]. figuresfor harm TCAs donot indicatea worse side-effect profilein RCTs reactions isprudent.Number-needed-to- may withdrawal occur andgradual bupropion. Allergicreactionsuncommon. areWithdrawal generally the useof aseizure disorder daytimeprecludes drowsiness.unwanted Thepresence of nightimedose,which may inasingle alsomitigate andgiven as amitriptyline) insomniaaccompanies pain,asedatingTCA may bechosen (such If [, 23]. usedantidepressants,commonly andmore detailsareelsewhere available Table 3.summarizes monoamineprofiles forsome and common sideeffects spondylitis) []‌. different arthritis conditions(osteoarthritis,rheumatoidarthritis,ankylosing for imipramine,andtrimipraminewereAmitriptyline, tobefavorable found Drug Selection Adverse events Arthritis Low back pain ------

terms of the number of subjects obtaining satisfactory relief. The few head- relief.Thefew subjectsobtainingsatisfactory thenumberof of terms RCTs results inindividual of in and sparsedataontheclinical meaningfulness () individualize therapy,() individualize (2) obtain a complete assessment, and (3) focus In selectinganantidepressant such asaTCA CNCP, for to itisimportant but this solution does not is seem found, to be imminent. “magic bullet” may (tricyclics, be necessary gabapentinoids, opioids, cannabinoids)unless a drugs paininhibition. Combinationsof onecomponentsystems are of only serotonin and noradrenaline or that descending monoamine right balance of Currently, antidepressants, for itseems that eitherwe not have struck the atbestintheselectedsubjects chosen. in CNCPindicateamoderateeffect allanalgesicsinRCTson other drugs, other andhave disorders. Theresults of practice not beachieved inordinary where patientsarecertainly older, are CNCP. 2 or 3 will almostNP or other causes of An RCT NNT result of mental models, butitisunclear whetherthismodelcanbeappliedtoother out in PHNand PDN, which proven have carried tobe good clinical experi theantidepressant research inNPhasbeen exclusion criteria [5].Mostof RCTs where selectedaccording patientsare usually tomany inclusion and NP seem reasonablethose for because there studies. are few pain, arthritis,andthemiscellaneous CNCPgroup, generalguidelinessuch as prophylactically. maytetracyclic mirtazapine beuseful For chronic low back balanced drugssuch astheTCA andthe theSNRIvenlafaxine, amitriptyline, andtensionheadaches, migraine drugsfor commercially available [2]. Of theSSRIsandSNRIs(duloxetine, milnacipran) studied size of the smalleffect the MAO inhibitors (moclobemide, pirlindole) and size of the medium effect Chapter 9.1). depressants are recommended NP refractory to other for therapies (see evidence, sufficient duloxetine) otheranti assecond choice. Duetolack of on age,concomitant disorders, andanSNRI(venlafaxine, andsideeffects) pregabalin) asfirst choice oragabapentinoid(gabapentin, (depending tyline NPoftenrecommendsuggested for aTCA such ornortrip asamitriptyline pregabalin.are gabapentin,and.7for Treatment 4.7,26.2for algorithms from figuresforwithdrawal dol. Number-needed-to-harm RCTsfor TCAs opioids (morphine,oxycodone), thedualmechanism agenttrama and4for pregabalin, gabapentinoidsaregabapentin,4.2for 2.5 values for 5. depressants > SNRIs > SSRIs. For comparison with other analgesics, NNT NNT valuesinRCTs of terms in NP trials as balanced S/NTCAs > N anti RCTssubstantial numbers of [5] (Table 2). This helps to rank these drugs in RCT beencalculatedand NNHsfor have inNPwhere withdrawal there are analgesics such asgabapentinoidsandopioids, NNTs 50%ormore for relief thesedrugsincomparison witheach other andwithother of andsafety cacy antidepressants over SNRIsandSSRIs [8]‌ TCA nonselective to-head RCTs of indicatethesuperiority mostcommonly Approach to therapy An important issue is the generalizability (external validity) of datafrom of validity) (external issueisthegeneralizability An important size datasuggestthat In FM,effect areTCAs (amitriptyline) superiorto . To effi judgetherelative further ------

17 Chapter 3 Antidepressants 18 Chapter 3 Antidepressants tant to inform them that the effect of adoseincrease may not beexperienced of themthattheeffect tant toinform isexperienced. occurs Itisimpor effect oranintolerableadverse relief tory week increased orso)untilsatisfac dose willbelow andwillbeslowly (every (occurs in50%–60%RCTs). Patients alsoneedtoknow thatthe starting treatment istotake thepainfrom severe ormoderate to mild that theaimof and ispossiblebutunlikely They needtounderstandthatcomplete relief topatients. treatment effects andadverse explainthegoals of to carefully atrial).Itis important ance, oraninadequatetrial(toolow adoseortoobrief result trialbecausemany from failures a careful highinitialdosing,noncompli antidepressant usageshouldnot dissuadeonefrom failed therapy, of ahistory coma, other medications, andalcohol intake. Indeciding onantidepressant (recent retention, myocardial glau conductionurinary defects), infarction, on issuesthatmay preclude disease thesedrugssuch age,heart asadvanced pressants, tocheck compliance butthey canbe useful andasaguide todose antide for bloodlevels routine measures. There isnotherapeuticrange of mouth spray are saliva useful astool softenerandanartificial prescription of compliance, doseincrements, effects.Preemptive andtodealwithadverse tosupervise is important 2 weeks initially) In addition,close follow-up (every patient. anisms may meanthatonedrugis more foranindividual efficacious andduloxetine) mech faxine differences in paininhibitory because individual desipramine,imipramine)totheSNRIs(venla amitriptyline, (nortriptyline, different antidepressants and move to try It mayevent. from be helpful TCAs or a significant adverse pain relief satisfactory amounts until an end point of week increase ortwo byunder 65andthenslowly thedoseevery similar reasonable patientsover those tobeginwith0mgfor 65and25mgfor events) itis oramitriptyline, (lesssignificantadverse such asnortriptyline treatmentwitha isstarted TCA antidepressant (mean,50–75mg).If effect in mind that with TCAs occurs the analgesic effect at lower doses than the low generalprinciple andgo isto“start slow,” A good diogram. keeping andanelectrocar electrolytes, ing, hematology, function, andkidney liver tamoxifen, and cisapride) (see Chapter 10). channel blockers, macrolide andquinoloneantibiotics, SSRIs, antipsychotics, antiretrovirals,ing ventricular tachycardia (antiarrythmics, calcium antifungals, caus P450),possibly or interferewithhepaticmetabolism(viacytochrome analgesics such asthosethateitherprolong theQT (eg,methadone) interval constipation) are minimized. Antidepressants may interactwithother non analgesics andsedatingdrugssothatdruginteractions(such assedationand possible,itisprudenttoeliminateallother ineffective paradoxical insomnia.If are allergicreactionssupraventricular), and such asrash,tachycardia (usually more in the younger important age groups. Less common effects adverse may inthealreadyoverweight be population.Sexualdysfunction particularly agents, inwhich casedietandappropriate weight monitoringare important, avoid daytime drug-induced drowsiness. Weight gain may occur with some insomniaisaproblem orto withthetotal doseatbedtimeif may beuseful AsedatingTCA shouldbegradual. stopped,drugwithdrawal (amitriptyline) if common withTCAs mouth,constipation, anddrowsiness) beingdry andthat, are stopped,sideeffects probable (themost oneweek ormorefor andthat,if Useful baselinetestsare bloodpressureUseful measurement supineandstand ------

good relief and therapeutic blood levels may andtherapeuticbloodlevels beachieved withlow doses good relief increments insomepatientswhorequire higherdoses. Insome patients, References with other analgesic drugs need to be considered many patients. for antidepressants the useful poor generalizability, for evidence combinations of deficiencies inthisarea andbecauseof drugs toguidetheclinician. Becauseof antidepressants by head-to-headRCTs quality comparingdrugswithold new new researchThere effectiveness of continuescomparative tobeaneedfor monotherapy. for tions, or“magicbullet” thereadvance hasbeennostriking the increase inplacebo-controlled RCTscondi antidepressants inpainful of comparison. Despite additionalmeansof NNT andNNHvaluesare auseful depressants withother analgesics. Indirect measures comparative such as practice. Therehead-to-headRCTsnary are few thatcompare differentanti trialdatatothe samedisorders inordi of orgeneralizability validity external TCAs andother analgesics.concern isthelimited Animportant subclass of themore specific and how thedrugscompare withthestandard therapy of theresults interest of particular inthesestudiesare theclinical meaningfulness RCTs. concerning quality antidepressantsreviews and pain and individual Of sants, guidelinesanddataregardingfrom andsafety recent efficacy systematic antidepres of This chapter provides aboutthepharmacology information nacipran) and SSRIs. the SNRIsduloxetine, (venlafaxine, mil desipramine) and a lesserof effect theTCAs imipramine, nortriptyline, (amitriptyline, of indicate thesuperiority oids, cannabinoids, topical agents). opi therapy cases (gabapentinoids, is reasonable in refractory and necessary treatment trialisreasonable;be age-related. combination A three-month tonote thatthisresponse 0–20mg,butitisimportant may not always of 2. 4. 3. . Summary In CNCP, head-to-headRCTs, NNTfigures, size datagenerally andeffect

Collaboration. The Cochrane Library: John Wiley & Sons Ltd.Available Collaboration. The Cochrane Library: John andpreventing tension headaches The Cochranemigraine (Review). serotonin Selective re-uptake inhibitors for Sterzi R, et al. Moja L, Cusi C, doi/0.002/465858.CD00703.pub3/abstract Wiley &Sons, Ltd.AvailableLibrary: John at: low TheCochrane Collaboration.TheCochrane back pain(Review). Urquhart DM,Hoving JL,AssendelftWJ,et al. Antidepressantsnon-specific for CD005454.pub2/abstract Available at: Wiley &SonsLtd. Cochrane Collaboration. TheCochrane Library: John T,Saarto PJ.Antidepressants The Wiffen inneuropathic pain(Review). 202: pp. 465–490. PainWall and Melzack’s Textbook of JR,Koltzenburganalgesics. M,Tracey In: McMahon I,andTurck DC(eds.) Watson CPN,Gilron I,Pollock BG,LipmanAG, SmithMT. Antidepressant http://onlinelibrary.wiley.com/doi/0.002/465858. . 2007. Accessed 9 November, 204. , 6th ed. Elsevier/Churchill Livingstone; , 6thed.Elsevier/Churchill Livingstone; http://onlinelibrary.wiley.com/ . 2008. ------

19 Chapter 3 Antidepressants 20 Chapter 3 Antidepressants

23. 22. 2. 20. 9. 8. 7. 6. 5. 4. 3. 2. . 0. 9. 8. 7. 6. 5.

Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic Pharmacologicalmanagementof Moulin DE,ClarkAJ,Gilron I,et al. Watson CP, head-to- of systematic review Gilron J.Aqualitative, I,Sawynok Watson CP, Gilron J, Lynch I,Sawynok ME.Nontricyclic antidepressants and Watson CP, Vernich versus L,ChipmanM,Reed amitriptyline K.Nortriptyline Lynch ME, Watson CP. review. chronic pain: a Pain The pharmacotherapy of ai fTherapeutics Basis of Brunton L,Chabner B, Knollman B(eds) with antidepressants: JAMA 2009; 30:98–209. a meta-analysis. Hauser W, fibromyalgia K,Uceyler Bernardy syndrome N,etal.Treatment of 2008; 59:279–298. treatment withantidepressants infibromyalgia syndrome. Rheum Arthritis of Uceyler the N, effectiveness Hauser W, A systematic Sommer C. of review fluoxetine onpainindiabetic neuropathy. JMed992;326:250–256. NEngl and desipramine,amitriptyline, of Effects Max MB, Lynch SA,MuirJ,et al. 2008; 7:27–22. Bennarroch EE.Descending monoaminergicpainmodulation.Neurology Ann Neurolhypothesis. 979; 4:45–462. and Basbaum AI,FieldsHL.Endogenouspaincontrol mechanisms: review 37:589–596. pain in orpatients depressedropathy with normal 987; mood. Neurology relieves Amitriptyline diabeticneu Max MB, et al. CulnaneM,Schafter SC, 982; 32:67–673. petic neuralgia. Neurology Watson CP, versus Amitriptyline placebo inposther EvansRJ,Reed K,et al. Medicine In: Rothwell PM,ed. Watson CP. trialsinneuropathic pharmaceutical pain. of validity External update. Mayo Clin Proc 200; 85(3 Suppl):S3–S4. andliterature overview neuropathic pain: an macological managementof RH,O’ConnorDworkin AB, AudetteJ,et al. Recommendations thephar for neuropathic pain. Pain 200; 50:573–58. ment of pharmacological treatFinnerup NB, for The evidence Sindrup SH, Jensen TS. recent guidelines. Am J Med 2009; 22(0 Suppl):S22–S32. of overview neuropathicO’Connor pain: an AB, RH.Treatment Dworkin of neuropathic pain: 200 revision.EurJNeur200;7:3–23. treatment of EFNSguidelinesonthepharmacological Attal N,Cruccu G,Baron R,et al. 32:237–25. recommendations. Pain 2007; neuropathic pain: evidence-based ment of Pharmacologicmanage RH,O’ConnorDworkin AB, Backonja M,et al. Society. Pain Res Manag 2007; 2:3–2. neuropathic pain-consensus statementandguidelinesfrom theCanadianpain Res Manag 200; 5:47–57. oralanalgesics inneuropathic pain.JPain head randomized, controlled trialsof 20; 52:2206–220. theserotonin norepinephrine reuptakepain: are inhibitorsany better?Pain in postherpeticneuralgia: a 998;5:66–7. randomized trial.Neurology Res Manag 2006; :–38. pub2/abstract at: http://onlinelibrary.wiley.com/doi/0.002/465858.CD00299. . Philadelphia: Elsevier; 2007: pp.. Philadelphia: Elsevier; 2–30. . 2005. Accessed 9 November, 204. . 2th ed. New York: McGraw Hill; 200. Treating Individuals: From Randomized Trials toPersonalized Goodman and Gilman’s Pharmacological Goodman andGilman’s Pharmacological - - - - -

which lower makes 600 mgthree its bioavailability at higher doses (35% for dosing [4]‌ allows twice-daily therefore ithaslinear pharmacokinetics,which makes dosetitrationeasierand pentin, because it does not require totransporters be absorbed, active and drug-drug interactions. Pregabalin possessesasignificantadvantage over gaba not metabolized by theliver, pharmacokinetic andthey are thereby of devoid response to pregabalin [3]. seeninchronic pain;neuroimagingconnectivity markers predict analgesic reduces activity, insularglutamatergic which reduces theincreased functional [2]‌ cytokines tory Gabapentin alsoactsonNMDA receptors, andinflamma protein C, kinase the via modulation of mostly Gabapentin andpregabalin are thoughttoexert their analgesicaction receptors []‌. release, glutamate andactionon pression of tion. Theseinclude sodium channel blockade, calcium channel blockade, sup actionsonthecentral system, nervous alldecreasingdiverse central sensitiza mostanticonvulsantsresults from acombination of of The analgesicactivity neuropathic pain. analgesicefficacy, limitedto andthey are only of limitedevidence very have neuropathic fibromyalgia. for painaswell asfor Otheranticonvulsantstive analgesicactivity,the moststudiedfor andthey beenshown have tobeeffec gabapentinoids gabapentinandpregabalin are been anticonvulsantsthathave trigeminalneuralgia.However, thetreatment as962for of the used asearly differentvarious and diseases. for degrees Historically, carbamazepine was beenshown anticonvulsantshave Several to topossessanalgesicefficacy LussierDavid Anticonvulsants Chapter 4 Gabapentinoids Mechanisms of action Introduction Gabapentin andpregabalin boundtoproteins are both andare minimally . A recent placebo-controlled suggeststhatpregabalin study . Gabapentin, the saturable absorption process of . Gabapentin,the saturable absorption process of α 2 δ - protein of the - protein of N -methyl- N -type calcium-type channel. D -aspartate (NMDA)-aspartate - - - - -

2121 22 Chapter 4 Anticonvulsants to open-label trials, evidence also suggests it might be effective totreat pain to open-labeltrials, alsosuggestsitmightbeeffective evidence by atleastoneR bar spinalstenosis[3]isalsosupported pes zoster [0],spinalcord [],postthoracotomy injury pain[2],andlum randomizedseveral controlled trials(R of gabapentinhasbeenthemoststudied,with which theanalgesicefficacy are theneuropathic conditions for andpostherpeticneuralgia[8, 9] [6, 7] toantidepressants,than olderanticonvulsants. Similarly diabeticneuropathy anditsbettertolerability itsefficacy studiessupporting ment, duetoseveral action than gabapentin [5]. tively. onset of Pregabalin has a faster gabapentin enacarbilallows administration, respec aonce- and twice-daily gastroretentive gabapentin and [4].However,daily of formulations thenewer 300mgdose),requires asingle vs60%for administration3–4times times daily creatitis [29]. Compared with a twice-daily administration of 300 mg, a single 300mg,asingle creatitis administration of [29].Compared withatwice-daily relieve painfrombowel irritable syndrome chronic andhas beenusedfor pan to make itafirst-line Itcanalso recommended analgesic(seeChapter 9.3). in itsefficacy fibromyalgia is sufficient mg/day duloxetine [28].Scientific dataof 600 mg/day pregabalin alongwith60or20 hadthe largest beneficial effects chronicfor peripheralneuropathic painandcomprising close to6000subjects, 7R of oid analgesics[27].Inameta-analysis antidepressants) andopi toother adjuvant(gabapentin, pathic painrefractory More importantly, prolongedfor neuro been shown 5-monthbenefitshave totreatpregabalin wasshowncentral painfrom effective spinal [26]. cord injury andpostherpeticneuralgia[5]‌ [24, 25] neuropathy diabetic neuropathic pain,including painful types of for diverse shown effective studiedand properties,with betterpharmacokinetic hasalsobeenextensively for gabapentinbut enacarbil [23].it is still insufficient use gastroretentive gabapentinasfirst-line therapyfor postherpeticneuralgia, recommendationdoses similartogabapentin[22].Evidence issupporting to tion. R dose-proportional exposure administra togabapentin,allowing atwice-daily gabapentinthatprovides sustained, prodrug transported of bil isanactively upto24-week treatment assessed for [2].Gabapentin enacar and safety titrationperiodthanimmediate-releaseshorter gabapentin[20],withefficacy atsimilardoses, isbettertolerated.andhasa effective dose, seemsequally a800mg administrationof which allow daily propertiesof pharmacokinetic the are formulation, not yet marketed in all countries. A gastroretentive is that some gabapentin evidence might relieve pain from fibromyalgia [9]. to treat postherpeticneuralgia[8].Albeitlimited,therethan nortriptyline diabetic neuropathy, butbettertolerated effective whereas itwasequally [7]‌ [7]ormore effective to beeitherequally rare.pain are Whencompared very gabapentinwasshown withamitriptyline, neuropathic for themanagementof different classes analgesicsof trials of neuropathic pain(seeChapter 9.2). AsexplainedinChapter 9., comparative [5], andmultiple sclerosis(HIV) neuropathy [6], as well as cancer-related from complex regional painsyndrome virus [4],humanimmunodeficiency Pregabalin, which possesses the same mechanism of action as gabapentin Pregabalin, which possesses the same mechanism of beenintroduced recently gabapentinhave but Two of formulations new anticonvulsants inpainmanage expanded the useof Gabapentin greatly elief of painassociated withpostherpeticneuralgiaseems tooccur at of elief CTs) it.Itsuseinacute her supporting CTs 7oralmedications evaluating andbettertolerated[7]totreat . Similarly togabapentin, . Similarly CT. Althoughlimited ------

with reduced total effects,however adverse adverse not specific toaparticular 300-mg nightdoseexerts infibromyalgia-related similaranalgesiceffect pain, moderate, serious adverse effects are effects moderate, notserious adverse uncommon [4] (Table 4.). any benefit [4]. although Furthermore, most adverse effects are mild to toillustrate failed have andradiculopathy diabeticneuropathy trials inpainful togabapentin[40].However,including inpatientsrefractory other clinical [39]andpostherpetic neuralgia[40], diabeticneuropathy inpainful effect with better tolerability,sess similar analgesic efficacy did indeed show some rarely used. such asleukopenia syndrome, andSteven-Johnson carbamazepine isvery However, lethal due tofrequent effects,including adverse somepotentially [38]. diabeticneuropathy than continuouspainful pain)[37]butalsofor forlancinating rather intrigeminalneuralgia(only that suggestedefficacy historical reasons for [36]and based onold studies nal neuralgia, mostly Carbamazepine isstillrecommended therapy trigemi for asfirst-line neuropathic pain [35]. gia as models of andpostherpetic neural diabeticneuropathy neuropathic pain,usingpainful in of ananalgesicefficacy evidence sufficient gabapentin have goodquality population [34]. been reportedinobstetricalsituations, cautioninthispatient which warrants have associated withpregabalin effects effects cal adverse [34].Lethaladverse neuropsychiatric, aswell ashepatitisassociated withgabapentinandhematologi beenmostly have 4.. Althoughuncommon,reported, effects seriousadverse chronic pain 3 months after surgery [33]. of tion before,during,oraftersurgery, orboth, doesnot reduce theincidence R 0 andfive [32]. However,ical function according toarecent of Cochrane meta-analysis after hospitaldischarge, reduced movement-evoked painandimproved phys 4 daysstarted andcontinued priortoatotal hiparthroplasty upto3weeks celecoxib twice daily, pregabalin and00mgof 75mgof administration of gabapentinoidsmightalso reduce chronic postsurgicalpain.Concomitant of pain oropioidrequirements Perioperative (seeChapter 9.4). administration period,todecrease acute tinoids intheperioperative eitherpostoperative pressants in neuropathic pain, are provided in Chapter 3. needed totreatgabapentinandpregabalin, for compared withvariousantide [3].Numbers 300and75mg,respectively session,atdosesof hemodialysis aftereach patients, whengiven inhemodialysis peripheral neuropathy painful and pregabalin, results intreating showed thatthey effective were equally dosing. and better tolerated than a twice-daily effective equally administrationis clinical experience [30].Thissupports thatanightly effect Carbamazepine andoxcarbazepine Oxcarbazepine, a metabolite of carbamazepine thatwaspredicted to pos Oxcarbazepine, ametaboliteof According to a recent Cochrane Database R for both effects, whichAdverse drugs, aresimilar are very detailed in Table There isaccumulatingapotential rolegabapen supporting evidence for of gabapentin trials comparing analgesic few efficacy the very In one of CTs of gabapentinandpregabalin,CTs respectively, theiradministra of eview, pregabalin and only ------

23 Chapter 4 Anticonvulsants 24 Chapter 4 Anticonvulsants

Table 4. Mechanism of action, dosing recommandations, contraindications and adverse effects of anticonvulsants most commonly used for pain management Drug Mechanism of Action Starting Dose Usual Effective Precautions and Commonly Reported dose Contraindications  Adverse Effects Gabapentin Modulation of the alpha- 00–300 mg daily; 300–200 mg tid Decrease dose in patients with renal Sedation, dizziness, tremor, immediate- 2-delta- protein of the titrate by 00–300 dysfunction (avoid in severe renal peripheral oedema, weight release N-type calcium channel, mg every one to dysfunction). gain, nausea, headache which decreases central three days to an Rapid discontinuation may result sensitization effective dose in headache, nausea, insomnia, and Gastroretentive 300 mg qd, titrate 800 mg qd diarrhea. gabapentin up to 800 mg qd over 5 days Gabapentin 600 mg qd, titrate 600 mg bid enacarbil to 600 mg bid after 3 days Pregabalin 25–75 mg qd 50–300 mg bid  Carbamazepine Blockage of voltage-gated 00–200 mg 300–800 mg bid • Contraindicated in bone marrow Somnolence, dizziness, blurred sodium channels → ↓ cell qd-bid depression, or within 4 days of vision, headache, confusion, excitability MAOI use. speech and memory • Caution in patients with cardiac difficulties, cardiovascular disease, hepatic or renal dysfunction. abnormalities (eg arrhythmia, bradycardia, hypertension, • Potentially fatal blood dyscrasias AV block), rash, SIADH, have been reported; monitor CBC, nausea, urinary retention, platelets, renal and liver function, hematologic abnormalities and serum sodium. (eg aplastic anemia, bone • Potentially fatal severe dermatologic marrow suppression, reactions (eg Stevens-Johnson thrombocytopenia), increased syndromes) are rare. liver enzymes, hepatic failure Oxcarbazepine 2 Idem as carbamazepine 50 mg qd; titrate 50–600 mg bid Clinically significant hyponatremia can Dizziness by 50–300 mg develop: monitor serum sodium at every 3–5 days to baseline, during the first 3 months and an effective dose periodically

Lamotrigine ) Blockage of 25 mg qd; titrate 00–200 mg bid Black box warning: severe and Headache, dizziness, ataxia, voltage-gated sodium by 25 mg every potentially life threatening skin rashes somnolence, tremor, nausea, channels → ↓ cell 7 days to an have been reported diarrhea, blurred vision, excitability effective dose insomnia 2) ↓ glutamatergic neurotransmission via glutamate receptors 3) ↑ GABAergic neurotrasmission

Topiramate ) Blockage of 25–50 mg qd; 00–400 mg bid • May significantly decrease serum Somnolence, dizziness, ataxia, voltage-gated sodium titrate by 25 mg bicarbonate; monitor serum psychomotor slowing, speech channels → ↓ cell every 5–7 days to bicarbonate at baseline and and memory difficulties, excitability an effective dose periodically. decreased serum bicarbonate, metabolic acidosis, nausea, 2) ↑ GABAergic • Often poorly tolerated: high rate of neurotrasmission withdrawal due to adverse effects paresthesia, tremor, abnormal vision, nystagmus, diplopia, weight loss, nephrolithiasis, secondary angle closure glaucoma

(continued)

25 Chapter 4 Anticonvulsants 26 Chapter 4 Anticonvulsants

Table 4. Continued Levetiracetam 250–500 mg bid 500–500 mg bid Somnolence, dizziness Lacosamide Unknown. Possible blockade 50 mg bid 200–400 mg bid Dizziness, fatigue, nausea/ of voltage-gated sodium vomiting Zonisamide channel 00 mg qd 00–300 mg bid • Use in patients with severe Somnolence, dizziness, sulfonamide allergy is cont- headache, confusion, ataxia, raindicated; potentially fatal insomnia, tremor, nausea, sulfonamide reactions (including weight loss, diplopia, Stevens-Johnson syndrome and toxic nystagmus epidermal necrolysis) are rare. • Use cautiously in patients with renal or hepatic dysfunction. Pregabalin is better tolerated, and equally effective, with a single nightly dose rather than twice-daily dosing. 2ketoanalogue metabolite of carbamazepine.

open-label studies. fortiagabineiseitheranecdotal orlimited to analgesicefficacy Evidence of zonisamideEvidence for is limited to one benefits in fibromyalgia [5]. diabetic neuropathy,failedto show andit has mildeffect, butwithavery totreatLacosamide neuropathic hasbeenshown painfrom tobeeffective post-stroke pain [48], multiple sclerosis [49], and polyneuropathy [50]. severalanalgesic in pain efficacy conditions, including central neuropathic to show any dosing, hasimental failed data, good tolerability, and ease of Levetiracetam, which wasonce apromising agentduetoanimalandexper dence itshas useinbeen neuropathicdeemed insufficient to support pain [47]. exerted viadecreased excitability peripheralnerve [46].However, evi available in patients life with low back pain [44]. Its analgesicmight be effect of quality ular pain [45], aswell asimprove anger, disability, subjective andhealth-related [43], chronicdiabetic neuropathy low back pain [44], and chronic lumbar radic randomized shown trialshave thattopiramatecanrelieve painfrom Individual concern [42]. of effects adverse given cant place intherapy chronic for neuropathic painandfibromyalgia, especially concludedCochrane databasereview thatlamotrigine doesnot asignifi have thisstudy, arecent of relief.Basedonmeta-analysis did not provide further gabapentin,oratricyclic antidepressantine toeitheranonopioidanalgesic, lamotrig yielded conflicting have betic neuropathy results, and the addition of neuralgia, HIV neuropathy, and central dia poststroke pain,studiesonpainful of lamotrigine has been for suggested trigeminal Although analgesic efficacy Lamotrigine Tiagabine Zonisamide Lacosamide Levetiracetam Topiramate R CT in diabetic neuropathy [52]. ------

27 Chapter 4 Anticonvulsants

28 Chapter 4 Anticonvulsants sants were there ontheanalgesicactiv evidence available, isnogood quality anticonvul beforenewer Despite largeclinical experience anduse,mostly efficacy. other analgesics with of better evidence after trials of beconsideredzonisamide, shouldonly asanalgesics tiagabine,andfelbamate to open-label studies. felbamateisalsoeitheranecdotal for orlimited analgesicefficacy Evidence of References effects ratio. those with the best efficacy/adverse and clinicians should favor pain, pharmacologicalmanagementof of scribing ananticonvulsantaspart effects,as serious adverse well as contraindications when considering pre all medications, consider oneshouldalways potential benefits, common and chronic postsurgicalpain.With pain,including prevention of perioperative of forfibromyalgia andthemanagement to possesssomeanalgesicefficacy thegabapentinoids. withmuch for Thelatteralsoseem betterevidence tive, oxcarbazepine, lamotrigine, and topiramate have been shown to be effec neuropathic whichEvidence pregabalin, isbestfor pain, gabapentin, conditions.of painful inavariety Anticonvulsants possessanalgesicefficacy these drugs [35]. any of of ity 7. 6. 5. 4. 3. 2. . Conclusions Phenytoin, valproate, clonazepam Felbamate Because of very limited evidence of analgesicefficacy, lacosamide, of limitedevidence very Because of

2000; 20:280–285. diabetic neuropathy: an open-labelpilot study.painful JPain Symptom Manage C, Mazzarello Dallocchio Buffa C, P, ChiroliS. Gabapentinvs. in amitriptyline ized controlled trial. JAMA 998; 280:83–836. random inpatientswithdiabetes mellitus: a neuropathy painful treatment of Backonja M,Beydoun A,E 09:26–35. arandomised, placebo-controlled clinical trial.Pain 2004; of ralgia: results improves sleepandmooddisturbances inpatientswithpost-herpetic neu Pregabalin reduces painand DA, R,Gálvezet al. Sabatowski R,Cherry Epilepsia 999; 40 (Suppl 9):S7–S3. Perucca Anesthesiol 203; 9:453–464. chemistry, connectivity, response inchronic andfunctional painpatients. RE,Napadow V,Harris HugginsJP, Pregabalin rectifies brain aberrant et al. gabapentin in neuropathic pain. Arch Pharm actionof Kukkar Implicationsandmechanism of AS. A,BaliSinghN,Jaggi ment: a Can J Anesth 2006; 53:562–57. bench-to-bedside perspective. painmanage anticonvulsantdrugsinpostoperative Gilron I.Therole of . The clinical pharmacokinetics of the new antiepileptic drugs. the new of E. The clinical pharmacokinetics , et al. Gabapentin for thesymptomatic Gabapentinfor dwards KR,et al. R es 203; 36:237–25. ------

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ment of postherpetic neuralgia: randomized controlled trial. JAMA998; postherpeticneuralgia: randomized ment of placebo-controlled trial. Pain 2004; 0:628–638. adouble-blind, diabeticperipheralneuropathy: painful treatment of 3:448–454. doses. DiabetesCare 2008; randomized, controlled trialsacross arangeof from 7 diabeticperipheralneuropathy: findings painful gabalin treatment of of pre Freeman R,Durso-Decruz E, mirB. Efficacy, and tolerability safety 25:9–202. care. Postgrad postherpeticneuralgiainprimary Med203; management of Harden RN,Kaye AD, KintanarT, CE.vidence-based the guidance for Argoff (PXN0748). J Pain 203; 4:590–603. carbil insubjectswithneuropathic painassociated withpostherpeticneuralgia of gabapentinena placebo-controlled andsafety trialtoassesstheefficacy Zhang L,R pentin in postherpetic neuralgia patients. Clin J Pain 203; 29:770–774. Jensen MP, G,R Irving 02:55–64. Sci 203; postherpeticneuralgia.JPharm thetreatmentpentin for of gaba of gastroretentive dosageform aonce-daily of and tolerability HanCH,SweeneyChen C, M,Cowles VE.Pharmacokinetics,efficacy, trial. Arthritis randomized, double-blind,placebo-controlled, fibromyalgia: a multicenter of Gabapentininthetreatment LM,GoldenbergDL, StanfordSB,Arnold et al. GONIP trial. Int J Clin Pharmacol Ther 2006; 44:358–363. post-herpetic neuralgia patients: a randomized, double-blind clinical trial—the Chandra K,ShafiqN, Pandhi in Gabapentin versus nortriptyline P, et al. pain. Archneuropathy Int Med 999; 59:93–937. ondiabetic peripheral of gabapentinwithamitriptyline comparing the efficacy Morello CM,Leckband SG,StonerCP, R et al. 5:609–6. paroxysmal symptoms inmultiplesclerosis 998; patients. Neurology ment of gabapentintreat Solaro Lunardi C, GL,CapelloE,et al. Anopen-labeltrialof 8:7–75. 9patients, observations.EurJNeurol preliminary 200; ropathy: a reportof La SpinaI,Porazzi D, MaggioloF, HIV-related et al. Gabapentininpainful neu dystrophy. J Pain Symptom Manage 995; 0:265–266. reflex sympathetic Mellick GA, Mellick LB. Gabapentin in the management of patients with lumbar spinal stenosis. Spine 2007; 32:939–942. Yaksiof gabapentintherapy in A,Ozgönenel L,Ozgönenel B. Theefficiency chronic post-thoracotomy pain. of gabapentininthetreatment Solak O, of MetinM,EsmeH,et al. Effectiveness neuropathic pain in spinal cord injury.treatment Spine 2004; 29:743–75. of F,Levendoglu OgünCO, Ozerbil O, et al.for the Gabapentinisafirstlinedrug in patients with herpes zoster.allodynia 2005; 9:444–447. Neurology JD, gabapentinreducesBerry acute painand Petersen doseof KL.Asingle blind, placebo controlled study. Pain 200; 94:25–224. 280:837–842. osenstock J,Tuchman M,LaMoreaux U. L, Sharma Pregabalin the for owbotham M, Harden N, Stacey B, et al. Gabapentin for thetreat al.Gabapentinfor owbotham M,Harden N,Stacey B, et t al.Arandomized, double-blind, ainka M,Freeman R,et Rheum 2007; 56:336–344. , et al. Long-term safety of gastroretentive gaba of safety auck R,et al.Long-term Eur J Cardiothorac Surg 2007; 32:9–2. andomized double-blind study andomized double-blindstudy ------

29 Chapter 4 Anticonvulsants 30 Chapter 4 Anticonvulsants 30. 29. 28. 27. 26. 4. 40. 39. 38. 37. 36. 35. 34. 33. 32. 3.

R Nasser K, Kivitz AJ, Maricic MJ, et al. Twice daily versus once nightly dosing of AJ,Maricic MJ,et al. TwiceNasser K,Kivitz dosingof versus once nightly daily Talukdar R, Ney JP, EB, of Devine Watanabe SD. JH,Sullivan efficacy Comparative Pregabalin inthetreatment of K,et al. Stacey RH,Murphy BR,Dworkin Pregabalin incentral neuropathic pain Siddall PJ,CousinsMJ,OtteA,et al. store/0.002/465858.CD007963.pub2/asset/CD007963.pdf?v=&t= Database Syst R Zhou M,ChenN, He L,et al. Oxcarbazepine neuropathic for pain. Cochrane Scand 2005; :229–232. tocarbamazepinepetic neuralgiaunresponsive andgabapentin.ActaNeurol et al. LippiS, AulettaC, OxcarbazepineCriscuolo S, monotherapy inposther ropathy: a randomized, placebo-controlled study. Oxcarbazepine diabeticneu Beydoun inpainful Mazzola S, S, J,et al. Dogra (Tegretol): double-blind cross-over trial. Diabetologia 969; 5:25–28. with carbamazepine peripheral diabeticneuropathy treatment of side effects. Arch Neurol 968; 9:29–36. neuralgia. Use and Killian JM, Fromm GH. Carbamazepine in the treatment of 32:237–25. recommendations. Pain 2007; neuropathic pain: evidence-based ment of Pharmacologicmanage RH,O’ConnorDworkin AB, Backonja M,et al. November, 204. com/doi/0.002/465858.CD00567.pub2/abstract Database Syst R Cochrane Cochranereviews. pathic painorfibromyalgia-an of overview Moore S, PJ, Derry Wiffen 203; 36:55–62. theFrench pharmacovigilance database.DrugSaf of review pregabalin: a drugreactions Adverse togabapentinand Fuzier R,SerresI,GuittonEet al. CD008307.pub2/abstract Jul 24;Available at: inadults. chronic Cochrane DatabaseSyst pain after surgery R tion of Chaparro L trial. Pain randomized prospective controlled six weeks aftertotal hiparthroplasty: a pregabalin andcelecoxib reduces scores painandimproves function physical NM, KatzCarmichael J, Clarke regimen H, et al. of perioperative An intensive 33:40–408. patients. 203; ClinDrug Investig inhaemodialysis life related of quality andhealth- peripheralneuropathy gabapentinversus pregabalin onpainful of Atalay H,SolakY, BiyikZ,etal.Cross-over, theeffects open-labeltrialof and safety. Care Arthritis efficacy pregabalin fibromyalgia: a for double-blind randomized clinical trial of creatic duct. World J Gastroenterol 203; 9:639–6328. 4:706–79. and indirect treatment comparisons. Pain Med 203;pain: meta-analysis chronic peripheralneuropathic thetreatment for of oral pharmaceuticals 2008; 9:202–208. a5-monthopen-labeltrial.Pain Med of neuropathicrefractory pain: results 67:792–800. associated withspinalcord placebo-controlled injury: a 2006; trial.Neurology ull JA, Quibrera R es Manage 203; 8:27–32. E , Smith LA, Moore eddy DN.Paineddy inchronic pancreatitis: managing beyond thepan ev 203Novev ;Available at: ev 203; Availableev at: R , Gonzalez-Millan H, Lozano Castaneda O. Symptomatic http://onlinelibrary.wiley.com/doi/0.002/465858. R . Accessed 9 November, 204. es (Hoboken) 204; 66:293–300. , et al. Antiepileptic drugs to treat neuro R, et al. R A, et al. Pharmacotherapy the preven for A, et al. http://onlinelibrary.wiley.com/ Eur J Pain 2005; 9:543–554. http://onlinelibrary.wiley. . Accessed 9 ev 203 ev ------52. 5. 50. 49. 48. 47. topiramateonperipheralnerve erdoganYücel C, M,AkgünH,et al. of Effects 46. 45. 44. 43. 42.

November, 204. i2qwqztu&s=4ea024550c8c53d249f0c40685fa5f97598e2 6:225–234. randomized, doubled-blind,placebo-controlled pilot study. Pain Med2005; diabetic neuropathy: a painful Zonisamide S. inthetreatment of Atli A,Dogra gia in adults. Cochrane Database Syst Moore S, SA.Lacosamideneuropathic for pain and fibromyal L,Derry Hearn cross-over trial. randomized, placebo-controlled, paininpolyneuropathy: a the treatment of Holbech JV, Otto M,Bach FW, Theanticonvulsant levetiracetam for et al. 6:860–869. levetiracetam in central pain in multiplesclerosis. trial of Holbech JV,Falah M,MadsenC, SindrupSH.Arandomized, placebo-controlled trial. neuropatic post-stroke pain—arandomized, double-blind,placebo-controlled Levetiracetam N,et al. inpatientswithcentral Jungehulsing GJ,IsraelH,Safar November, 204. =i2qx837z&s=55fcba05d2d3f2980e9a8f65348fbbb8f86bd store/0.002/465858.CD00834.pub3/asset/CD00834.pdf?v=&t inadults. Availableand fibromyalgia at: S, LunnMP, PJ,Derry Wiffen Moore SA. for neuropathicTopiramate pain excitability. 202; 29:268–270. J Clin Neurophysiol lar pain. J Pain 2005; 6:829–836. Khoromi Patsalides S, A, Parada et al. TopiramateS, in chronic lumbar radicu study. Clin J Pain 2006; 22:526–53. randomized, double-blind,placebo-controlledwith chronic low back pain: a Muehlbacher M, Nickel MK, Kettler et al. C, Topiramate patients in treatment of Neurol Scand 2004; 0:22–23. from three double-blindplacebo-controlledneuropathy: findings trials. Acta Thienel U, NetoW, Topiramate Schwabe SK, et al. diabetic poly inpainful Accessed 9 November, 204. onlinelibrary.wiley.com/doi/0.002/465858.CD006044.pub4/pdf fibromyalgia inadults. Cochrane Database Syst R S, Moore PJ, Derry Wiffen Eur J Neurol 203; 20:33–337. Eur J Pain 20; 5:608–64. A. Lamotrigine for chronicRA. Lamotrigine for neuropathic pain and R ev 202 Feb 5.ev http://onlinelibrary.wiley.com/ ev 203;Availableev at: Eur J Pain 202; . Accessed 9 . Accessed 9 http:// - - - .

31 Chapter 4 Anticonvulsants

∗ theendocannabinoid endocannabinoid system (Figure 5.).Modulation of the pounds such as the anandamide basis and of 2-arachidonoyl form glycerol neurons,sensory onmicroglia, andinperipheraltissues. Endogenous com were alsodetected inthebrain,dorsalroot lumbarspinalcord, ganglia, on not exclusively, althoughthey inperipheraltissueswithimmunefunctions, By contrast, CB afferentfibersandspinal alongthepainpathways cord).also found (primary receptors localized inthecentral are system, nervous andthey mainly are cannabinoidreceptorinhibiting type), (CB) two cloned G-protein coupled receptors (G of lation viathe activation many datasuggestthatthecannabinoid system isimplicatedinpainmodu cannabis, theprincipal psychoactive component of Since theidentificationof cannabinoids in various pain conditions is presented. system, the role of thecannabinoid differentpain conditions. Afterarapidpresentation of of theirpotential role clinical inseveral trialsfor inthetreatmentbeen evaluated 2% 2.5 ± has acontent of Δ whole plant,there are prescription synthetic compounds for available such as bigerol, etc).Inadditiontothe cannabichromene, tetrahydrocannabivarin, ( chemical compounds including approximately 70different phytocannabinoids special medicalauthorization.Marijuanainhalationexposestheusertomany Canada, theseedlingsare produced by anddelivered HealthCanadawitha Federal government continues toenforce itsprohibition inthesestates. In Columbia—approve andregulate itsmedical use as theDistrictof Mexico,New Oregon, RhodeIsland,Vermont, andWashington, aswell Maine,Massachusetts,Jersey,Hawaii, New Michigan, Montana,Nevada, Colorado,8 states—Alaska,Arizona, California, Connecticut, Delaware, United States and is not approved prescription for as medicine; however, medicalpurposes.for However, cannabisremains illegalthroughout the marihuana(marijuana,cannabis)isauthorized America,theuseof States of countries,In several such asCanada,andinsomestatestheUnited Beaulieu andPierre Julie Desroches Cannabinoids Chapter 5 Δ

The cannabinoid system http://medicalmarijuana.procon.org/view.resource.php?resourceID=00088 9-THC or synthetic derivatives (Table9-THC orsynthetic derivatives 5.).Thedistributeddriedmarijuana 9-tetrahydrocannabinol [ 2 receptor expressionpredominantly, seemstobefound but Δ 9-THC], cannabinol,cannabidiol(CBD),canna Δ 9-THC. Cannabinoid-basedmedicines have9-THC.  andCB 2 receptors []‌ (accessed 25 March 203) . TheCB ∗ . The i/o, - - -

3333 34 Chapter 5 Cannabinoids

Table 5. Cannabis-Based Medicines Available in Clinical Practice Cannabinoids Aspect Indications Posology Commercial Remarks Name Marijuana Plant Mostly in chronic pain Individual – In Canada, requires a special medical authorization from Health Canada Dronabinol 2.5, 5, and 0 mg Severe nausea and 2.5 to 5 mg Marinol Also used in capsules vomiting associated with every 2 h chronic pain cancer chemotherapy; management max. 20 mg/day AIDS-related anorexia associated with weight loss Nabilone 0.25, 0.5, and Severe nausea and  to 2 mg Cesamet Also used in  mg capsules vomiting associated with every 2 h chronic pain cancer chemotherapy management max. 6 mg/day

Nabiximols Oromucosal Adjunctive treatment for Start with  Sativex Causes (THC/ spray containing the symptomatic relief spray every irritations in cannabidiol) 2.7 mg THC of neuropathic pain 4 h or less the mouth and 2.5 mg associated with multiple in 20–25% Average dose: cannabidiol per sclerosis and advanced patients in 00 µL cancer pain 5 sprays/day clinical trials

Abbreviations: AIDS, acquired immune deficiency syndrome; max., maximum; THC, Δ9-tetrahydrocannabinol. mGluR neurons, and generating arachidonicglycerol acid. not exclusively, by lipase (MGL) in presynaptic a distinct enzyme monoacylglycerol ethanolamine and arachidonic but acid, whereas predominantly 2-AG is degraded, acid amide hydrolase (FAAH)the enzyme fatty in postsynaptic neurons, producing 2-AG are controlled by distinct enzymatic pathways. by Anandamide is hydrolyzed AEA and remains controversial. (4) Degradation: the synthesis and metabolism of 2-arachidonoylglycerol similar mechanisms for (2-AG) transport The existence of the synaptic space by shown been recently have a specific to be facilitated transporter. anandamide (AEA), endoCBs, in and most notably synaptic currents. (3) Reuptake of excitatory inhibiting glutamatergic post neurotransmitter thus temporarily glutamate, the excitatory synapse, endoCBs can inhibit the releaseillustrating a glutamatergic of effects. In this figuresignalization cascade leading to analgesic and anti-inflammatory presynaptic cannabinoid receptors terminals, where they can activate and downstream from depolarized postsynaptic neurons into the extracellular space, they to can travel (2) Release: endoCBs can act through a retrograde signaling mechanism: released endoCBs. membrane phospholipid precursors and subsequent synthesis of age of increases in intracellular calcium levels, or receptor stimulation, leading to the cleav neurons. Enzymatic processes either by membrane depolarization, can be activated synapse-specific manner, from and endoCBs can be postsynaptic released immediately endoCBs. () Synthesis: endoCB operates on demand in a signaling machinery of central system.nervous It is regulated by synthesis, release, reuptake, and degradation excitability and synapticboth excitatory transmission throughout and inhibitory the neuronal synapses.at glutamatergic Endocannabinoid signaling is a key regulator of tors and their agonists, and the endocannabinoid (endoCB)-mediated synaptic signaling Figure 5. …. Nabiximols Dronabinol Nabilone Synthetic … (degraded byFAAH) ∆ Natural Agonists: Anandamide(CB 9 -THC 5 , type  metabotropic, type receptors. glutamate

Schematic figure illustrating cannabinoid receptor (CB)

> CB … Analgesia 2 )

CB Ca . . . K G-proteinactivation Intracellular signalling . ActivationMAPK . + InhibitionofAC ++ channels0 channels0

… Anti-inammatory

2 CB Δ 9 -THC, -THC, 2-AG (CB ∆ Natural Agonists: … (degraded byMAGL,FAAH) ? Synthetic 9 Δ …. -THC 9 -tetrahydrocannabinol; 2  and CB

> CB) 2 recep - - -

35 Chapter 5 Cannabinoids

36 Chapter 5 Cannabinoids inflammatory stimuli, even potent and effective drugs evensuch stimuli,as potentopioids often and effective inflammatory volunteer studies using noxious heat and tant to note that in this setting of [3, 4]. outcome,onstrated ananalgesiceffect itisimpor Despitethisnegative volunteers dem studieshave whowere administeredafew cannabinoids, only setting.pain inhumanvolunteers andinthepostoperative Indeed,healthy pain. However,and inflammatory they are in alleviating acute least effective of acute innumerous efficacy animalmodels shownCannabinoids have great endocannabinoid system in various pain conditions. system [2],indicatingasignificantforthe reviewed hasbeenrecently role 2 patients suffering 2from patients suffering posttraumatic or postsurgical neuropathic pain a randomized, placebo-controlled smoked evaluated cannabisamong study peripheral neuropathic painwhenusingsmoked cannabis [9].More recently, in38patientsreportedsignificantdecreasesover in trialperformed central and neuropathic pain.For example, one randomized, placebo-controlled, cross dronabinol and nabilone [7, 8]. comes were reportedby two trialsamong neuropathic painpatientsusing concomitantly with other analgesic drugs[3–6].However, out negative differentetiologiesbenefitsafter reported treatment with of neuropathic painstates. P treatment of effects in adversethe oftenassociated with but significantanalgesiceffects Overall, cannabinoidshadmodest neuropathic pain(seealsoChapter 9.). central orperipheral of therelief cannabinoidsfor evaluated studies have randomized,Several placebo-controlled, double-blind,crossover andparallel Neuropathic pain ders, fibromyalgia, or other chronic a pain(for review,conditions see[, 2]). (SCI),painassociated withmultiplesclerosisinjury (MS),musculoskeletal disor virus[HIV]neuropathic(including humanimmunodeficiency pain),spinal cord chronic pain,such asneuropathic pain fromtypes of patients suffering several shown inpain patientshave thatcannabinoidswererelieving effective ber of chronic painconditions recent [0].Several studiesusingasubstantialnum thetreatment for of effective In general,cannabinoidsare moderately painmanagement. cannabinoids inacute postoperative of ontheeffect drawn condition andusingappropriate dosageisneededbeforeaconclusion canbe recruitingstudy patientsundergoing operationswithareproducible painful at high doses [9].antianalgesic However,or even effects a large multicenter different noeffects fromplacebo [6, 7], [8], eithermoderateeffects and have that cannabinoidsadministrationisnot appropriate pain totreat postoperative pain,concluding cannabinoidsinpostoperative published reportsontheuseof cannot achieve significantpainmanagement[5]‌ Chronic pain Acute pain Numerous clinical trials have examined the efficacy of smoked cannabis for of smoked for cannabis Numerous clinicalexamined theefficacy trialshave atients suffering fromatients suffering neuropathic pain . Moreover, therefour are only Δ 9 -THC/CBD ------

inhalation of 25 mg of 9.4% 25mgof inhalation of toconventional therapies[20].P refractory randomized clinical studiesusingcannabisextract difference in the overall scores spasticity usingtheAshworth scale[32].Other group, better in thespasticity were cannabinoids significantly but there was no painscores from Subjective 5weekscebo and in630patientssuffering MS. for oralcannabisextracts trial, evaluated Sclerosis (CAMS)study, alarge multicentre, randomized, placebo-controlled ment associated withMSwere For example,theCannabis inMultiple positive. cannabinoids in pain and spasticity treat all clinical trials devoted to the use of ate symptoms [3]).Accordingly, associated inRef. withMS(reviewed mostly Preclinical studies cannabinoids useto and allevi many clinical studies support sclerosisMultiple cannabinoids in patients suffering from SCI. potential benefit of clinical Although nodefinitive conclusionsa canbemade,thesestudiessuggest with placebo afteratreatment withnabilone(0.5mgb.i.d.) 4weeks [30]. for patients withSCIreportedimproved scores (spasticity) Asworth compared recent double-blind,placebo-controlled, crossover in2 performed study cant improvement scores inspasticity in patientswithSCI [29].Moreover, a placebo-controlled using parallelstudy oral est improvements inpain,spasticity, muscle spasms, with andsleepquality crossover in patients from studies suffering performed SCI suggested mod incontinence, sleeping. anddifficulty Two double-blinded,placebo-controlled, associated withneuropathic SCIsuch aspain,spasticity, muscle spasms, urinary animal studies[25–27]suggestingthatcannabinoidscouldsymptoms alleviate preclinical thefindingsof clinical datasupport Although stilllimited,available Spinal cord injury analgesics. patientswhoare for not responding toother conventionaltant alternative symptoms associated withneuropathic painandasanimpor a treatment of designed clinicalalthough it studies.remains to be demonstrated in adequately ers toinhalecannabismay decrease itstoxicity compared withsmoked cannabis, vaporiz inaclinical setting[24].Therecent itsfuture of development vinced of smoked for medicalmarijuana[23],andsomeopponentsare notfuture con troversial, arguing with supporters that it is premature to claim that there is no whethersmoked cannabisshouldbeusedinclinical practice iscon The issueof athigherdoses. andmodestacute effects,predominantly cognitive (smoking) administration smoked marijuana may be limited by its method of utilization of neuropathiccannabis[22].However, paininpatientssmoking sensory medical than30%reductiona greater inpain[2]and30%decrease inHIV-associated HIV-associated neuropathic painpatients, according totwo studiesthatreported pain intensity, with significant improvements and anxiety [20]. in sleep quality days, significantaverage daily therereductionin wasamodestbutstatistically In conclusion, there is some clinical evidence cannabinoids supporting as Smoked cannabisalsoexerts antinociceptive effects compared withplacebo in Δ 9-THC and/or Δ 9-THC/CBD [3, 28]. A randomized, double-blind, A randomized, 9-THC/CBD [3, 28]. Δ 9-THC herbal cannabis three times daily for five five for 9-THC herbalcannabisthree timesdaily Δ Δ 9 -THC/CBD, oral 9-THC showed a statistically signifi 9-THC showed astatistically atients reported that after a single atients reportedthatafterasingle Δ 9-THC/CBD [33, 34] and and 9-THC/CBD [33, 34] Δ 9 -THC, orapla -THC, ------

37 Chapter 5 Cannabinoids

38 Chapter 5 Cannabinoids concluded that an administration of 0 mg of dronabinol hadamodestbut 0mgof concluded thatanadministrationof Moreover, arandomized, double-blind,placebo-controlled, crossover trial profileing painandsleepdisturbances withagoodeffects [38, 39]. adverse that theoromucosal cannabisextract frompatients suffering central neuropathic painassociated withMS revealed placebo-controlled, parallel-grouptrial in and its extension) performed perceived benefits[37]. Two other studies(arandomized, double-blind, wereconcluded effects maintainedinpatientswhohadinitially thatpositive using study open-label,follow-up scale [36],andalong-term, oral of ment effect spasticity not measures. confirmed by objective improvementsjective of standardized cannabisextractcapsules [35] reportedsimilarresults, withsub retain any lasting benefitafteritsdiscontinuation. A multicenter retrospective tender pointsnorthepoint pain threshold, and it did not number of Questionnaire scores. However, nabilonetreatment did not attenuatethe and anxiety,improvements aswell asinFibromyalgia inpainrelief Impact b.i.d. consecutive weeks. four P for from in40patientssuffering fibromyalgia [47]withnabilonemg performed double-blind,placebo-controlledpatient dropout. trialwas A randomized, a highdose[46].However, causedahighrateof effects intolerableadverse somepatients experienced significantpain with relief, and reportedthatonly induced pain,axondronabinol onexperimentally reflex flare, andpain relief of from in patientssuffering fibromyalgiaeffect examinedthe performed frompatients suffering thatdisease. For example,anopen-labelpilot study asubpopulationof inonly In somediseases, cannabinoidsmightbeeffective Fibromyalgia reducing from pain in patients suffering rheumatoid arthritis [45]. weak thatoromucosal evidence currently cannabisissuperiortoplacebo in compared with placebo. However, according to a recent review, there is culoskeletal pain[44]showed thatnabilonehadsignificant analgesiceffects from mus placebo patientssuffering involving [43].Anotherrefractory study cannabis favoring over sleepwithoutcomes exerted of benefitsonquality for pain on movement significant analgesic and at statistically rest, and it also that a fromindicated in58patientssuffering rheumatoidarthritis performed study domized, double-blinded,placebo-controlled, multicentre parallelgroup A ran [42](seealsoChapter 9.3). andrheumatoidarthritis osteoarthritis from patientssuffering end-stage cannabinoid system inthekneesynovia of functional endo a rheumatoid arthritis, as suggested by the identificationof symptoms associated with Cannabinoids may aroleof have inthealleviation Musculoskeletal pain a to (for review, MS associatedrelieve may pain be effective see Ref. [4]). measures, onsubjective cannabinoids significantmostly seem tobeclinically pain reduction similartotraditionalanalgesics[40].Overall, althoughresults witha on central paininpatientswithMS, relevantanalgesiceffect clinically Nevertheless, a CAMS showed follow-up study a treatsmall long-term Δ 9 -THC/CBD extract administered for five weeks wasamodestbut -THC/CBD extractadministeredfive for Δ 9-THC onmuscle measures spasticity by theAsworth atients subjectively reportedsignificant atients subjectively Δ 9 -THC/CBD was effective in reduc -THC/CBD waseffective Δ 9-THC/CBD ------

suffered from considerable limitationshamperingits credibility [48].P infibromyalgia, butthestudy alsosuggestedcannabinoidseffectiveness study see Ref. [55]). tic potential regarding a review, antiemetic and antitumour properties (for cannabinoidsadditional therapeu in cancer given pain are needed,especially wereeffects mild to moderate (somnolence, dizziness, and nausea). cebo groups.Both cannabinoidregimens were well tolerated,andadverse patientswhoachieved thisresponse inthe the numberof improvement reported a 30% or greater inpainscore,tively which was twice patientssubjec relieved by strong opioids[54]. Approximately 43%of fully fromplacebo in77patientssuffering intractablecancer-associated painnot acannabisextract( evaluated study produceeven seemed to increase and analgesic effects pain perception [53]. onstrated thatbenzopyranoperidine (asynthetic analogof fromand placebo inpatientssuffering chronic painduetomalignancies dem [52]. In contrast, comparing a study a profile effects the adverse because of log was not considered useful clinically codeine phosphate,thesynthetic ana to50mgof approximately equivalent wassuperiortoplacebo and patients andreportedthatalthoughpainrelief testedanitrogentext. Indeed,another study analogof interferedwithcannabinoidsbenefitsinthis apparently con effects Adverse analgesicpotential seemedtohave inthesepatients. effect, its sedative vision. However, authorsconcluded thata0mg Δ codeine [5].P 60 and20mgof in36cancer patientscomparing 0and20mg was performed alsoexperienced severe effects.Thesecond adverse study unfortunately [50]. P 5,0,5,and20mg patients treated withanescalatingdoseof in0cancer wasperformed cancersevere refractory pain.Thefirst study oral of tiveness ized, double-blind, placebo-controlled the analgesic effec trials evaluating cancer-relatedpotential for pain treatment. The first two studies are random agovaluedcannabinoids have moreFour than34 years studiesperformed fibromyalgia. the treatmentnoids for of Overall, thereatic. isinsufficient clinicaldatatoendorsecannabis or cannabi sufferedfromthe study many limitations,itsinterpretation making problem [49].Unfortunately,and well beingassociated effects withtolerableadverse nabis reportedsignificantbenefitsinpain,stiffness, relaxation,somnolence, patientswithfibromyalgia usingself-administered can cross-sectional of study months. seven A recent such as treatmentopioids after an average period of in pain scores,concomitant medications depression symptoms, and intake of 7.5mgof doseof daily on anaverage Cancer pain 9-THC highestdoseinduced somnolence, dizziness, ataxia, andblurred Additional clinical trials evaluating the therapeutic efficacy of cannabinoids the therapeutic efficacy Additional clinical trials evaluating A recent randomized, double-blinded, placebo-controlled, parallel-group atients reported significant pain relief withthetwo higherdosesbut atients reportedsignificantpain relief Δ 9 -THC (dronabinol)from inpatientssuffering moderateto atients reportedmildanalgesiceffects,but Δ Δ 9 Δ 9-THC reportedasignificantdecrease -THC/CBD), a 9 -THC nitrogen analog with codeine Δ 9-THC regimen, despite Δ 9 Δ -THC extract,and 9-THC incancer Δ Δ 9 9 -THC andpla -THC) didnot Δ 9 -THC with Δ 9 atients -THC ------

39 Chapter 5 Cannabinoids

40 Chapter 5 Cannabinoids patient compliance withtherapy [0],andsignificantobstacles remain before are to effects themaindrawbacks with cannabinoids[56].Theseadverse patientstreated tocannabinoidshasbeenreportedin0%of dependency of reported. Nodeathrelated tooverdose hasbeenreported.Development diovascular, reproductive, pulmonary, and immune systems also have been onthe car cannabinoids. effects Adverse reversible upon discontinuation of are rare. 5.2). Althoughpossible,psychosis effects Theseadverse isrelatively iness, amnesia,psychomotor retardation, (Table impairment and cognitive on thecentral system nervous anxiety, andinclude euphoria,dysphoria, drows cannabinoidsare related totheiractions of The mostcommon effects adverse and synthetic cannabinoids [60, 6]. In acute pain trials, negative or equivocal and synthetic cannabinoids[60,6].Inacute orequivocal pain trials, negative of smoked marijuana als are lessconclusive regarding theanalgesicefficacy tors incontrolling nociceptive transmission, dataobtainedfrom clinical tri cannabinoid recep Although preclinical highlights of the evidence importance humans in order to reduce requirements opioids. for synergistic antinociceptive effects, emphasizing their clinical inrelevance or alteringmetabolism [59]. plasma opioid levels out significantly nabis augments analgesia in patients already on a stable opioid regimen with sustained-release morphineoroxycodone. Theauthors concluded thatcan ing from chronic painusinginhaledvaporized cannabisconcomitantlywith [58]). Moreover, arecent in2 patientssuffer clinical trialwasperformed a review, thesepatients (for adjuvant analgesicfor seeRef. may be a useful opioidsandhasconcluded thatdronabinol stabledosesof despite taking patientsexperiencing chronic pain addingacannabinoidtotheregimen of of chronic paininhumanvolunteers. hasexaminedtheeffect Inaddition,astudy pain, acute pain, and peripheral inflammatory cannabinoids and opioids for both compounds. and cannabinoids to enhance of the potency different opioids considerable clinical interest combinations in investigating of onpainmodulationandpain-relievingmechanisms,effects there has been Because cannabinoidsandopioidsare distinctdrugclasses withdifferent medical cannabinoids [57]. issues relatedacterize to the use of safety exposure char trialswithlong-term aretion. High-quality required tofurther addic including druginteractions, andrisksof tolerance, impairment, cognitive cannabinoidtherapy, is therefore of required effects adverse onthelong-term relevantoutcomes effects.More withminimaladverse clinically data achieving adjuvant analgesics Conclusions oncannabinoids as Opioids-cannabinoids interactions Adverse effectsofcannabinoids Overall, opioid and cannabinoid interactions may lead to additive or even Overall, oreven opioidandcannabinoidinteractionsmay leadtoadditive combined administrationof theuseof Some clinical reportssupport

------analgesic activity and safety of smoked cannabisare stilllimitedand generally of andsafety analgesic activity chronic pain.However, of other types for the scientific studiessupporting neuropathic isalsoaccumulating butevidence for pain associated withMS, of cannabinoids is medicines. ananalgesicefficacy for Thebestevidence cannabisorcannabinoid-based results been reportedwiththeuseof have Respiratory Tract Depression, • Cognitive • Psychomotor • Transient • Drowsiness, • Amnesia, • Anxiety/nervousness • Euphoria, • Central Nervous System On Different Systems Table 5.2 No • Overdose/Toxicity Behaviors • Dependence • Tolerance, Dependence and Abuse Precancerous • Mutagenic • Carcinogenesis and Mutagenesis Association • Implication • Liver Peripheral • Myocardial • Coronary • Fluctuations • Dose-related • Cardiovascular System Increase • Decline • Slightly • Reduced • Reproductive and Endocrine System Immunomodulatory/immunosuppressive • Immune System Pulmonary • Chronic • Decreased • reddening documented increased in obstructive in neonatal

confusion, impairment dysphoria impairments insufficiency of sperm vasodilation, effects Moderate to Severe CannabisAdverse Effects abnormal infections pulmonary infarction in with in

amotivational dizziness, preoccupation, in tachycardia chronic retardation pulmonary blood  moderate evidence count, risk out birth airway depersonalization sperm pressure of of liver of somnolence function postural

weight

concentration 0 people sudden sensory pathology of diseases syndrome, to diseases morphology compulsion,

death severe and length infant death hypotension, and directly perceptual fibrosis psychosis, and reinforcement, effects motility attributable and schizophrenia functions characteristic to and cannabis withdrawal conjunctival overdose

41 Chapter 5 Cannabinoids

42 Chapter 5 Cannabinoids cannabinoids and to monitor the patients carefully. of profile associated theadverse-effect withtheuse patients of inform fully treatment option [62].However, butasathird orfourth itisstillcrucial to includedpathic painhave cannabinoidsintheiralgorithm, not asafirst-line neuro thetreatment guidelinesfor of medicationsbecauseinternational of theoptions becomingfrom available thecannabinoidclass should beawareof painconditions. refractory gesic for Clinicians inpainmanagement working consideration asanadjuvantanal of the subjectmake cannabinoidsworthy the potential rolecannabinoidsinpainmanagementandongoing work for on clinical practice are mandatory. smoked largeclinical trialsevaluating marijuanain inconclusive. Thus, further 2. . 0. References 7. 8. 9. 6. 4. 3. 2. . 5. Overall, the publication of several important clinical studiesemphasizing important several Overall, thepublicationof

72:735–744. randomized trials. BrJClinPharmacol20; of pain; asystematic review Lynch chronic ME,Campbell F. non-cancer treatment Cannabinoids for of 0:353–368. cannabistreatmentchronic for pain.P of meta-analysis TA, E,Furukawa al.Systematic andMartin-Sanchez review Taylor J,et Opin Anaesthesiol 2007; 20:473–477. pain. Curr ment of Beaulieu P Can J Anaesth 2006; 53:769–775. Beaulieu P 06:69–72. pain.P oral delta-9-tetrahydrocannabinolinpostoperative of analgesic efficacy al. Lack of DJ, ToogoodBuggy et L, Maric S, 04:040–046. 2006; painmanagement.Anesthesiology postoperative (Cannador) for an oral cannabisextract of effects theanalgesicandadverse of study al.Amulticenter dose-escalation Holdcroft A,Maze M,Doreet C, Suppl):320S–326S. pain.JClinPharmacol98;2(8–9dol andplacebo inacute postoperative intramuscular levonantra Evaluationof JR,McMahonFG,et al. AK,Ryan Jain 05:79–88. subjects under experimental pain conditions.bination in healthy delta-9-tetrahydrocannabinol (THC), morphine, and aTHC-morphine com M,CuratoloP Naef capsaicin-induced responses in human skin. Rukwied R, Watkinson A, McGlone F, Cannabinoid agonists attenuate et al. 24:07–024. Med Res Opin2008; nabiloneonexperimentalheatpain.Curr of effects P Redmond WJ,Goffaux Disord Drug Targets 2009; 8:403–42. Guindon J,HohmannAG. Theendocannabinoidsystem andpain.CNSNeurol Pain tem. In: Beaulieu P Guindon J,HohmannAG, BeaulieuP : IASP . Effects of nabilone, a synthetic cannabinoid, on postoperative pain. nabilone,a synthetic cannabinoid,onpostoperative of . Effects , Ware M. Reassessment of the role of cannabinoidsinthemanage the role of , Ware M.Reassessment of Press, Seattle; 200: pp. –38. , LussierD, P etersen-Felix S, et al. The analgesic effect of oral of al.The analgesic effect etersen-Felix et S, , P otvin S, et al. Analgesic and antihyperalgesic Analgesicandantihyperalgesic et al. otvin S, orreca F, Dickenson AH,eds. harmacology of thecannabinoidsys of . Pharmacology P ain 2003; 02:283–288. hraooyo of Pharmacology ain Med2009; P ain 2003; ain 2003; ------3. 3. 30. 29. 28. 27. 26. 25. 24. 23. 22. 2. 20. 8. 7. 6. 5. 4. 9.

P P mine whetherwhole-plantcannabisextractscanimprove intractableneuro Wade DT, Robson P 36:45–59. spinal cord injury. Arch inpersonswith nabiloneonspasticity over of assessingtheeffect pilot study 2007; 45:55–562. Delta9-tetrahydrocannabinol inpersons withspinalcord injury. SpinalCord with spasticity Thetreatment of Hagenbach U, N,et al. Ghafoor Luz S, Psychiatry Clin Neurosci 990; 240:–4. casedouble-blindtrial.EurArch inasingle antispastic andanalgesiceffects Maurer M, Henn V, Delta-9-tetrahydrocannabinol shows Dittrich A, et al. 2009; 33:57–7. system ismodulatedinresponse tospinalcord inrats. Neurobiol injury Dis Garcia-Ovejero D, A,P Arevalo-Martin pain. J Rehabil 2009; 46:35–43. Res Dev neuropathic spinal cord injury agonist WIN55,22-2over timeinratmodel of cannabinoid receptor Hama A, Sagen J. Sustained antinociceptive of effect in rats with a spinal cord injury. Exp Neurol 2007; 204:454–457. cannabinoidagonist WIN55,22-2 of Hama A,SagenJ.Antinociceptive effect Ther 2008; 83:57–59. ClinPharmacol much future. Kalant H.Smoked marijuana asmedicine: not Ther 20; 90:769–77. Ware MA.Clearingthesmoke around medicalmarijuana.ClinPharmacol 2009; 34:672–680. pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology Ellis RJ,Toperoff W, Vaida F, et al. Smokedfor neuropathic medicinal cannabis 68:55–52. randomized placebo-controlled 2007; trial. Neurology neuropathy: a sory HIV-associated Cannabisinpainful sen Abrams DI,JayCA,ShadeSB, et al. pain: a randomized controlled trial. CMAJ 200; 82:E694–E70. Ware MA,Wang T, Shapiroet al. S, Smokedchronic cannabis for neuropathic cannabiscigarettes inneuropathic pain.JP crossover trialof pain: randomised, crossover, double blind study. BMJ 2008; 336:99–20. nabiloneanddihydrocodeinechronic for neuropathic of patient tolerability and analgesiceffects Comparisonof Frank B, SerpellMG,HughesJ,et al. neuropathic in refractory pain? Eur J tive Attal N,BrasseurL,GuirimandD, Areand effec et al. oralcannabinoidssafe placebo-controlled clinical trial. arandomised,double-blind, ropathic paincharacterised by allodynia: treats neu successfully Sativex B,Nurmikko TJ,SerpellMG,Hoggart et al. 2004; 59:440–452. ”studies. Anaesthesia of from 34 “N chronic cannabisfor pain: results of Notcutt W, Price Initialexperiences M,MillerR,et al. withmedicinal extracts a randomised controlled trial. sion: results of central neuropathic painfrom brachial plexusavul of relief extracts for of two cannabisbasedmedicinal Birch Symonds C, JS, R. Efficacy Berman genic symptoms. Clin Rehabil 2003; 7:2–29. Wilsey B, Marcotte T, Tsodikov Arandomized, placebo-controlled, A,et al. ooyania T, EthansK,Szturm S, Arandomized, double-blinded,cross et al. ertwee RG.ertwee Cannabinoids and multiple sclerosis. Mol Neurobiol 2007; , HouseH,et al.controlled Apreliminary todeter study hys Med Rehabil 200; 9:703–707. Phys P ain 2007; 33:20–220. etrosino et al. S, The endocannabinoid P ain 2004; 8:73–77. P ain 2004; 2:299–306. ain 2008;9:506–52. ------

43 Chapter 5 Cannabinoids 44 Chapter 5 Cannabinoids 35. 34. 33. 32. 48. 47. 46. 45. insger M,Schimetta W, Volc anadd-ontreatment with 44. P D, [Benefitsof et al. 43. 42. 4. 40. 39. 38. 37. 36.

Vaney Heinzel-Gutenbrunner C, M, Jobin P P Davies Collin C, Wade DT, Makela P Zajicek J,Fox P of a multicenter survey. Anesthesiol Res of treatment in chronic central neuropathic pain and fibromyalgia patients: results TetrahydrocannabinolWeber J,Schley M, Casutt M,et al. (Delta9-THC) fibromyalgia. J Skrabek RQ, painin Galimova L,EthansK,et al. thetreatment Nabilone for of Med Res Opin 2006; relief. 22:269–276. Curr induced pain,axonmyalgia patientsonexperimentally reflex flare, andpain A,SkoppSchley M,Legler G,et al. Delta-9-THC basedmonotherapy infibro ment inrheumatoidarthritis.Cochrane DatabaseSyst 202; :CD00892. Rev Richards BL,WhittleSL,Buchbinder R.Neuromodulatorspainmanage for randomized controlled trial]. Wien Klin Wochenschr 2006; 8:327–335. the synthetic cannabinomimeticnabiloneonpatientswithchronic pain—a (Oxford) 2006; 45:50–52. pain caused by rheumatoid arthritis. Rheumatology inthetreatment acannabis-basedmedicine of (Sativex) of andsafety ability Blake DR,Robson P Res Ther and 2008; rheumatoid 0:R43. arthritis. Arthritis noid receptor system in synovial tissue andfluid inpatients withosteoarthritis Richardson D, P 20; 25:87–20. Zajicek JP crossover trial. BMJ 2004; 329:253. central double blindplacebo paininmultiplesclerosis? controlled Randomised Svendsen KB,Bach FW. JensenTS, Doesthecannabinoiddronabinol reduce trolled, open-label, 2-year extension trial. Clin Ther 2007; 29:2068–2079. neuropathiccannabidiol for painassociated withmultiplesclerosis: an uncon Rog DJ,NurmikkoTJ,Young CA.Oromucosal delta9-tetrahydrocannabinol/ 65:82–89. cannabis-based medicine incentral paininmultiplesclerosis. 2005; Neurology controlled al.Randomized, trialof Rog DJ,NurmikkoTJ,Friede T, et sis. Mult Scler 2006; 2:639–645. andother spasticity symptoms inmultiplesclero medicine inthetreatment of Wade DT, acannabis-based useof Long-term Makela PM,HouseH,et al. Neurosurg follow up. J Neurol for 2 months data and efficacy (CAMS) study: safety Zajicek JP placebo-controlled, crossover study. Mult Scler 2004; 0:47–424. randomized, double-blind, spasticity in patients with multiple sclerosis: a administered cannabisextractinthetreatment anorally of of erability 2007; 4:290–296. cannabis-based medicine causedby inspasticity multiplesclerosis. EurJNeurol Scler 2004; 0:434–44. randomized, placebo-controlled on60patients. study Mult A double-blind, on symptoms generalorspecific inmultiple extracts have effects sclerosis? randomised placebo-controlled trial. Lancet 2003; 362:57–526. and other symptoms related tomultiplesclerosis (CAMSstudy): multicentre , Apostu VI. Role of cannabinoidsinmultiplesclerosis. CNSDrugs VI.Role of , Apostu , Sanders H Psychiatry 2005; 76:664–669. P ain 2008; 9:64–73. , Sanders H, et al. Cannabinoids for treatment of spasticity treatment Cannabinoidsfor of , SandersH,et al. earson RG, Kurian N, et al. Characterisation of thecannabi earson RG, Characterisation of Kurian N,et al. reliminary assessment of theefficacy, toler , HoM,et al. assessmentof Preliminary , Mutiboko IK, et al. Randomized controlled trial of controlled al.Randomized trialof , Mutiboko IK,et P , Wright DE, et al. Cannabinoids in multiple sclerosis, Wright DE, et al. , Robson P t al. Docannabis-based medicinal , et Pract 2009; 2009. , et al. Efficacy, and tol safety , et al. ------49. 62. 6. 60. 59. 58. 57. 56. 55. 54. 53. 52. 5. 50.

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45 Chapter 5 Cannabinoids

of local anesthetics. of administration thevariousroutes andtechniques of provides of anoverview cortex.Table tothesensory thehumanbody 6. rons of from theperiphery transmittedby ascending afferentneu nociceptive information as blockers of orspinal cord.nerves Inasimplisticview, localanestheticsmay beconsidered peripheral of are orinjected into tissueorinthevicinity appliedtotheskin systemperipheral nervous tothebrain.For thispurpose,localanesthetics from the nociceptive information thetransmissionof ics aimsatinterrupting Pharmacologicaltherapy withlocalanesthet pain by higherbrainfunction. cortex andinterpreted as istransmittedtothesensory information ceptive conducting structures distributedthroughout[2]‌ thehumanbody specific nociceptive information Pain sensationresultsof from theactivation beneficial pharmacological agents. extremely of potent group avery approachpharmacological andneurophysiological totheclinical useof protocols thisclinical use.Thischapter for a offers beendeveloped have some indications. for Treatment or topically also be administered systemically anesthetics intobloodvessels canalsobedecreased. Localanestheticscan local injectionof by nerves theinjectionneedleandinadvertent damage of physical Furthermore, thelocalanesthetic. nique helps toreduce thedoseof undervisualcontrol. peripheralnerves Thistech of intothevicinity directly localanesthetics Ultrasoundimagingallows thepreciseas safe. injectionof been localanestheticshasnever lipid rescue therapy [6],theapplicationof ultrasound-guided regional anesthetic techniques [5] and of With the advent block,nerve severe toxic complications result drugeffects. from inadvertent from complications resulting from the technical difficulties in performing these drugs [4]. Apart the pharmacologic properties of well as knowledge of blocks nerve [3],as of andintheperformance in localizingperipheralnerves peripheralandcentral paintransmission[2],technical skills of and physiology the anatomy localanestheticstherefore requires basicknowledge of use of complications []‌ paintherapythetic technique for withalow rateof accepted beneficial andeven regional anes asbeingasafe anesthesiaiswidely a peripheral nerveor spinal cord. Local andinjected into the vicinity of pharmacologicalagentsthatare Local anestheticsconstituteof agroup Patrick Friederich Local Anesthetics Chapter 6 of paintransmission Local anestheticsandtheanatomy

. Thenoci . Clinical - - - - -

4747

48 Chapter 6 Local Anesthetics from theupperand lower [3] ‌ extremities, respectively and thesciatic transmitsensation nerves orthefemoral and ulnarnerves brachial plexusor thelumbosacral plexus. Peripheral such nerves astheradial from blocked eitherthe derive most frequently by localanesthetics clinically from. is theanatomicregion Theperipheralnerves ittransmits information tothebrain.Themore isfrombody distal thenerve thebrain,smaller thehuman Peripheral from peripheralregions transmitinformation of nerves peripheral nerves Transmission ofnociceptive information by needs to be considered [3] the body ‌ gesia that covers a larger region of than asmallanddefinedlocalarea, block aperipheralnerve orneuraxialanal istransmitted from largerregions nociceptive information tomical region. If smallsuperficial insultisrestricted ana toavery theregion of makes senseif orsuperficial tissueonly localanestheticsintotheskin neurons. Infiltrationof afferent theprimary locatedperipheral endingsof superficially very ade of nociceptors andblock of at preventing painsensationby activation blocking aims localanestheticsintohumantissue such as theskin as pain.Infiltration of and the spinal cordnerves is interpreted tothebrainwhere this information via peripheral neural information ates nociception, that is, the transmission of nociceptors initi or chemical insultthreatening tissueintegrity. of Activation ceptors. by They noxious are activated stimuli such asmechanical, thermal, afferent neuronsThe primary involved in pain transmission are called noci Nociception Neuraxial blocks and bursa blocksIntra-articular Incision blocks Topical of LocalAnesthetics Table 6. Other Parietal blocks blocks Peripheral and plexus nerve blocks

Routes andTechniques ofAdministration Paravertebral • Dorsal • Pectoral • Rectus • Block • Intercostal blocks • Proximal • Plexus • Caudal • Rachianesthesia • Epidural • • Mucosa: vaporisation • Cutaneous: creams • Ophthalmic, •

abdominis plane block extremities bronchial, anal, etc) gastric, local anesthetics), patch, gels, dental paste Subcutaneous, of blocks: brachial, penile abdominis block block

block abdominal and otologic: drops distal nerve block block subfascial nerve transverse (eutectic . They are blocked for (buccal, lumbosacral blocks: face, mixture

pharyngeal, or transversus of .

- - - - -

ies for a fractured arm or leg. If the region of interest is too large for a single interestasingle istoolargefor theregion of afracturedorleg.ies for arm If upperorlower a single extremity such as surger of surgeries onlargerparts of localized neuropathic pain [3]. of A lidocaine 5%patch isoftenrecommended asfirst-line therapyfor treatment topical lidocaine and 5%lidocainegelmightalso produce localanalgesia. neuropathic pain,including postherpeticneuralgia.High-concentration of in leg ulcers types alsosuggestsefficacy treatingsome [2].Limitedevidence often usedtoprevent pain from needle puncture, incision, ordebridementof andproduceswhich penetratestheskin adenselocalcutaneous anesthesia,is A Topical application oflocalanesthetics widespread recommendations. however, evidence sufficient tosupport clinical [0, ]; theseisalack of inselectedcancer patients survival forlong-term benefits thetics offering Furthermore, neuropathic pain. beenshownmexiletine) have torelieve of sometypes sodium petic neuropathic pain, including central pain, posther as well of assometypes andacute painduetoburns, paininabdominalsurgery ing perioperative beenreportedin treat lidocainehave of results infusion withanintravenous ongoing clinical studies. Promising of unclear clinical benefitandpart still of mexiletine) inrecenthas been advocated years [7–9]. This application is systemic neuralstructures, the from of injectinglocalanestheticsinthevicinity Apart Systemic application oflocalanesthetics proprioception and motor control. the transmission of sible for temperature sensation is transmitted by other columns than those respon ascending ordescending withinthespinalcord toandfrom thebrain.Pain and isdistributedintodifferent peripheralnerves columns, individual ized fibersof by special carried thespinalcord, information different neurophysiologic of converge columns to nerve body such as the spinothalamic tract. At the level the thespinalcord [2, 3]. from different regions of arriving Nerves of the level peripheralnerves, nociception may beblocked at oralimitednumberof ity painsensationdoesnot result from regionsextrem attributabletoasingle If Transmission ofnociceptive information by thespinal cord from thoracotomy or rib fracture. pain resulting alleviating postherpetic neuralgia or for treatment for of formed nerves thespinal nerves. Intercostal andsubcostal supplied by thedorsalramiof are the body the back of to the spinal cord.nerves of The muscles and skin thespinal intercostal andsubcostal viathedorsalandventral nerves ramiof blockade by local anesthetics. blocks, nerve theentire plexusmay beapproached for or alimitednumberof mixture Nociceptive information originatinginthethoracic region istransmittedbyNociceptive information neuralgia, can channel application of easily

prilocaine some and blockers be studies peripheral blocked of

and local similar lignocaine suggest anesthetics by diabetic local to local anti-inflammatory (eutectic anesthetics. neuropathy. (eg, anesthetics intravenous mixture Such (flecainide, Oral action of blocks

local lidocaine formulations of anesthetics), may

local tocainide, be or anes per oral of ------

49 Chapter 6 Local Anesthetics

50 Chapter 6 Local Anesthetics locaine, ropivacaine, and bupivacaine. Local anesthetic agents differ intheir Localanestheticagentsdiffer andbupivacaine. locaine, ropivacaine, pri cocaine. usedaminoamidesinclude lidocaine,mepivacaine, Frequently includes drugssuch asprocaine,mer group chloroprocaine, tetracaine,and into Based applied on a limited skin area. not be appliedtoopen wounds or mucous be membranes, andit should only absorption, and hence it is not associated with toxicity. However, it should diac side effects after inadvertent systemic application.The desired after inadvertent increasediac sideeffects severe neurological andcar actionand, unfortunately, theoccurrence of of onset,aswell astheduration thespeedof the localanesthetic, of potency thealkylsidechain asdoes the increaseshydrophobicity withthelengthof pyl ring theiralkylside chains attached to thearomatic from thedifferentlengthof Thedifferences between thesedrugs andbupivacaine. resultropivacaine, aminoamidelocalanestheticsmepivacaine, with thehomologseriesof action.Thisprinciple isbestdemonstrated and thelongerdurationof lower thesameclinical endpoint,theslower thedoseneededfor theonset, action[4]‌ onsetanddurationof speed of anesthetic potency, as well as of determinant seems tobetheprimary H Anesthetic potency, onset,anddurationof action the drug molecule. tural properties of aswell astoxicologicaladvantages result disadvantages from thesamestruc nourishedby theknowledge thatbothThis debateislargely significant clinical ofsomedebate. intheir differ toxicologicalnificantly profile isstillamatter usedlong-actinglocalanestheticsatequipotent concentrationscurrently sig long-durationaminoamidelocalanestheticagents. Whether of apeutic safety keted and introduced into clinical practice with the hope to increase the ther the been long-actinghave mar amino amidesand bupivacaine ropivacaine systemic circulation. injectedinto the wheninadvertently seizure andsevere cardiac arrhythmia of action.Thelonger theduration,however, the durationof thehigherrisk theonset,shorter considerations.and hence pharmacokinetic Thefaster therapeuticeffect by thedesired determined onsetanddurationof largely thespinalcord. Choosingonelocalanestheticagentover another is of level block,may localinfiltration,peripheralnerve orblockade atthe beusedfor localanesthetic aspects. other pharmacodynamic Thus,every out affecting structural structure.pharmaceutical From asimplisticview, toarguethattheir itissafe Pharmacology oflocalanesthetics ydrophobicity, byas determined the octanol-buffer partition coefficient, Most result insystemic localanestheticsdoesnot usually Local applicationof group (Figure two on local groups pharmacological differences (ropivacaine), 6.). anesthetics [4]‌ The : amino strongly alkyl and are properties, side ester a influence used chain butyl or as is group amino most racemic the a methyl onset . Thehigherthecoefficient, the local (bupivacaine), amide mixtures. group and anesthetics local duration (mepivacaine), anesthetic. Purified respectively. can of

be action isomers classified The a with pro The for of ------

fibers or nerve columns that carry undesired neurophysiological information undesired information neurophysiological fibers ornerve columns thatcarry thoseTherapy nerve with blocking only local anesthetics aims at differentially andmotor fibersDifferential block ofsensory local anesthetics. pharmacological properties of of a summary from excessive systemic application.Table dosingorinadvertent 6.2provides loss for Inusinglocal anestheticagents theclinical effect. injected togetherdetermine andthevolume thechosen localanesthetic, agent, theconcentration of in analgesiabutalso actionandalongerdurationof results onsetof inshorter from 0.25%to0.5%withoutchanging theinjectedvolume bupivacaine of thesamevolume. For example,increasing theconcentration solution of the same concentration or by administering a more concentrated volume of alocalanestheticcanbeincreased by administeringeitheralarger dose of analgesiaincreases. The andthe duration of block becomes faster onset of anesthetic [4]‌ thelocal charge, vasodilatororvasoconstrictor properties, andthedosageof such asmolecular other factors, maycal potency berelated toanumberof cardiac localanestheticswithneuronal and ontheinteractionof hydrophobicity of of by anincreased actionispaidfor risk anddurationof in anestheticpotency the length of the alkyl side chain. the length of group amide Figure 6.

less Apart from lipophilicproperties,Apart localanestheticsdifferences inthe clini severe pain of (ropivacaine), local differential

differential ion therapy,

anesthetics. side Differences channels . As the dosage of an individual localanestheticisincreased, the anindividual . Asthedosageof effects. the nerve nerve and desired (see The in a This butyl block the block alkyl below). molecular analgesic group relationship side (see (see chain (bupivacaine). below). below) structure effect is a can methyl The and has between be (2) the Hydrophobicity to choice group explained be balanced frequently (mepivacaine), of risk

the of by

local adverse increases against used the anesthetic influence amino a propyl () the effects with -

51 Chapter 6 Local Anesthetics 52 Chapter 6 Local Anesthetics tion as delivered bytion as delivered the manufacturers. practicalreasons for attributabletothedrugformula solely to ourpharmacy tion. Two additionallocalanesthetics, were prilocaineandropivacaine, added andcentral thousand peripheralnerve several neuraxialblocks inourinstitu of allows performance the successful andbupivacaine, thetics, mepivacaine two localanes only theuseof localanesthetic, agiven the injectedvolume of dependsonthe concentration block differentialnerve and largely achieving more and drugs been used [3]. study equipotentthese studies have solutions of However,and wascompared studieswithbupivacaine. inseveral in rarely very R motor activity. ing adequateantinociception withoutprofoundinhibitionof than epiduralblocks becauseitseemedbetter became popularinthe980sfor from ent local anesthetics becauseblock differential nerve result does not solely motor neurons will result. fiberswillbe,andthemore nerve blockade of ade of Thehigherthedose,lessdifferentialblock alocalanesthetic. dosing of [4]‌ localanestheticsthanmotor neurons ceptible of tothepharmacologicaleffects are information more sensory sus walking. Nerve fibers carrying capable of painbutwould stillbe motor neurons. Thepatientswould thenbefree of andhence thedescending withoutblocking motor information blockade of is blocked the ascending nociceptive without information if helpful extremely such asnociception. Whenalocalanestheticisusedinclinical setting,itis R Etidocaine Levobupivacaine Bupivacaine Mepivacaine Prilocaine Lidocaine Amides Tetracaine Chloroprocaine Procaine Esters Agents Table 6.2 opivacaine became popular in the 990s and early 2000s for the same reason 2000s for became popular in the 990s and early opivacaine opivacaine Given the complex interaction of local anesthetic with tissue and nerves localanestheticwithtissueandnerves thecomplex interactionof Given Differential . Differential the the the simplistic amount previously pharmaceutical

Pharmacological Properties ofLocalAnesthetics

nerve blockade approach 274 276 288 288 246 220 234 264 27 236 Weight Molecular of

available confounding

block of structure to

neural 8. 7.7 8. 8. 7.6 7.6 7.9 8.5 8.7 8.9 p long-acting can the K a

be influence choice 94 95 95 95 75 55 65 80 ? 6 (%) Binding Protein information of

achieved

a agents specific of

on Intermediate Short Intermediate Intermediate Short Short Short Long Short Long Action Onset of drug

local with (such can local may be

anesthetic a as

anesthetic. be wide achieved etidocaine) 2.5–3 .5–2 .5–2 0.5– (h) of Action Duration warranted. –.5 3–4 3–3.5 3–3.5 2–3 3–4

variety drug by Bupivacaine the in of effects,  0.5 Potency 3.3 4 4 4    4 Because produc correct

differ a ------

options if they result from direct drugeffects. options if To for theseside reduce the risk mayeffects lastfrom days damagewithouttherapeutic topersistentnerve 5%) some include ropathies, or cauda equina syndrome. toxic These underlying mechanisms thatresultperipheral nerves peripheralneu intransientradicular irritation, severe intoxication has become easier [6]‌ treatmentand successful of lipid rescue therapy, of with the advent the situation has changed considerably therapy challenging andneedstobeinstalledquickly. isthenextremely However, dangerous whenresulting from long-actinglocalanestheticssuch asbupivacaine; are effects most ClassA side in drug-induced seizure andcardiac arrhythmia. onthe brain or the cardiovasculardrug effects happens system. Thisusually thedrugthatresults indirect result systemic from application of inadvertent be and sudden cardiac death [20]. channels andother molecular structures [9]may causesevere arrhythmia ion such asthecentral where system nervous ortheheart, blockade of thebody eral nerves. However, of undesirableatother parts itisentirely paintransmissioninperiph theblockade of isdesirablefor result usually action.This pears from thereceptor andhence thelongerdurationof phobicity. Themore hydrophobicthedrugis, theslower thisdrugdisap time constant disappearance for or unblock by is determined the hydro disappear from thesodiumchannel whenthey are closed. However, the hydrophobic siteonthechannel whenthey are open.Thedrugmolecules potentials by sodiumchannels drugbindingtoapartially blocking following suppressing cardiac action [8] statesthatlocalanestheticsare capableof provided forthis famousexplanation relationship is Themost coefficient [6, 7]. lular structures such asionchannels correlates withtheiroctanol-buffer research [4, 5]. area of pharmacological strategiesremains animportant be achieved by alternative for clinicalapplication.Whetherthiswill have yet tobedeveloped side effects However, long-actinglocalanestheticswithoutthepotential toinduce severe application. lidocaine,intravenous allowing,tic margineven as in thecase of of application systemic afterinadvertent severe sideeffects but alsothehigherriskof the onset;however, effect, thehigherpotency, thelongerdurationof orthehigheroctanol-buffer coefficient,the hydrophobicity the slower thumb,toassumethatthehigher itseemsfair applicableruleof As aclinically Toxicity oflocalanesthetics

Class localanestheticscan view, of severe sideeffects From atherapeutic pointof localanestheticinteractionwithmany different cel of The potency action divided and extent, induction the B (such by into side (Figure regional the class two as effects guarded of lidocaine 6.). classes: class B

anesthetic inflammation side results Local receptor effects or mepivacaine) from anesthetics technique A and depend and hypothesis direct class apoptosis (spinal with toxic on B have side the (Figure a drug anesthesia) short of a effects. choice relatively

nerve effects 6.2). or Class of medium cells

This [23]. drug wide on A side [2, 22]. central hypothesis These (lidocaine therapeu . duration effects side and To ------

53 Chapter 6 Local Anesthetics 54 Chapter 6 Local Anesthetics

Time [ms] 0 00 200 300 400 500 600 700 800 900 000 00 200 300 400 500 600 700 800

40 20 0 ventricular –2 action- potential –40

Potential [mV] –60 –80 – 00

50 0 –50 sodium – 00 current – 50 –250–200

Potential [mV] –300 –350 O IIR O R Bupivacaine

Ropivacaine block 0.5

Inhibition Lidocaine

Figure 6.2 According to the guarded receptor hypothesis, local anesthetics block sodium currents during systole and dissociate from the ion channels during diastole. The time constant for disappearance is determined by the hydrophobicity. The more hydrophobic the drug, the slower this drug disappears from the channel and the higher the risk of cumulative block and cardiac arrhythmia. Experimental data on ropivacaine are limited. I, inactivated channel; O, open channel; R, resting channel.

When local anestheticshould not beexceeded. dose of effects, themaximumdaily nized and hasbeenincluded inguidelinesandrecommendations asissuedby olism [6]‌ intoxication anddirectoncardiac effects metab such asthe“lipidsink”theory of local anesthetic alipidemulsion inthecase of infusing the beneficial effect anesthetic parenteralfor nutritionconstitutes anexcellent treatment local option for given acheaplipidemulsionusually commercially available gest thatinfusing Several Lipid rescue therapy whichagents, can cause allergic reactions. such as methylparabene, butlocalanestheticssolutionscancontaina localanesthetic, conservation neurological 2 600 patients. more than cardiac arrestswere populationof not inthestudy observed lasting longerthan6 months. Theincidence seizure for wasbelow 0.%,and neurologic symptoms postoperative and0.9for lasting longerthan5 days techniques, neurologic symptoms theincidence postoperative was.8%for symptoms resulting from ultrasound-guided peripheralregional anesthetic localanestheticsystemic toxicity neurologic andpostoperative dence of rare, occurring in0000patients. Inarecent []‌ study neurologicsuch ascaudaequinasyndromeing longer-term impairment are upto30%.Fortunately, neurotoxic caus reported incidence sideeffects of localanestheticswith a more thanany other toxic frequently of sideeffect block.dural anesthesiaormajornerve Transient occurs radicular irritation cardiac no such complication incaudalanesthesia,theincidence wasobserved of up to 2 in000. Although ics are associated with a seizure incidence of localanesthet adult patients, blocks majornerve requiring largedosesof distributedamongdifferent regional anesthetictechniques.is not evenly In toxic complications seemslow,dence of localanesthetic-induced toxicity and cardiacinducing severearrest. Although arrhythmias the overall inci cific interactionswithcardiac ion channels, localanestheticsare capableof peripheral such caudaequinasyndrome, astransientradicular irritation, aswell as R Levobupivacaine Bupivacaine Prilocaine Lidocaine Cocaine Table 6.3 opivacaine Clinical signs of localanesthetics toxicity cardiovascular are mostly and Clinical signsof Several various arrest case . The therapeutic approach of lipid infusion has widely beenrecog haswidely lipidinfusion . Thetherapeuticapproach of epidemiologic intoxication. neuropathies

Maximum Daily DosesofLocal Anesthetics reports (Table local is 6 times anesthetics 6.4). and 3 mg/kg 3 mg/kg 3 mg/kg 8 mg/kg 4.5 3 mg/kg Several mg/kg ranging higher Allergic studies animal (7 are mechanisms ( studies from mg/kg [24, 25] reactions in used, 600) in  if in over

the used report 8000 are have doses the with spinal rare to incidences last been epinephrine/adrenaline) are  after anesthesia in 5 years additive suggested 6. Due administration of

(Table 6.3). strongly ontheinci to nerve than to their explain in injury spe sug epi of ------

55 Chapter 6 Local Anesthetics

56 Chapter 6 Local Anesthetics 7. Herroeder Weinberg 6. Gray 5. Berde 4. 3. Wedel Yaksh 2. . Sites References local anesthetic intoxication. resuscitation in case of the art circumstances been have established that allow immediate state of paintherapy uselocalanestheticsfor when toonly able online.Itisadvisable management in anesthesiology of department every The Society the Neurological Cardiovascular Table 6.4 R Seizures Coma consciousness Loss of Tremors disturbances Visual or auditory Headaches Metallic Tinnitus Peribuccal paresthesias Syncope Hypotension Asystole with cardiac arrest Rhythm Atrioventricular conduction disturbances placebo-controlled length other Anesthesia 7th 7th ed, Reg ultrasound-guided temic toxicity neurologic symptoms andpostoperative associated with2,668 Association espiratory arrest espiratory Helsinki Pain Management ed. ed. Anesth of

BD, A. drug TL, CB, of

taste disturbances Philadelphia, Philadelphia, DJ, Regional

Ultrasound

hospital Clinical SignsofLocalAnestheticsToxicity . Taenzer Declaration of Luo GL. Strichartz 7th overdose. Horlocker Pain S,

of local ed. Pecher ZD. Lipid

Anaesthetists Med stay Anesthesia Philadelphia,

nerve anesthetic AH, trial. Anatomy (mostly PA: Churchill PA: Churchill guidance . emulsion GR. Anesthesiology 202; st after TT. S, on Herrick Ann blocks: an Local ed. Schönherr Nerve Patient ventricular: tachycardia, colorectal 37:478–482. Philadelphia, Surg of for toxicity. [26], infusion: resuscitation PA: Churchill anesthetics. of

MD, the regional

Livingstone; Livingstone; 2007; blocks. Great analysis Safety pain and ME, et al. 202; surgery: a Several Europe provide a protocol the for 246:92–200. processing the Britain In: Miller et al. PA: Saunders; anesthesia. in

from Incidence In: Miller Livingstone; 7:80–87. Anaesthesiology American 200: pp. 200: pp. of Systemic double-blinded, a and

prospective fibrillation) these R, system. R, for of Ireland, In: Miller ed. ed. 200: pp.

93–939. 639–674. 2007: pp. –20. protocols Heart local local lidocaine Miller’s Anesthesia Miller’s Anesthesia In: Waldman

anesthetic clinical anesthetic the requires R, Association. randomized, 675–704. ed. American are shortens registry. Miller’s avail that sys and SD - - . .

. Marret 8. 26. Auroy 25. Auroy 24. Zaric 23. Werdehausen 22. Friederich 2. 20. Butterworth 9. Clarkson 8. Siebrands 7. Punke 6. Weiniger 5. Kohane 4. Polley 3. Attal 2. Stow . 0. Chen 9. De

caine 2002; thesia 87:479–486. anesthesia: results Syst anaesthesia anaesthetics neuronal bupivacaine. Albright GA.Cardiac regional arrestfollowing anesthesiawithetidocaineor ity: a slow diac 06:523–53. go-go-related 2007; geneblockAnesthesiology channels by for bupivacaine. 2008; amino-amide local anesthetics with human Kv. channels. Anesthesiology lations 04:45–42. sia from tetrodotoxin-enhanced local anesthetic microspheres. Pain 2003; Anesth treatment neuralgia: efficacy 202; matory local Piegeler T, Votta-Velis 203; cancers: a gery. recovery laparoscopic afterambulatory sur improve of quality postoperative 95:33–338. Oliveira conduction: Rev recovery anesthetics: inhibition review. Anesth N, PJ, WK, and 97:274–280. 09:895–904. 7:548–559. 8:e56540. in D, LS, Y, Y, for E, Analg MA, Src France: The DS, 2009 Cruccu Glynn Benhamou apoptosis. Narchi CW, Pace CF, Columb

Rolin of local postoperative meta-analysis P, CC, signaling Miao with

in Anesthesiology Analg Reg JF neuropathic Smith Schmitz Friederich GS Golovanevski 2003; from Apr R, Hondeghem a NL.

4th. anaesthetic CJ, M, Friederich lidocaine neuroblastoma fast P, CH. G, Fazeli Anesth Jr, and MO.

5;(2):CD003006.

Messiah 202; of Beaussier Minor block SE, Transient Models independent 96:25–253. Eur Fitzgerald Baron SOS D, block

The G, Liu G, et al. Antimetastatic potential of amide-linked EG, Liu G, et al. Antimetastatic potential of TP. pharmacokinetic a

Ropivacaine S, Bargues

Louis J prospective of Pain Anaesthesiol P. Regional 5:262–267. pain: 200 recovery Braun Lidocaine-induced during versus effect B. of

of R, agents. LM. L, A, retrospective and P. Lipophilic 979;

EMLA

sodium M,

Med Domb lung DN, et al. neurologic et al. Structural P, Mechanism L, mechanisms S, cell diastole. of Bonnet other of Streicher et al. Anesthesia et al.

adenocarcinoma 200;

5:285–287. Anaesthesia

anesthetic after et al. sodium and EFNS

cream line. Serious revision. survey AJ, channels 2002; local profile. Major and Apoptosis bupivacaine: concentrating Ickowicz F. Br

35:67–76. abdominal Anesthesiology Prolonged and requirements symptoms guidelines Meta-analysis in for

channel J anaesthetics. complications in LF, stereospecific 9:564–570. Anaesth of cell Eur Hotline the

prospective complications technique during France. bupivacaine Pain

202; local et al. J death D. treatment Neurol induction blockade. 989; cell Extended surgery. anesthetic the on duration Service. 2009; (TNS) 67:906–96.

Systemic Anesthesiology in migration

the on action of 985; of Cochrane 200; 39:30–305. a studies. related depression

survival 03:7–78. human intravenous of human of by pharmacological interactions following Br Anesthesiology Anesthesiology

release

local

regional 62:396–405. potential different post cardiac 7:3-e88. J lidocaine Surg and to PLoS on

model Database in anesthe ether-a- herpetic regional dosing! formu human inflam of

spinal 2008; 997; toxic anes local One lido

with car of of to ------

57 Chapter 6 Local Anesthetics

reported to evaluate thiscentral sensitization(RIII reflex[4,5].Some reported toevaluate etc…) and anindexcan becalculated [2,3].More complex alsobeen toolshave hyperalgesia isthenmeasured inflammation.Thearea of immediate area of awayfrom thewound, beyond further the andisevaluated supra-spinal level) Central sensitizationoccurs atthecentral system nervous (spinaland level hyperalgesia.” wound, [1].Thisphenomenoniscalled“primary –2cm apart nerve level, and it canby be evaluated mechanical stimulations next to the generated attheperipheral sensitization iscorrelated withhypersensitivity pain,peripheral postoperative tion intheclinical setting. Inthecontext of analgesia, or rescue analgesia use). on movement andanalgesicconsumption (opioid titration,patient-controlled are painscores atrest and/or painhypersensitivity injury. Indirect markers of andbecomes aftertissue much more painful painful stimulation thatisslightly after tissue injury.becomes painful Hyperalgesia is referred to as a mechanical mechanical stimulation that field,itmightbedefinedasanonpainful operative provokeas “painduetoastimulusthatdoesnot normally pain.”Intheperi Pain of for theStudy Association isdefined by theInternational sia. Allodynia tions. The clinical symptoms encountered are and hyperalge called allodynia towhatisseeninchronicand central paincondi painsensitization,similarly pain is known and postoperative to induceAcute intraoperative peripheral hyperalgesia. and hypersensitivity, allodynia pain namely tant todefinethe clinical signsof introduce whatisexpected from theiruseintheclinical setting,itisimpor pain onand bothchronic acutetheir effect postoperative pain conditions. in this chapter,pathic painhasbeenlessstudied.Nevertheless, we willreview NMDA receptor chronic antagonists for neuro postsurgical pain.Theuseof chronic of andthedevelopment allodynia, cal symptoms such ashyperalgesia, toreduce central theirability pain sensitizationanditsclinifor postoperative for theirdirectbut painmanagementnot analgesiceffects perioperative field of N LaurentBollag,Philippe Richebé, andCyril Rivat Antagonists N Chapter 7 The definitionof hyperalgesia andallodynia -Methyl- It ispossibletodifferentiatebetween peripheraland central sensitiza To NMDA receptor antagonists andto betterunderstandtherole of -Methyl- D -aspartate (NMDA)-aspartate receptor antagonistsbeenusedinthe have D -aspartate -aspartate ------

5959

60 Chapter 7 N-Methyl-D-aspartate Antagonists scores hasbeenreportedinsomeclinical trials, althoughconflicting results pain andhigherpostoperative An association between hyperalgesia/allodynia • experience: will likely hyperalgesia After surgery, patients of with a high level drugs [6, 7]. so-called anti-hyperalgesic the therapeutic impact of to evaluate experimentalmodelsinhumanvolunteers inorder further authors developed receptors, it has been reported that the activation of µ-opioidreceptors receptors, of ithasbeen reportedthattheactivation administration [2, 13]. by all routesanesthesia and given of opioidsusedduring oid consumption of all types [2, 12–14]. Thisis true for painintensity, allodynia, and decreases hyperalgesia, postoperative and opi painmanagement opioidusedduringanesthesiahelpswithpostoperative of Decreasing and allodynia. thetotal amount pain sensitization,hyperalgesia, opioidsmightincrease central postoperative dosesof high intraoperative There isconsiderable from evidence, both animalandclinical studies, that Intraoperative opioidmanagement improve pain management intra- and postoperatively. toreduce central strategy interesting painsensitizationandto perioperative chronic pain. developing increaseswhich in turn the risk of hyperalgesia, central pain sensitization and postoperative induce of higher level NMDA alsobeenshownhave toactivate receptors and,asaconsequence, to duringandaftersurgery opioidsgiven during andaftersurgery. Highdosesof stimulationoccurs asseen painful receptors of whenhighintensity are activated are receptors, theglutamate such asNMDA receptors. like pain [9]. painisoftendescribed residual asaneuropathic-Long-term postoperative its occurrence [3,10,11]. iscorrelated hyperalgesia withacute postoperative painhasbeenreportedin many studies[8,9],and postoperative Long-term Increased • requests and consumption [2]. patientshadhigheropioid 4/0orless, themosthypersensitive of intensity jects were instructedtousepatient-controlled analgesia(PCA)providing pain beenreported.Inrandomizedhave controlled trials(RCTs) inwhich sub

adjuvants ofpostoperative painmanagement N hyperalgesia The consequences ofpostoperative E Therefore, NMDA receptors modulation and/or blockade might be an central painsensitizationprocess The key receptors of involved intheactivation Increased pain and increased postoperative analgesic consumption -methyl- ven if opioids are not per se drugs that ahave direct on NMDA effect ven if likelihood D -aspartate modulators-aspartate as of

long-term chronic pain N -Methyl- D -aspartate -aspartate - -

This hypothesis explains why high intraoperative doses of opioids induce the doses of high intraoperative explains why This hypothesis andthenmodulatesNMDA phosphorylates receptors’indirectly function. [16] with permission of Wolters Kluwer. of [16] with permission Adapted from hyperalgesia. postoperative This might lead to an exaggeration of γ N Figure 7. and toobtainadecrease [20,21]. inpainandopioidconsumption aftersurgery effect [19] at 30ng/mLseemstobesufficient to aminimalanalgesic achieve the receptor. ketamine acting onaspecific subunitof Plasma concentration of Ketamine isanNMDA-receptor antagonist. Itblocks thisreceptor channel by Ketamine regional OIH include anesthesia [18]. intraoperative postoperative acute and chronic pain [17]. Other opioid-sparing techniques that reduce and acute hyperalgesia postoperative tion anditsconsequence of in terms todecrease onNMDA theireffect as abeneficial strategy receptors activa so-called “Opioid Induced Hyperalgesia (OIH)” [15, 16] (Figure 7.). , opioids have the ability to modulate or enhance the activity of NMDA receptors. of to modulate or enhance the ability , opioids have the activity -methyl- “Reduction of high intraoperative doses of opioids” istherefore proposed dosesof highintraoperative “Reduction of P D ain Inhibitor -aspartate (NMDA)-aspartate receptors. a specific proteinkinase By activating C

The graphic illustrates the link between µ-opioid receptorsThe graphic and Systems re μ Opioid Opioids ce = ANAL ptors – + + – y GESIA + NOCICEPTION PK C γ + + Ca ++ = HYPERAL P ain Fa re Systems T NMD T ce rauma issue + cilitato ptors + + + A GESIA ry -

61 CHAPTER 7 N-Methyl-D-aspartate Antagonists 62 CHAPTER 7 N-Methyl-D-aspartate Antagonists erature to obtain an anti-hyperalgesic effect and to effect reduceerature acute postopera to obtain an anti-hyperalgesic management [27]. ketamineacute pain for perioperative theuseof clinical trialsfavor of ity sitization. Themostrecent todateindicatedthatalargemajor meta-analysis painsen long-term of onthedevelopment demonstrated long-lastingeffects block pain sensitization processes after surgery. As a consequence, ketamine to thanits own pharmacologiceffect amine possessesalongerlastingeffect thedrug[24–29].Thesefindingssuggestthat ket of the eliminationhalf-life painandopioidconsumptionketamine onpostoperative waslastingbeyond when tested around the surgical woundhyperalgesia [2, 22, 23]. Administered duringandaftersurgery, ketamine hasbeenshown toreduce in perioperative pain management. in perioperative clinical studiesare neededtounderstandtherole that the drug. More than the racemicsaid to bepresentation2–3 times greater of thanthatof timesgreater isfour ity ketamine insomecountries. aloneisnow available ItsNMDA receptor affin is aracemic mixture of different countries. the various solutionsusedin usage, due to the possible neurotoxic of effect block painsensitization[32].However, thisisnot arecommended modeof chronic pain at 6 months or 2 months after laparotomies [3, 8, 31]. ketamine were(i.v.) alsoshown toreduce of thedevelopment low dosesof intravenous to bepracticalandrelevant[27,30].Intra-postoperative painandopioidrequirements.tive Table 7.presents regimens thatappear Ketamine Regards to theLevel ofExpected Postoperative Pain Table 7. Other authors also reported on the use of Other authorsalsoreportedontheuseof ketamine wasreportedtoeffectively Finally, theepiduraladministrationof theketamine regimens usedinthelit There isconsiderable of variability of recent demonstratedthatthebeneficialSeveral effect meta-analyses

Recommendations for Intravenous Ketamine Usein Induction Postoperative Maintenance S (+) ketamine and infusion Continuous of surgery) before end 30 min bolusing boluses (stop Repeated R (−) ketamine,is andtheanalgesiceffect none = 5 0.25 mg/kg per h 30 min every 0.25 mg/kg 0.25 mg/kg Moderate Pain µ R g/kg per min (−) ketamine. However, S -ketamine. Regular ketamine S Surgery (+) ketamine willplay for 48 h for 2 = 0.25 mg/kg per h = 5 0.25 mg/kg per h 30 min 0.25 mg/kg every 0.5 mg/kg of Pain High Level µ µ g/kg per min g/kg per min g/kg per min S (+) ------

used in anesthesticdoses. However, some studiesnoted samesideeffects outstanding results [40–43].However, from evidence RCTs isconflicting, does not cross [39]. nesium injected the intravenously blood-brain barrier recent state. Asshown inavery is initsinactive andoutstanding study, mag NMDAMagnesium isthephysiological receptor blocker, when thereceptor Magnesium current literature. countries. Recommendation itsclinical usecannot bedonebasedonthe for drug hasbeenabandonedandremoved from themarket insomeEuropean itsanti-NMDA properties[38],butthis pain managementalsobecauseof clinical practice setting.dation for can be made to date in the perioperative thesedrugs, norecommen poorliterature addressingvery theutilizationof NMDA receptor antagonist) also antagonize NMDA receptors. Based on the andtor methadone antagonist ( effects), usedtotreat flu symptoms, drug; nally weak NMDA antiparkinsonian recep Memantine (NMDA receptor drugorigi antagonist), amantadine(antiviral pain management Other all patients.used for high-riskpopulationorshouldbe beusedinaspecific, ketamine shouldonly tively. Future to address studies will have whether this issue and will evaluate periopera NMDA toeverybody blockade ormodulationshouldbegiven tion, thatis, beforeheundergoes hisfirst“majorsurgery,” we suggestthat patients with chronic pain and chronic opioid exposure. ketamine’s beneficial pain on postoperative management effects in high-risk administration thanalow-risk patient.Onerecent [39]demonstrated study condition and chronic opioid tolerance) would benefit more from ketamine example,apatient withchronic pain painsensitization(for riskfor erative thatapatientwithhighpreoppersistence. itseemslikely Nevertheless, andpain paindevelopment between of high-andlow-risk patientsinterms differentiating donot riskfactors identifypreoperative these meta-analyses ketamine improving pain management [27]. Unfortunately, postoperative RCTs intheliterature of are of analyses reportingavastmajority infavor benefitfromketamine utilization.Currentmeta- perioperative maximally tion ketamine/opioid in the same solution cannot be recommended [35, 36]. ketamine separatedfrom thei.v. opioidPCA.Therefore, theassocia of infusion for managinghispainappearedtoa offered tothepatientinferior continuous above-mentioned subanesthetic ketamine doses. side effects,itis recommended notthe toexceed intra-andpostoperatively smallsubanesthetic doses were used [33, 34].Towhen only minimize these Ketamine when has psychomimetic mostly and hallucinogenic side effects Most animalstudies usingmagnesiumtoblock NMDA receptors reported Dextromethorphan hasbeenproposedpostoperative asanadjuvantfor painsensitiza of “naive” onceinterms inhislife Because apatientisonly challenge willbetofindtherightpatientpopulationthat The future the opioid used in the PCA ketamine with the solution of The combination of N -methyl- D -aspartate antagonists-aspartate andperioperative µ -receptor opioid agonist and ------

63 CHAPTER 7 N-Methyl-D-aspartate Antagonists

64 CHAPTER 7 N-Methyl-D-aspartate Antagonists beneficial effect in perioperative painmanagement,butmore studies inperioperative beneficialare effect 24 hours [50]. 500mg/hfor of withanaverage is continued intra-andpostoperatively anesthesiainduction,andit 30–50mg/kgatthetimeof as ani.v. bolusof 00)[50] ‌ ment onascaleof (4.2atrest, painintensity 9.2onmoveto alesserextent,postoperative could decrease the overall 24 hour morphine consumption by 24.4% and, recent reported that i.v. meta-analysis perioperatively magnesium given the blood-brain barrier,crossing as mentioned of above. Nevertheless, a i.v. magnesiummightbeexplained by thepoor of effect 49]. Thislack of itsuse[47– tosupport painmanagement[44–46],andothers failing erative i.v. magnesiumtoimprove results postop of with somereportingpositive even more potent than when given parenterally (ratio 3–2:). When given by (ratio 3–2:).Whengiven more parenterally even potent thanwhengiven orally.hours whengiven Someauthorssuggested thatoralketamine mightbe 5 minutes. Itsduration analgesic is approximatelyeffect 3 an onset time of with intramuscularly 30 minutes, is93% whengiven whereas itsbioavailability amine isa“controlled-substance” inmany countries, complicating patientaccess. complex regional painsyndrome [59].Finally,ketamine inthetreatment ket of andpoortolerance [58]‌ cacy However, extended ketamine usagemightbeproblematic duetolessenedeffi ketamine mightimprove painscores inpatientswithchronic noncancer pain. considered in this specific population. administrationmustbe chronic for painpatients. Otherroutesstrategy of i.v. ketamine Asaconsequence, arethe longterm. not low theright dosesof chronic pain.However, mostchronic painpatientsdonot i.v. have access in Ketamine istheNMDA receptor antagonist alsousedinthemanagementof practice. opioid consumption. Future toaddress studieswillhave thisquestioninclinical and pain,hyperalgesia, administrationonpostoperative itsintraoperative of more than 50 years, has yet no study been designed to look at the impact N [57].Inhumans, if even intraoperatively opioidtolerance N inanimals receiving andanimprovementeffect of tor antagonist [55,56].Animalstudiesreportedpromising anti-hyperalgesic properties. ItisanNMDA andanxiolytic recep analgesic, It hassedative, Nitrous oxide (N Nitrous Oxide concern. might be of side effects administration[3,2,55, 63]. Hemodynamic thisspecific needed for route of adjuvants ofchronic painmanagement N Given orally, ketamine has a bioavailability of 20% with an onset time of 20% with an onset time orally, of Given ketamine hasof a bioavailability 29studies(579patients)andsuggested that A literatureevaluated review inhumans, magnesium mighthave orepidurally intrathecally When given -Methyl- D 2 O) has been used in anesthesia for moreO) hasbeenusedinanesthesiafor than50years. -aspartate modulators-aspartate as . One study showed a possible beneficial effect of showed. Onestudy apossible beneficial effect . Inmoststudies, magnesiumisadministered 2 O has been used in anesthesia for O hasbeenusedinanesthesiafor 2 O only O only - - - - -

every 4 days to a maximum of 000 mg per day. 4 daysevery to a maximum of 0.5mg/kg withanincrease of this route,with0.5mg/kgorally dosingstarts References administered a prolonged for period. icity,of ketamine(or any otherNMDA antagonist) when safety, andefficacy chronic painconditions. However, clinical studiesneedtolookattox further postoperative pain. magnesium orN chronicerative pain.OtherNMDA receptor modulators,example for painmanagement,andperhapstodecrease postop erative long-term centralto prevent painsensitization,toimprove postoperative postop used NMDA receptor antagonist by anesthesiologistsandpainphysicians pain.Ketamine postoperative isthemostcommonly management of N nists mentioned in the previous section. 63]. Thesameconclusion appliestotheother NMDA modulators/antago recommendation ketamine tosupport useinchronic painpatients [58,62, and efficacy, evidencevide sufficient on safety which will help tobuild robust chronic painconditions mustbedoneonlargepopulationsinorder topro double-blindstudiesonketamine inpatientswithProspective advantages thispractice are anecdotal andnoclinical recommendations canbemade. of chronic pain,reports amine asanadjuvantmedicationinthetreatment of usage, or presenting intolerable opioid-related [61]. side effects patients, demonstratingeitherhighopioidtolerance, resistance toopioids oral ketamine [60]. Ketamine is then usedin selected the use of to support 4. 2. 1. 3. Conclusion -Methyl- Ketamine and other NMDA receptors could for be administered orally ket thatmany clinicians reportedontheuseof Hence, despitethefact In cancer pain,two concluded articles thatthere isnot enoughevidence

26:25–228. with complex regional painsyndrome: asystematic review. CNSDrugs202; Azari P,of ketamine inpatients Lindsay DR,Briones D, andsafety etal.Efficacy 5:482–489. surgery.in patients undergoing major orthopedic Acta Anaesthesiol Scand 2007; analgesic requirements: randomized, aprospective, double-blind,controlled trial spinalanesthesiato reduce post-operative supplementationof nesium sulfate Arcioni R,Palmisani Tiganoetal.Combinedintrathecalandepiduralmag S, review. 2006; 04:570–587. Anesthesiology Clark JD.Angst MS, systematic a qualitative Opioid-induced hyperalgesia: Anaesthesia 203; 68:79–90. pain:ameta-analysis. magnesium sulphateandpostoperative istration of Albrecht BrullR.Peri-operative E,KirkhamKR,LiuSS, admin intravenous D -aspartate receptor-aspartate role modulationhasanimportant inthe 2 O, require further evaluation in terms of their effects on theireffects O, of interms evaluation require further ------

65 CHAPTER 7 N-Methyl-D-aspartate Antagonists 66 CHAPTER 7 N-Methyl-D-aspartate Antagonists

24. 23. Elia N,Tramer MR.Ketamine system pain—aquantitative andpostoperative Preventingisenach who, chronic JC. pain aftersurgery: how, andwhen? Reg 22. E 21. 20. 19. 18. 17. 15. 14. 13. 12. 11. 10. 16. 9. 8. 6. 5. 7.

Bell RF. Ketamine chronic for non-cancer pain. Pain 2009; 4:20–24. spinalNMDA receptors, PickeringBegon S, pro G,Eschalier A,etal.Role of PickeringBegon S, G,Eschalier A,DubrayMagnesiumincreases C. morphine PickeringBegon S, G, Alloui A, Begon S, Anesthesiology 2000; 93:409–47. Anesthesiology remifentanil increasestive pain and postoperative morphine requirement. Guignard B, Bossard etal.Acute opioidtolerance: AE,CosteC, intraopera randomised trials. Pain 2005; 3:6–70. of atic review Anesth Pain Med 2006; 3:–3. Scand 2006; 50:–3. dextromethorphan inpost-operative pain.Acta Anaesthesiolperi-operative of Duedahl TH, Romsing systematic DahlJB. review J, Møiniche S, Aqualitative 2002; 97:59–596. Anesthesiology central neuronal sensitization. acontributionpain: clinical indicationsfor of postoperative HilstedKL,DahlJB.Dirks J,Moiniche S, Mechanisms of period: is there a ketamine?operative place for Pain 200; 92:373–380. De Kock P, M,Lavand’homme Waterloos H.‘Balanced analgesia’ intheperi in man. Br J Anaesth 98; 53:27–30. ketamine of andanalgesiceffect Pharmacokinetics Clements JA,NimmoWS. tolerance. fentanyl Can J Anaesth 999; 46:872–877. operative Chia YY, Liu K,Wang induces high dosefentanyl post JJ,etal.Intraoperative drugs?]AnnFr[How AnesthReanim 2009;28:e3–25. canwe useantihyperalgesic Chauvin M,Fletcher D, Richebé P, AnesthesiaandResuscitation. French of Society randomized trials. Br J Anaesth 200; 04:40–406. of patient-controlled review pain: a qualitative acute postoperative analgesia for Carstensen M, Moller AM. Adding ketamine intravenous to morphine for 998; 88:82–88. Anesthesiology volunteers: relationship plasmaconcentrations. tosteady-state in healthy Bowdle TA, AD,ketamine Radant Cowley etal.Psychedelic of DS, effects chronic pain management: a review. oral ketamine in Blonk MI, Koder BG, van den Bemt PM, Huygen FJ. Use of analgesic requirement.tive Br J Anaesth 2007; 98:59–523. ErkanA,OzcelikBilir A,GulecS, A. Epidural magnesiumreduces postopera anesthesia 7:592–597. clinical morphineconsumption. of administration onpostoperative Journal systemic ketamine timing of Bilgin, H., B. Ozcan, etal.2005;Theinfluence of Acta Anaesthesiol Scand 2005; 49:405–428. review). (Cochrane systematic review andqualitative pain:aquantitative operative Bell RF, DahlJB, Moore RA,Kalso E.Peri-operative ketamineacute post- for in rats.sium deficiency Br J Pharmacol 200; 34:227–236. Candnitricoxide inducedtein kinase by synthasemagne inthehyperalgesia 96:627–632. 2002; of pain.Anesthesiology indifferent experimentalmodels analgesic effect 887:436–439. neuropathic pain.Brain Res 2000; intwo experimentalmodelsof similar effect 2002; 70:053–063. andperipheralinflammationinmagnesium-deficient rats.Sci Life hyperalgesia schalier A, et al. Assessment of the relationship between Eschalier A, et al. Assessment of Eschalier A, Dubray Magnesium and MK-80 C. a have Eur J Pain 200; 4:466–472. ------25. 42. 41. 39. 38. 37. 36. 35. 34. 32. 31. 30. 28. 27. 26. 40. 33. 29.

poral summation (wind-up) of theR(III)nociceptive flexion reflex andpainin poral summation(wind-up)of ketamine onthetem Guirimand F, of DupontX,BrasseurL,etal.Theeffects model in healthy volunteers.model in healthy Br J Anaesth 200; 86:87–873. associatedand withhyperalgesia secondary the heat/capsaicin sensitization Mikkelsen Dirks J, Fabricius P, S, magnesium onpain intravenous of etal.Effect randomized, controlledspective, study. Br J Anaesth 202; 09:208–25. magnesium sulphate make any difference? Apro of infusion does intravenous hip arthroplasty: inpatientsundergoingnesium levels spinalanaesthesiafor Mercieri M,DeBlasiRA,Palmisani etal.Changesincerebrospinal S, fluidmag in rats. Reg Anesth Painadministered perioperatively Med 202; 37:448–454. is whenhigh-dosefentanyl late stress-induced hyperalgesia of the development Laboureyras inpreventing C, E,etal.Sciatic block nerve fails Rivat Meleine MC, contents. Analg 2004; 98:385–400, table of receptor analgesia.Anesth antagonists inpreventive N-methyl-d-aspartate of therole of systematic CJ,SinhaA,Katz review McCartney J.Aqualitative and after total knee arthroplasty. Anesth Analg 05:85–82. before testing and clinical evaluation sensory quantitative surgery: orthopedic V.,Martinez, D. in hyperalgesia primary Fletcher, of etal.2007;Theevolution contents. Anesth Analg 2007; 04:532–539, table of randomized trials. of analgesia:asystematic review vant topostoperative Tramèr C, Lysakowski DumontL,Czarnetzki C, MR.Magnesiumasanadju pain undergoing back surgery. 200; 3:639–646. Anesthesiology opiateconsumptionoperative inopiate-dependentpatientswithchronic back Loftus RW, Yeager MP, ketamine reduces Clark JA, etal.Intraoperative peri nal cords. 200; 96:236–245. Pharmacol Biochem Behav neuroinflammation inthespi receptor neurotransmission andsuppression of NMDAnaloxone attenuatesmorphinetolerance inratsviaattenuationof Lin SL, Tsai RY, ultra-low dose Shen CH, et al. Co-administration of surgery.undergoing major digestive 2005; 03:83–820. Anesthesiology combined withketamineanalgesiainpatients preventive provides effective P,Lavand’homme De Kock M, Waterloos epidural analgesia H. Intraoperative P.Lavand’homme Perioperative OpinAnaesthesiol2006; 9:556–56. pain. Curr analgesia. Can J Anaesth 20; 58:9–923. nous ketamine postoperative for Laskowski K,StirlingA,McKay WP, intrave of LimHJ.Asystematic review 200; 95:395–402. ketamine, and lidocaine. Anesthesiology S(+)- alfentanil, intravenous of the effects in human skin: and hyperalgesia evoked pain electrically Koppert W, modelof SK,SittlR,etal.Anew Dern prevention. Lancet 2006; 367:68–625. CJ.PersistentKehlet and Woolf postsurgicalpain:riskfactors H,JensenTS, and its 2005; prevention03:47–55. with small-dose ketamine. Anesthesiology V,Joly Richebe P, Guignard B,hyperalgesia etal.Remifentanil-induced postoperative 998; 4:460–463. ing gas)isanNMDA antagonist, neuroprotectant andneurotoxin. NatMed Jevtovic-Todorovic V, Todorovic et al. Nitrous SM, Mennerick S, oxide (laugh Analg 2003; 97:80–85. involunteers Anesth withcapsaicin-induced hyperalgesia hyperalgesia. drawal Hood DD, remifentanil Intravenous R, Eisenachproduces JC. with Curry 2005; 02:2–220. Anesthesiology DurieuxM E. Ketamine painmanagement. Himmelseher S, perioperative for humans. Anesth Analg 2000; 90:408–44. ------

67 CHAPTER 7 N-Methyl-D-aspartate Antagonists 68 CHAPTER 7 N-Methyl-D-aspartate Antagonists 48. 47. 46. 45. 44. 43. 59. 58. 57. 56. 55. 54. 53. 52. 51. 50. 49.

Quinlan J. The use of a subanesthetic infusion of intravenous ketamine intravenous to of a subanesthetic infusion Quinlan J. The use of Quibell R, Prommer pre-emptive ketamine on YucelOzyalcin NS, of A,CamlicaH,etal.Effect Owen RM,ClementsJA,etal.Analgesia from H,Reekie morphineandket chronic L,etal.KetamineNoppers I,NiestersM,Aarts thetreatment for of Mion G,Tourtier JP, Rousseau JM.Ketamine inPCA:whatistheeffective Analg 2007; 04:374–379, table of contents. Analg 2007; 04:374–379, table of randomized controlled surgery: trial.Anesth ment analgesiaafterambulatory magnesiumtosupple doseof asingle Tramer of CJ.Anevaluation MR,Glynn Eur J Anaesth 2006; 23:055–059. decreases tramadolrequirement postoperative afterradicalprostatectomy. Tauzin-Fin P, magnesiumsulphate etal.Intravenous Sesay S, M,Delort-Laval gesia. Anesth Analg 2005; 0:777–784. ketamine anal thatenhances epidural bupivacaine-and-morphine-induced of M,KinoshitaT,Suzuki KikutaniT, theplasmaconcentration etal.Determining 05:–9. potentiates epidural analgesia after thoracotomy. 2006; Anesthesiology M, Sugimoto HaragutiSuzuki S, K, et al. Low-dose intravenous ketamine Obstet Anesth 202; 2:30–36. analgesia after cesarean postoperative section. Int J for phine with bupivacaine epiduralmagnesiumand/ormor Sun J,Wu X,Xu X,etal.Acomparison of 997; 4:24–32. central surgery. sensitizationtopainfollowing ActaAnaesthesiol Scand sor of around asurgical incision demonstratesthatketamine suppres isapowerful punctuatehyperalgesia H,EidePK,etal.Mappingof Stubhaug A,Breivik gery. Br J Anaesth 2006; 96:444–449. decreases remifentanildosagerequired painmanagementaftercardiac for sur Steinlechner B, Dworschak M,Birkenberg B, etal.Magnesium moderately Neuroreport 2003; 4:–7. pain? ornormal abnormal Opioid-induced hyperalgesia: C. Simonnet G,Rivat outcomes. Pain 999; 82:–25. current techniques and of pain: a review acute postoperative management of of low-dose ketamineinthe Schmid RL,SandlerAN,Katz J.Useandefficacy 2005; 03:845–854. properties. Anesthesiology potent antihyperalgesic Richebe P, Creton et al. Nitrous C, C, oxide Rivat for revisited: evidence 2007; 52:76–723. Neuropharmacology attenuates NMDA receptor-mediated neurotransmission intheamygdala. A,KurzRanft J,Becker K,etal.Nitrous oxide (N2O)pre- andpostsynaptically 3:524–525. outcomeopioid tolerance at 6 months. and hyperalgesia: Pain Med 202; prescribed opioids in people with chronic medically pain, allow of withdrawal 20; 4:640–649. epidural and intramuscular routes. Br J Anaesth 2004; 93:356–36. painafterthoracotomy: changes andpostoperative comparisonsensory of analgesia. Anaesthesia 987; 42:05–056. tive morphineandketaminepostopera for of infusions amine. Acomparison of non-cancer pain. dose? Eur J Anaesthesiol 2008; 25:040–04. xpert Opin Pharmacother 200; :247–2429. Expert , Mihalyo M, et al. Ketamine*.EE, Mihalyo J Pain Symptom Manage ------60. 63. 62. 61.

surgery isassociated withchronicsurgery thoracic painyraftersternotomy. 202; van GulikL,AhlersSJ,deGarde duringcardiac EM,etal.Remifentanil Obstet Anesth 200; 9:40–404. double blindrandomisedstudy.nal-epidural anaesthesia:aprospective IntJ caesarean sectionusingcombined inelective spi andfentanyl bupivacaine addingmagnesiumsulphatetoepidural of AA,AmrYM.Theeffect Yousef pain. Acta Anaesthesiol Scand 997; 4:023–027. sion and postoperative Wilder-Smith CH, Knopfli R,Wilder-Smith OH. magnesium infu Perioperative 04:92–97. controlled, randomized trialafterabdominalsurgery. AnesthAnalg2007; analgesia:adouble-blinded,placebo- postoperative totramadolfor infusion asmall-doseketamine Webb etal.Theaddition of LeongS, BS, AR,Skinner Br J Anaesth 09:66–622. - -

69 CHAPTER 7 N-Methyl-D-aspartate Antagonists

of the complexity of peripheralpainsignalingmechanisms withinteractions thecomplexity of of in peripheralpain signalinginneurons, aswell asanincreased understanding molecular mechanisms involved past decadehasalso seenidentificationof pain conditions. in several The pain relief action for toa site of drugs locally applying provides theapproach information validationfor of of this body oralandtopicalanalgesics. Taken oncombinations of information together, also provide databetween comparative topicaland oral analgesics, aswell as conditions whencompared with placebo. More importantly, somestudies thatindicatestopicalagentsareevidence indeedefficacious inthesepain capsaicin neuropathic patch for pain.There isnow aconsiderableof body neuropathicplaster orpatch for pain,and,more recently, ahigh-concentration indications, topicallocalanestheticsas a inflammatory drugs (NSAIDs)for approved use,andtheseinclude topicalnonsteroidal for anti-inflammatory is desirable. (eg,sedation, effects confusion) central system nervous iscommon), andavoidance of drugs (ie,polypharmacy the elderly, where there areother medicalconditions likely beingtreated with systemic AEs. Topical benefitin particular the burden of analgesicsmay beof multiplesuppressing actions for pain without increasing recruitmentfor of tion with oral analgesics. In the latter instance, this would allow potentially therapiesorasadjuvantsincombinaanalgesics canbeusedeitherassingle andlocalAEsinresponse theskin, tothedrug(eg,redness, itching). Topicalof absorption by diseasestates andtissuepenetration),alterationof dermal for propertiesthatallow action(thedrugneedsphysicochemical access tositeof (eg,first-passbioavailability metabolism).Limitationstothisapproach include factors thatlimitoral druginteractions,avoidance fewer and effects (AEs), of topicalanalgesicsincluding low systemic systemic adverse drug levels, fewer of are not regarded astopicalanalgesics. There totheuse are advantages several as apatch systemic have fentanyl), actionsthatinfluence and painsignaling(eg, matrix.Someanalgesicsapplied ters where thedrugisembeddedinaphysical ascreams,such formulations lotions, gels, andsprays, aswell aspatches orplas adjacent to, endings. nerve They encompass andinteractingwith,such sensory endings and/or influence nerve cellular targets pain by localactionsonsensory Topical drugs that are and applied to the skin analgesics represent a class of Jana Sawynok Topical Adjuvant Analgesics Chapter 8 Introduction Over the past decades, several topical analgesic formulations have been have Over thepastdecades, topicalanalgesicformulations several - -

7171

72 Chapter 8 Topical Adjuvant Analgesics more extensive body of literature within cited reports. can be found of body more extensive sustain an interest in this approach topain management. This chapter willconsider somekey recent thatvalidateand observations therapeuticchoices painmanagement. for rangeof clinicians withagreater agents, andthesewillprovide willbedeveloped, as well ascombinations of molecular targets, new novelthat inthefuture, topicalanalgesicsconsisting of novel developing likely topicalanalgesics. Itisvery cal interest intheideaof between neurons andadjacent structures, andthere isconsiderable preclini sis of two trials indicates significantly moreAEswiththe topical, localskin two trialsindicatessignificantly sis of analy acteristics, safety andthey are A pooled amenable topooledanalysis. thesetrialsshare common char to demonstrateinthiscondition. of Several ment the analgesia provided can be difficult by theoraldrugor that additivity actioncannot aug atopicalagentwiththesamemechanism of addition of alone[4].Thisresult tooralortopicaldiclofenac suggestseitherthat cacy that the combination and found oral group diclofenac had comparable effi Italsoincluded acombinationcal andoralformulations. topicaldiclofenac/ between nodifference and observed thetopi inefficacy with oraldiclofenac knee OA over 2weeks [4].Thelattertrialalsocompared topicalD-DMSO withtopical D-DMSO compared function with vehicle with pain and physical hand [2]‌ withtopicalDSG,comparedimproved withvehicle, function with physical of topicalNSAIDsin OA. the efficacy Two trials reportreduced painand drug delivery. tissue drug concentrations may be higher than those attained after systemic N afferent neurons.sitize sensory Additional novel mechanisms (eg, block of that actonG-protein-coupled receptors endingstosen nerve onsensory tor, prostaglandins proinflammatory which leadstodecreased production of osteoarthritis (OA) []. cyclo-oxygenaseDiclofenac is a nonselective inhibi sions), whereas the other two are formulations approved treatment for of acute epolaminepatchpain(strains, isindicatedfor diclofenac sprains, contu sodium saltin45.5%DMSOsolution[D-DMSO],approved in2009) []‌ approved sulfoxide (DMSO)(.5% in2007),andasasolution with dimethyl epolamine salt,approved sodium%gel[DSG], in2007),as agel(diclofenac the US Food and Drug Administration (FDA) are as a patch diclofenac (.3% beenapprovedlations have useintheUnitedStates. for Drugsapproved by has beenelaborated,andbasedonthesefindings, threeformu topicalNSAID 6–2 weeks),more homogenous painconditions, (for longer intervals and for agentin onasingle information tions. Inthepastdecade,acoherent of body duration, and mixed shorter disease condi NSAID agents, trials of number of aheterogenous Earlier trialsontopicalNSAIDswere confounded by use of drugs and pain Topical nonsteroidal anti-inflammatory -methyl- Table 8. summarizes recent randomized controlled trials examining andkneeOA [3]over 8–2weeks. Another trialreportedimproved D -aspartate receptors)-aspartate may whenlocal alsobeinvolved, especially R eference toa much

. The ------to 39.5% application-site AEs and 7.5% systemic AEs; conclusions of this to 39.5%application-site AEsand7.5%systemic AEs;conclusions of topicalNSAIDdrugsinolder adultswithOA reported up enous datasetof alargerandmore heterog of groupsprofile [6].Meta-analysis inthetwo placebo inolderpatients)[6].P with placebo inyounger patientsvs45%–50%compared with 35%–39%with 39%–46%compared with28%–35% (improvements inboth groups cacy of three 2-week trialsreportedsimilareffi of (<65 years) inapooledanalysis versus in DSG older effects (≥65 years) younger patients of A comparison AEs (25.4%vs39.0%)butcomparable cardiovascular AEs(.5%vs3.5%)[5]. compared gastrointestinal (24.%vs.9%)andfewer withtheoral,diclofenac of Topical NSAIDsfor Osteoarthritis Table 8. Veh, vehicle; WOMAC, Western Osteoarthritis Index. OntarioandMcMaster Universities oDiclo, P oraldiclofenac; DMSO, sodiumgel;GI,gastrointestinal; DSG,diclofenac OA, dimethylsulfoxide; osteoarthritis; HandIndex; AEs, effects; AUSCAN,Australian/CanadianOsteoarthritis adverse Simon et al [4]‌ et alBarthel [3]‌ Altman et al [2]‌ Diclofenac SodiumGel % Trial Diclofenac .5%/DMSO45.5%

Summary ofRecent RandomizedSummary Controlled Trials 2 weeks (N = 775) oDiclo; tDiclo/oDiclo Placebo; DMSO; 4 ×daily; tDiclo R 2 weeks (N = 492) vehicle 4 ×daily; DSG R 8 weeks (N = 385) vehicle 4 ×daily; DSG R Characteristics Study CT knee OA CT knee OA CT hand OA , placebo; R CT, randomized controlled trial;tDiclo, topicaldiclofenac; ooled safety analysis alsoindicatedasimilar analysis ooled safety +Global function +WOMAC +WOMAC pain +Global function + WOMAC +WOMAC pain −Global +AUSCAN +OA pain Outcomes Efficacy vs .2% DMSO 9.6% 6.5% tDiclo vs GI AEs tDiclo/oDiclo 30.9% 7.3% oDiclo vs vs 6.8% DMSO vs 7.6% 26.6% tDiclo vs Local AEs Veh 5.9% DSG vs 5.0% GI AEs Veh 5.% DSG vs 2.5% Local AEs Veh 7.6% DSG vs 3.7% GI AEs Veh 2.5% DSG vs .% Local AEs Outcomes Safety tDiclo/oDiclo 25.7% vs 23.8% oDiclo vs P P

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73 Chapter 8 Topical Adjuvant Analgesics

74 Chapter 8 Topical Adjuvant Analgesics evidence does not support use of topical NSAIDs as analgesics [8]‌ use of does notevidence support musculoskeletal pain,andperipheralneuropathic painconditions, thecurrent OA. for treatment strategy For acute andchronic low back pain,widespread andsafer It indicatesconsiderable promisetopicalNSAIDsasauseful for beenincorporatedrecent, intotreatment guidelines. andithasnot yet fully is information low-riskthe needfor strategies. The above of emergingbody NSAIDs in the elderly [7]. topical dataare of required safety todetermine suggestfurther meta-analysis pain is well localized [5]. therapy for cases[4].Thelidocainepatch isnow considered a first-line in 82.2%of more than50%in45.5%andmore than30% pain) withpainreductions of mixed(PHN,postsurgical,andposttraumatic neuropathic etiology pain of efficacy profileagainstneuropathicIn clinical practice, LMPhasafavorable capsaicin,amitriptyline, gabapentin,pregabalin) differed from placebo [3]. thiscondition for showedNetwork (LMP allinterventions meta-analysis tooral pregabalinriority withrespect AEs[3]. topainreduction andfewer (DPN)reportednoninfe diabeticperipheralneuropathy LMPfor of review more thancapsaicin, gabapentin,andpregabalin effect [2].A systematic and gabapentindifferedfrom placebo; from LMPhad another perspective, PHNstudies,with oralpregabalin for LMP [2].Inanetwork meta-analysis AEscompared andfewer life, improvementpain relief,greater of inquality theLMPwithrespect to of 5% LMPwithpregabalin indicatesnoninferiority low AEs[2].Inaddition,comparisonreduces of withgenerally allodynia, and [2]. Placebo-controlled studiesindicate5%LMPprovides painrelief cebo recently reviewed andwithother interventions, hasbeensystematically concentrationssteady-state within 4 days [9]. lowing patch application,withpeakplasmaconcentrations after4hoursand lidocainefol studiesindicatelow systemic[]. Pharmacokinetic of levels brainregionsseveral representingfunctions sensory, andhedonic affective, 5% LMPinhibitsspontaneouspain,andthisisreflected in in reduced activity In PHNpatients, both acute (6hours)andchronic (2weeks) applicationof insmallA ity activ volunteers, acute6hoursleadstoinhibitionof patch applicationfor andreducedity afferentneurons. ectopicdischarges insensory Inhuman thisresults inreducedact by inhibitingsodiumchannel activity; hyperactiv upto2hours[9]‌ for lidocaine,andupto3patches are applied containing 700mg(5%w/w)of inEurope. available Theplasterisa0 × 4 cmand isalsocurrently adhesive postherpeticneuralgia(PHN)since 999, treatmentthe UnitedStatesfor of in Lidocaine 5%,asamedicatedplasterorpatch (5%LMP),hasbeenavailable Topical lidocaineandneuropathic pain The efficacy of 5%LMPinrelievingpainPHN,both compared withpla The efficacy isachronicOsteoarthritis condition, andtreatment guidelinesemphasize N, especially in elderly patients, and is most useful when the patients, and is most useful in elderly PHN, especially δ - and C-fibers, although the extent of block isvariable[0]. - andC-fibers, althoughtheextentof . Lidocaineisalocalanestheticandunderstoodto . - - - - - ,

N who fail neuropathicPN D who fail for pain.Thus, in those withPHNandpainful in painover 2weeks virus-associated inPHNandhumanimmunodeficiency 3 studies(double-blind, multicentre trials)demonstrate asignificant reduction managedwith oralanalgesicsand/orcooling (ice). Phase pain canbefurther caine/2.5% lidocaine) to mitigate local pain reactions [20]. site Application topicallocalanesthetics(4%lidocaineor 2.5%prilo utes afterapplicationof from 60 min determined applied for these studies. The 8% patch is generally treatment; whetherthe0.04%patch alsoproduces someanalgesia cannot be of thestudy concentration issufficient to produce local reactionsandblinding comparedis usually witha0.04%patch asthecontrol condition, andthelow fibers [9]‌ nerve anddermal epidermal reversible retraction of neurotrophic and factors, membrane potential, altered of transport loss of nociceptors, which reflects capsaicin of isattributedto“defunctionalization” area. At thisconcentration, thepainful theactionof the size and shapeof patch is280 cm approved in 2009 in the European Union and the United States [9]. The those who do not respond to, or cannot tolerate, other treatments [8]. cream, eitheraloneorincombination withother in agents, may be useful 2.5)[8].Itwasconcluded thatcapsaicin valuesof (number-needed-to-harm andstinging)are (burning 6.6)andsideeffects common treat valuesof neuropathicismodest(number-needed-to- 0.075% for painindicatesefficacy of capsaicin efficacy pain conditions. Themostrecent of meta-evaluation (OA,treat inflammatory andneuropathic rheumatoidarthritis) (PHN,DPN) beenusedto 980sandhave since theearly beenavailable use)have daily Topical low concentration capsaicin creams andpatches (0.025%–0.%,for andresults inanalgesia. integration, sensory the channels, leadstolossof afferents; chronic exposure intosensory tocapsaicin desensitizesion entry loid  (T medical practice. Capsaicin interactswithtransientreceptor potential vanil usein from of Capsaicin hot isderived chili peppersandhasalonghistory of topical agents. profileside-effect benignsystemic therelatively pies beingaddedtooraltherapiesbecauseof amenabletotopicalthera nation therapies[7].Thisapproach isparticularly treating neuropathic pain,there isincreasing tocombi attentionbeinggiven agentsin of individual thelimitedefficacy over Given alongertimeinterval. manner withcombinations compared withmonotherapy directly alone,and analgesia. However, thisapproach ina prospective willneedtobeevaluated action,canleadtoenhanced two treatments adifferentmechanism have of atopicalregime toanoralregime, inwhich the eral notion thatadditionof during the8week combination phase[6].This treatmentthegen supports thetwo approaches provides relevantpainrelief clinically combination of to respondagentsover toeitherLMPorpregabalin 4weeks, asindividual Topical capsaicin andneuropathic pain There are some data on combinations of 5% LM There are some data on combinations of A highconcentration (8%)capsaicin patch (Quetenza)wasrecently RP V) receptors located on A 2 , contains 79 mg of capsaicin (8%w/w),andiscut tomatch , contains 79mgof δ - and C-fibers, and it leads to cat P with oral therapies . The8%patch ------

75 Chapter 8 Topical Adjuvant Analgesics

76 Chapter 8 Topical Adjuvant Analgesics of AEsdidnot increase upto52weeks (4cycles). with multipledosesfor of thecontrolhigher afterthe8%patch thanfor patch (0.04%).Theincidence pain); these resolvereactions within 7 days. (erythema, R report treatment-related AEs, which areapplicationsite mostcommonly participants are[23].Afterpatchparticipants) application,67%of available reduction), respectively [22]. two groups, and there was a 47% and 44% responder rate (more than 30% 3%and28%were over observed 2–2weeks inthese reductions inpainof [2].Inanopen-labeltrial effects comparing outcomes inPHNandDPN, applications inPHNindicatesthelongertimesproduced significanttreatment 30-, 60-, and90-minutepatch the control of condition [9].A comparison 30%–33%comparedneuropathy, with20%–25%in withpainreductions of altered inchronic pain,andexpress TRPreceptors [27],itmay bethattopical recent appreciation that keratinocytes neurons, interact with sensory are withthe and more signaling [26].Furthermore, complex actionsonsensory receptors (eg,TRPV3,V4,M8, of thetransient receptor potential family membersof edies) actonseveral (aswell asother compoundsand eucalyptol present intraditionalherbalrem addition, itisnow appreciated thatcompounds such ascamphor, menthol, sants, ketamine, clonidine, and several other acting centrally drugs) [25]. In trinitrate,antidepres drugsregarded agents (eg,glyceryl asinvestigational of clinicalalso adeveloping literature topicalapplication onanalgesiafollowing thisnature. There is there systematic studiesof prospective isaneedfor combinations between topical and oral medications, but the potential of There are somedata,usingboth direct andindirect approaches, thataddress neuropathicfor pain [7], and this can include oral and topical formulations. tolerated. There isincreasing tocombination therapies attentionbeinggiven reactionscan bedermal withthetopicalapproach, well theseare generally drugsandindicatealow systemic AEprofile. Althoughthere applications of of peripheral theefficacy thatsupports information lations provide of abody approved useby theFDA for inrecent years. Clinicaltrialswiththeseformu been thathave The above ontopicalformulations focused sectionshave different mechanisms by the two approaches. ment of thetopicalandsystemic agent,despitetherecruit with thecombination of seen effect temic druguse.However, anadditive there of wasnoevidence sys ropathic painmedications;inboth cases, painwasreduced regardless of studies, the8%patch wasadministered aloneortogetherwithsystemic neu datafromcontrolled four integrated PHNstudies[24].Inthese of analysis in combination with oral medications has been approached by indirectly prick, and deep tendon reflexes after patch application. vibrationorpin warmth, with respectsensationsof toallodynia, function impaired neurological testingindicatedthatthere of wasnoevidence Sensory Novel topical agents andfuture directions The question of whether the 8% capsaicin patch produces effects additive The question of P ooled tolerability data from 8 randomized-controlled trials (N = 327 datafromooled tolerability 8randomized-controlled trials(N = 327 A) and may have further direct A) andmay further have escue medication is ------

their effects on sensory function. The potential for function. Thepotential recruiting localperipheral onsensory their effects analgesics are abletoactonboth neurons inproducing andonkeratinocytes 6. 5. 4. 3. 2. . 0. References the management of pain. for and adjuvant strategy toreceive asanovel considerablemechanisms islikely attentioninthefuture 9. haroutiunian Drennan S, DA, LipmanAG. Topical8. NSAID therapy muscu for 7. 6. r 5. 3. 2. . 4.

Simon LS, Grierson LM, Naseer Z, et al. Efficacy and safety of topical diclofenac of topicaldiclofenac andsafety Efficacy Simon LS,GriersonLM,NaseerZ,et al. and diabetic polyneuropathy. Med Curr with 5%lidocaine medicated plaster and pregabalin inpost-herpetic neuralgia Baron R,Mayoralof V, combinationtherapy LeijonG, et al. andsafety Efficacy update. Mayo Clin andliterature overview neuropathic pain: an macological managementof RH, O’ConnerDworkin AB, AudetteJ,et al.R Manag 20; 6:259–263. clinical experience. P years of 5% lidocaine-medicated plaster: five ML,Legout Navez V, C, neuropathicDelorme painwith Treatment et al. of 200; 40:297–306. systematic review. Swiss MedWkly (DPN): a diabeticneuropathy painful RF,Wolff BalaMM,Westwood 5%Lidocainemedicatedplasterin M,et al. a systematic review. Acta Neurol Scand 20; 23:295–309. other relevant interventions and placebo post-herpetic for neuralgia ( RF,Wolff BalaMM,Westwood 5%Lidocaine-medicatedplastervs M,et al. 2007; 28:88–00. postherpetic neuralgiaanditsmodulation by lidocainepatch therapy.of P Geha PY, spontaneouspain for Brainactivity MN,Chialvo DR,et al. Baliki A tial blockade of Krumova EK,Zeller M,Westermann A,et al. Lidocainepatch (5%)induces par its use in postherpetic neuralgia. Drugs 2009; 69:249–265. Garnock-Jones KP loskeletal pain. ture review. J drugsinolderadultswithosteoarthritis: a systematic litera anti-inflammatory topicalnonsteroidal Makris UE,Kohlwer MJ,Fraenkel of effects L.Adverse 20; 7:393–399. care inlong-term patients. osteoarthritis TherClinRiskManag agement of CE,Gloth FM. forman Argoff drugs Topical nonsteroidal anti-inflammatory J analysis. pooled safety kneeosteoarthritis.P DMSO vehicle for andoraldiclofenac topicalplacebo, sulfoxidecontaining (DMSO)compared dimethyl withthoseof 39:203–22. Rheum2009; sodiumgelinkneeosteoarthritis.SeminArthritis diclofenac of D, HR,Haselwood R Barthel S3rd, Longley et al. trial. J randomized, double-blind,placebo-controlled handosteoarthritis: a primary Altman RD, Dreiser RL,FisherCL,et al. sodiumgelinpatientswith Diclofenac NSAIDs. Med Curr CE.R Argoff oth SH,FullerP Rheumatol 2009; 36:99–999. Rheumatol 200; 37:–8. ecent developments in the treatment of osteoarthritis with osteoarthritis ecent in the treatment developments of P ain Med 200; :535–549. . Diclofenac topicalsolutioncompared. Diclofenac withoraldiclofenac: a δ , Keating GM.Lidocaine5%medicatedplaster. of A review Proc 200; 85(Suppl):S3–S4. - and C-fibers to variable extent. R es Opin 20; 27:35–327. P ain R es 20; 4:59–67. R es Opin 2009; 25:677–687. ecommendations thephar for andomized controlled trial P ain 202; 53:273–280. ain 2009;43:238–245. ain R PH N): ain es - - - - -

77 Chapter 8 Topical Adjuvant Analgesics 78 Chapter 8 Topical Adjuvant Analgesics 2. 20. 9. 8. 7. 27. 26. 25. 24. 23. 22.

P Webster LR,MalanTP Webster LR,NunezM,Trak MD, NGX-400, Tolerability acapsa et al. of Anand P Lloyd Topical S, R,Moore RA,et al. Derry chronic capsaicin for neuropathic Vorobeychik Y, Gordin V, MaoJ,ChenL.Combinationtherapy neuro for Smith 92:45–424. Clin J Zur E.Topical neuropathic painusingcompounded medications. treatment of 202; 28:0–07. medications, reduces paininpatientswithpostherpeticneuralgia.ClinJP patch, administered aloneorincombination withsystemic neuropathic pain GA,BackonjaIrving M,R pathic pain. Drugs 200; 70:83–842. patch. PL.CapsaicinInnon-diabeticperipheralneuroMcCormack dermal eral neuropathic pain. Diabetes patientswithperiph NGX-400, capsaicinof 8%patch, inanopen-labelstudy Webster LR,P :972–982. postherpetic neuralgia. J P capsaicin patch, the treatment for of NGX-400, ahigh-concentration double-blind, controlled of dosefindingstudy doi:0.86/47-2253--25. 2.5% cream inpatientswithpost-herpetic neuralgia.BMCAnesthesiol20; patch, pretreatmenticin following 8%dermal withlidocaine2.5%/prilocaine Br J Anesth 20; 07:490–502. high-concentration thenew capsaicin 8%patch. actionof and mechanisms of pain in adults. Cochrane Database Syst current CNS Drugs evidence. 20; 25:023–034. pathic pain. A review of remkumar LS, Abooj M. T P S. HS. ain 203; 30:73–9. , Bley K.Topical painmanagement: therapeutic capsaicin potential for P ain—Skin deep at times? ain—Skin eppin JF, FT,of Murphy Efficacy, andtolerability et al. safety , Tuchman MM, et al. Amulti-centre,, Tuchman randomized, MM,et al. , et al. NGX-400, acapsaicin 8%dermal auckj R,et al. RP R channels and analgesia.Sciences Life 203; es Clin P ain R Pract 20; 93:87–97. ev 2009 Oct 7;(4):CD007393. ev hysician 2009; 2:99–92. Physician ain 200; ain - - - -

PainDetect. Neuropathic Pain Questionnaire, NP: The ID Pain, and the symptoms of tools are self-administered itemsrelated questionnaires to including only examination(ie,signs).Theother threerelated screening tothesensory (ie,symptoms)including both anditems itemsrelated totheinterview tions »(DN4)questionnaires—are clinician-administered questionnaires Symptoms and Signs(LANSS)andthe«DouleurNeuropathique en4ques Neuropathic screening thefive tools—the LeedsAssessmentof Two of painqualities(ie,descriptors). reliance onverbal reportsof principally NP(refs in[6]‌ identification of the screening Several for over beendeveloped toolshave thelast0 years clinical consistency [5]. NPhasstrong despite obvious differences inetiology, of the clinical entity pathic characteristics are shared by mostNPetiologies, which indicatesthat voked by brush,pressure, cold, orheat[3].More importantly, these neuro definedwith stimulusandmayevoking reference bepro tothe is generally “stabbing,” or“electricshock-like” orallodynia) [4].Evoked NP(hyperalgesia NP, oftenreferredtoaspain paroxysms, isoftendescribed as“shooting,” pain qualities, cold, such asburning, sharp, andsqueezing[3]‌ temporal variationsinpainintensity, withNP often reportvarying individuals (eg, pain paroxysmsor intermittent in trigeminal neuralgia). In addition to Spontaneous NPmay becontinuous painindiabeticneuropathy) (eg,foot (orstimulus-dependent)components,and “evoked” which oftencoexist. are also common conditions in the general population [2]. (SCI) pain.Traumatic radiculopathies orpostsurgicalneuropathies andpainful neuralgia, trigeminalandcentral poststroke orspinalcord injury NPinclude diabeticpolyneuropathies,postherpetic [2]. Classicexamplesof the generalpopulation in some European countries as much as7% of affect system NP[]‌ thesomatosensory affecting alesionordisease Neuropathic pain(NP)may ariseasaconsequence of Nadine Attal Neuropathic Pain Chapter 9. Diagnosis ofneuropathic pain Introduction Patients exhibit“spontaneous” (orstimulus-independent) withNPgenerally ). Onefeaturecommon toallthesetoolsisa . Neuropathic painisestimatedto . Intermittent . Intermittent - - -

7979

80 Chapter 9. Neuropathic Pain nostic evaluation and pain management but cannot nostic replaceevaluation clinical judgment. clinician-diagnosed NP, diag further indicating that they mayfor guidance offer however, patientswith toidentifyapproximately screening 0%–20%of toolsfail NPindifferent countries. More importantly, studies of needed epidemiology badly theconduct of abettertherapeuticmanagement,andfacilitate cial for NP,and cultures shouldcontribute toincrease therecognition of which iscru these tools in different languages The use of therapeutic intervention. toms for nonspecialists, not butthesetoolshave beenvalidated tomeasure NPsymp these tools is to identify potential patients with NP,strength of by particularly in languagesother thanthoseinwhich Themajor they developed. were initially feasible andensures tion intodifferentlanguagesistheir andvalidity reliability these tools are based on descriptors, their linguistic adaptation and revalida initiated at30mg/day nausea andthentitratedto60mg/day toavoid after 20 mg.and 20mg/day, Treatment shouldbe of withno clear superiority duloxetine rangebetween 60 Adequatedosagesof (seeChapter 9.2). thy peripheralNPsuch aschemotherapy-induced neuropa of other types for However, recent indicatedthatduloxetine studieshave hassignificantefficacy duloxetine indiabeticPPN[3]. isestablishedmainly andvenlafaxine of theserotonin-norepinephrine reuptake inhibitors (SNRIs) The efficacy Serotonin-norepinephrine reuptake inhibitors analgesics is provided in Chapter 3. onvariousantidepressants Moreusedasadjuvant information equivalent). or amitriptyline from onepatient toanother (eg,25–50mgof dosages vary is75mg/day, amitriptyline dosagefor as tolerated.Theaverage buteffective titrated doseatbedtime)andthenslowly at low dosages(0–25mginasingle nels hasalsobeenreported[7, 9]. Tricyclic antidepressants shouldbeinitiated controls, inhibitory onsodium chan althoughaperipheraleffect modulatory mediated byactionondescending is pressant andthisefficacy probably effect, of theirantide isindependent betic PPNandPHN.Theiranalgesicefficacy of tricyclic antidepressants india (TCAs) isestablishedmainly The efficacy antidepressantsTricyclic venous injections will not be reviewed. drugsusedasintra onthedrugsusedatrepeatedfocus dosagesortopically; monotherapy and were placebo controlled. Here, we of willonly effects studiedthe (PPN).Thesetrialsmainly polyneuropathy and diabeticpainful inpostherpeticneuralgia(PHN) beenperformed NPhave Most studiesof Peripheral neuropathic pain effects. reported adverse most commonly action,dosingrecommendations and pathic pain,alongwithmechanisms of adjuvantanalgesicsrecommended useinneuro for provides adetailedlistof attempts amoreseveral todevelop rational therapeuticapproach. Table 9.. patients withchronic NPischallenging [7–],despite The managementof Management ofneuropathic pain Screening gainedacceptance toolshave inthemedicalcommunity. Although ------Table 9.. Summary of Evidence-Based Recommendations for Treatment of Peripheral Neuropathic Pain* Drug Main Common Precautions Other Benefits Efficacy: Level Starting Dose/ Titration Mechanisms Major Side A/B Ratinga Maximum of Action Effects Dose Tricyclic antidepressants Nortriptyline Inhibition of Somnolence, Cardiac Improvement of A. Diabetic neuro 0–25 mg at Increase by Desipramine reuptake of anticholinergic disease (ECG), depression, although pathy, PHN bedtime/ 0 mg to 25 monoamines, effects, weight glaucoma, at generally higher 50 mg daily mg every 3 Amitriptyline B. Spinal cord block of gain prostatic dosages than pain injury/central to 7 days up sodium adenoma, (75 mg/h) and sleep poststroke pain, to efficacy channels, seizure, use of (amitriptyline) traumatic nerve and side anticholinergic tramadol lesions, cancer effects neuropathic pain Serotonin–norepinephrine reuptake inhibitors Duloxetine Inhibition of Nausea Hepatic disorder, Improvement of A. Diabetic 30 mg once May start at serotonin and use of tramadol, depression and neuropathy daily/60 mg 30 mg once norepinephrine hypertension generalized anxiety, twice daily daily and then reuptake improvement of sleep increase by 30 mg after  week as tolerated up to 20 mg daily

Venlafaxine Inhibition of Nausea, Cardiac disease, Improvement of A. Diabetic 37.5 mg once or Increase by serotonin and hypertension hypertension, depression and neuropathy twice daily/225 37.5–75 mg norepinephrine at high dosages use of tramadol generalized anxiety, mg daily each week as reuptake improvement of sleep tolerated

(contiuned)

81 Chapter 9. Neuropathic Pain 82 Chapter 9. Neuropathic Pain

Table 9.. Contiuned Drug Main Common Precautions Other Benefits Efficacy: Level Starting Dose/ Titration Mechanisms Major Side A/B Ratinga Maximum of Action Effects Dose Calcium channel α2δ ligands Gabapentin Acts on α2δ Sedation, Reduce No clinically A. Diabetic 00–300 mg Increase by subunit of dizziness, dosages in renal significant drug neuropathy, once to 3 times 00–300 mg voltage-gated peripheral insufficiency interactions, PHN, cancer daily/200 mg 3 times daily calcium edema, improvement of neuropathic pain 3 times daily every channels, which weight gain generalized anxiety B. Spinal cord 3 to 7 days as decreases and sleep injury pain tolerated central sensitization

Pregabalin Acts on α2δ Sedation, Reduce No clinically A. Diabetic 25–75 mg once Increase by subunit of dizziness, dosages in renal significant drug neuropathy, daily/300 mg 75 mg daily voltage-gated peripheral insufficiency interactions, PHN, spinal twice daily after 3–7 days calcium edema, improvement of cord injury and then by channels, which weight gain generalized anxiety 50 mg every decreases and sleep 3–7 days as central tolerated sensitization Topical lidocaine Lidocaine 5% plasters Block of Local None No systemic side A. PHN –3 patches/3 None sodium erythema, itch, effects, potential patches channels rash effect on allodynia Capsaicine patches 8% TRPV agonist Pain None No systemic side A. hIV neuropathy –4 patches None Erythema effects—potential and PHN to cover effects on burning the painful Elevated blood pain, itch, and area—repeat pressure due to allodynia every 3 months initial increase in pain Opioid agonists Tramadol Mu receptor Nausea and History of Rapid onset of A. Diabetic 50 mg once Increase agonist and vomiting, substance analgesic effect, effect neuropathy, or twice by 50–00 inhibition of constipation, abuse, suicide on inflammatory pain phantom pain daily/400 mg mg every monoamine dizziness, risk, use of B. Spinal cord daily as 3–7 days reuptake somnolence antidepressants injury long-acting drug in elderly patients Morphine Oxycodone Mu receptor Nausea and History of Rapid onset of A. Diabetic 0–5 mg After –2 Methadone agonists vomiting, substance abuse, analgesic effect, effect neuropathy, morphine every weeks Levorphanol (oxycodone constipation, suicide risk, risk on inflammatory pain PHN, phantom 4 h or as needed convert to may also cause dizziness, of misuse on pain (equianalgesic long-acting κ-receptor somnolence long-term use doses for other opioids, use antagonism) opioids)/ short-acting up to 300 mg drugs as morphine has needed and been used in as tolerated neuropathic pain Abbreviations: ECG, electrocardiogram; HIV, human immunodeficiency virus; PHN, postherpetic neuralgia; TRPV, transient receptor potential vanilloid receptor-. aRecommendation grading: Level A = good scientific evidence from several Class I trials; Level B = some scientific evidence from Class II trials (lower-class trials). *Data modified from references [7, 9, 2].

83 Chapter 9. Neuropathic Pain

84 Chapter 9. Neuropathic Pain at bedtime are recommended to reducefor older side effects, especially 75mg/day beeninitiatedat50mg/day,balin hasusually butinitialdosesof [6]‌ ER orgabapentinenacarbil)are alsoeffective gabapentin(gabapentin 50mg/day). of Extended-release formulations of gabapentinand50–600mg/daypregabalinfor (withinconsistent effects for NPare dosages800–3600mg/day Effective calcium channels [7, 8]. of sensitization andnociceptive transmission through actiononthe related toadecrease ismainly in Theanalgesiceffect central PHN [4, 5]. of gabapentinand pregabalin isestablishedindiabeticPPN and The efficacy α to alleviate NP. (50–225mg/day) are venlafaxine effective  week. Ingeneral,highdosesof older patients and those with renal or cirrhosis. impairment dosages rangefrom 200to400mg/day. Dosereduction is recommended in patients (50 and mg then once titratedelderly as tolerated. daily), Effective (see Chapter 0). Tramadol in shouldbe initiatedatlow dosages, particularly serotonin selective reuptakelarly inhibitors, butalsoother antidepressants) madol isusedincombination with other serotonergic medications(particu the seizure threshold, such asTCAs. tra Serotonin syndrome may occur if seizures inpatientswithepilepsy drugsthatreduce orthosereceiving risk of substance abuse. There is an increased of caution in patients with a history abuseislower thanwithother opioids, tramadolshouldbeusedwith risk of in the elderly. particularly impairment, cognitive Although the or aggravate mouth,nausea, constipation,dizziness, andsomnolence dry andcancause indiabeticPPN[7,8,0–2].Tramadolestablished predominantly may induce of tramadol, including the combination with acetaminophen, is The efficacy Tramadol Titration to be safe. is not been found necessary.have mended tocover area,upto24hours butlongerapplicationsfor thepainful recom 2 hours within a 24-hour period is usually per day a maximum of for four plasters been[8].Upto (eg,mildskin reactions)have reported effects localadverse littlesystemic andhave absorption; only safe ters are generally outcomeplacebo measure ontheprimary [8].Lidocaine5%medicatedplas toshowenriched adifference enrollment between designfailed lidocaineand modestcomparedis very withplacebo [7],andonerecent trial usingan properties. plasters may reduce ectopicdischarges through itssodiumchannel-blocking inPHN.Lidocaine of lidocaine5%plastersisestablishedmainly The efficacy 5%medicatedLidocaine plasters anticonvulsants used as adjuvant analgesics is provided in Chapter 4. gabalin shouldbeadministered twice perday. onvarious More information three timesperday (except gabapentinextendedrelease), for whereas pre administeredeffects. andsideGabapentinisgenerally uptoefficacy formed titrationshouldbeper (upward Individual increase 3 days). by 75mgevery pregabalin titrationschedule for titration,withashorter need individual patients orthosewithsignificant comorbidities orpolypharmacy. Both drugs 2 δ ligand agonists H owever, a meta-analysis, the therapeutic gain on the basis of . Inclinical studies, prega α 2 δ subunit ------

Opioids ropathy (30 minutes). The effects of thistreatment onmultiple symptoms of (30minutes). Theeffects ropathy to produce wasdistinctinPH N (60minutes)andHIVneu analgesicefficacy 48-week extension [26,28, 29]. However, thepatches theoptimal durationof inan open-label with confirmed safety [5, 26, 27] virus (HIV) neuropathy been demonstrated from weeks 2 to 2 in PHN orhumanimmunodeficiency 30minutescompared(8%) for with alow concentration patch (0.04%) has many days starts. before the analgesic effect they require many applicationsperdaysensationfor andcauseaburning for PHN,but effective creams tobemoderately beenfound (0.075%)have Standard capsaicin-containingcess alsoreferredtoas“defunctionalization.” axons application,TRPV-containing sensory are desensitized, apro days of painsignalstothespinalcord [25].Afterseveral tial, andthetransmissionof anactionpoten causesdepolarization,theinitiationof in turn This activity TRPVligand-gatedchannels onnociceptive fibers.(TRPV) andactivates transientreceptor potential vanilloidreceptor- Capsaicin isanagonist of patches Capsaicin ing NP, in all current recommendations [7, 0, 24]. opioids are considered tobesecond-line treatmentnoncancer NP, for includ and there isconcern thatitmightoccur inhumans[23].For these reasons, opioids, hasbeendemonstratedinanimalmodels, withtheuseof sensitivity defined as [22].an increaseOpioid-induced hyperalgesia, functions in pain affect, reward,andmotivational brain regions implicatedintheregulation of changesopioid dependence in isassociated withstructural andfunctional tematic studies [2], may represent a concernuse. Prescription in long-term misuseoraddictioninchronic pain,althoughlow (2.6%)inrecent sys of [0].Theriskbe associated with immunologic changes andhypogonadism reported inchronic morphineadministrationmay noncancer pain.Long-term drug abuse. of caution in patients with a history with great constipation [20].Opioidsmustbeused treatment, withtheexception of decreasesea, dizziness, andvomiting, afterlong-term althoughthesegenerally NP trial. studiedinperipheral NPwithencouraginginonediabeticrecently effects µ ties, andsleepdisorders. a Another opioid,tapentadol(500mg daily), psychological life, comorbidi ated withsignificantimprovement of in quality obtainedwithNPare associ theeffects not necessarily pain. Furthermore, fornociceptive toreach forNPthan ages necessary efficacy maybehigher oxycodone,20 mgfor Thedos themoststudieddruginNP[7–9,, 2]. indiabeticPPNandPHNatdosagesrangingfrom efficacy 0to phine) have (R in chronicefficacy NP[9].However, randomized several controlled trials over the past cally decade. There has been a longstanding debate about their chronic painhasincreased dramati thetreatment opioidsfor of The useof -opioid agonist withnorepinephrine reuptake inhibition,hasbeenmore CTs) now have establishedthat opioids(oxycodone, methadone,mor The efficacy of a single application of high-concentration capsaicin patch application of asingle The efficacy The problems opioiduseare associated withlong-term increasingly opioidsare constipation, sedation,nau The mostcommonof sideeffects ------

85 Chapter 9. Neuropathic Pain

86 Chapter 9. Neuropathic Pain ing. In human volunteers, only a transient ( week) impairment of epidermal epidermal ing. of atransient(week) Inhumanvolunteers, impairment only ing (QST)measures, including thresholdsvibration,heatpain,andcool for capsaicin test patch produced sensory nochange insequentialquantitative [29],thehigh-concentration HIVneuropathy painful the controlled trialof patientsin after repeateduptooneyear applicationsfor [29].Inasubsetof inPHNandIVneuropathy evaluation standard sensory of impairment duetosevere paininsomepatients).Thedrugdoesnot produce(probably highbloodpressure duringapplication thepotential riskof tored becauseof often necessitated moni opioids, andbloodpressure shouldbecarefully sometimes edema,anditching). Initialpain erythema, application site(pain, pain, wereitch or burning not addressed. tothisdrug,including mechanical allodynia, sensitive that may beparticularly suggested the benefit of TCAs,for SCI pain. gabapentin,andtramadol suggested thebenefit of poststroke butnot for pain[33],whereas lower-classpain [7, 32] trials of forSCIpregabalin confirmed thebenefit SCI pain.These trials have incentral NP, performed beenrecently trialshave Several particularly Other neuropathic pain indications antiepileptics [7, 0]. includes strong opioidsortramadol,andthird-line treatments include other ability, are recommended asfirst-line treatmentforPHN.Second-line therapy recommends duloxetine [3]. Lidocaine plasters, with their excellent toler ClinicalExcellencement [24],andtheUnitedKingdom NationalInstitutefor recommends Neurology pregabalin asfirst-line treat American Academy of diabetic neuropathy, recommendations first-line for treatment diverge: the (Figure 9..).However,indicated asfirst-line treatmentforNP[7, 0] in [7, ], despite positive inlarge-scaleR effects demonstratedmild ordiscrepantcarbamazepine, lacosamide) generally have other anticonvulsants(eg,topiramate,oxcarbazepine,neuralgia. Trials of studied inNP, carbamazepine intrigeminal withthenotable exception of Antiepileptics other thangabapentinandprégabaline beeninfrequently have drugOther treatments such treatment.the best candidates for tomechanical pain,itch,orheatstimulimightbe andallodynia with burning effects, compliance with the treatment, or drug-drug interactions. Patients whenthere are concerns particularly withsystemic side neuropathy focal apeutic recommendations beproposedpatientswith butshouldprobably for the face. 4patches, andshouldnot beappliedto area, uptoamaximumof painful to60minutes(other areas) to themay 30minutes(feet) beappliedfor after repeated applications. InPHN,thehigh-concentration capsaicin patch whether thesedataare lesions applicabletopatientswithperipheralnerve but there [28].However, wasa93%recovery after6 months itisnot clear wasnoted application, punch fiberdensity nerve biopsy afterasingle by skin In summary, TCAs, pregabalin/gabapentin, and duloxetine are generally Capsaicin patches not ther have inevidence-based beenconsidered sofar duetocapsaicin-related were effects Adverse primarily reactions atthe CTs. Initialdataaboutvalproate are still controversial R CTs in diabetic NP and PHN [7, , 24]. ------Figure 9.. Therapeutic algorithm proposed for peripheral neuropathic pain (NP) in clinical practice. This algorithm is based on current evidence-based recommendations and systematic reviews in peripheral NP [7, 9, , 30]. Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants are generally recommended as first choice, but duloxetine has higher evidence for peripheral NP. The choice between first-line drugs depends on the clinical profile (for example, tricyclic antidepressants should be avoided in the elderly), contraindications, and comorbid conditions (for example, patients with anxiety, sleep disorders, or depression may benefit more from pregabalin/gabapentin or SNRI antidepressants). Capsaicin high-concentration patches have not been considered yet in this therapeutic algorithm.

88 Chapter 9. Neuropathic Pain effects of amitriptyline and low-dose venlafaxine onpostmastectomy pain andlow-dose amitriptyline venlafaxine of effects outcomecebo) [36].Lower-class ontheprimary moderate studiesfound (difference that 0.62 pregabalin effective found versus pla was moderately [35].Another trial life butimprovedintensity painrelief,sleep, of andquality thatgabapentin(upto2400mg/day)onpain One trialfound hadnoeffect as peripheral NP. respondThus, tothesamedrugtreatments central NPseemsto generally comes, duloxetine tobrushandcold, including allodynia favored [34]. central painduetostroke out secondary orSCI,butseveral come of duloxetine over out placeboshowed ontheprimary of nosuperiority forlevorphanol centralpain[7]‌ of high-dose efficacy found trial choice SCIpain.Onecomparative for Pregabalin isnow thedrugof triptyline indiabeticNP[4].These resultstriptyline may berelated tosmall sample and PHN[39],pregabalin [40]andlamotrigine andamitriptyline andami indiabetic NP of gabapentinand nortriptyline als reportedsimilar efficacy [7]‌ life responders, of painrelief,andquality the proportionof respect to overall and tolerability, pain intensity on but it was less effective toimipramine50mg/day 225mg/day with was equivalent venlafaxine of different TCAs [7,0, ]. Inonestudy, similarefficacy These trialsfound studies aimedtocompare TCAs. drugs from thesameclass, particularly but moststudiesare trialswithsmallsamplesize. single-center Mostinitial inNP, beenperformed studieshave head-to-headcomparative Several Combination andhead-to-head studies most common NP conditions in the general population [2]. NP, thesepatientshave the of represents andradicular painprobably oneof back syndrome, becausealargesubset amongpatientswithfailed particularly NPcannot beexcluded. theseindications, studiesarefor New warranted of clinical orimprove phenotypes exhibiting particular somedimensions only patients inasubset of trials, thatthesedrugsmightbeeffective thepossibility inmost painquality specific assessmentof [38]. However, thelack of given worst painand relief for the combinationof slighteffects only found outcome the primary andin lumbosacral for was negative radiculopathy morphine,andtheircombination nortriptyline, placebo-controlled of study [7]‌ pregabalinfor lumbosacral radiculopathy no benefitof capsaicin patches (see below)useful. were to be moderately found whereas lamotrigine, smoked cannabis, andmore high-concentration recently topicallidocaine,gabapentin[7,9, ],with amitriptyline, andpregabalin [37], other NP conditions.for In todrugsthatare responsive useful tobepoorly beenfound generally have for cancer to be efficacious NP [7,has 0, ].amitriptyline been found forphantomlimbpain,and tobeefficacious beenfound and tramadolhave drome andcancer NPand discrepant results inphantomlimbpain.Opioids and discrepant results with topical capsaicin [7]‌ A recent usinganenrichment phasedemonstrated large-scalestudy and chronic virusneuropathy Human immunodeficiency radiculopathy results inGuillainBarrésyn positive found gabapentinhave Studies of beenreported. have posttraumaticneuropathy large-scaletrialsof Several HIV neuropathy, results were negative obtained . . A Class I trial . A Class I trial . A crossover . A crossover . Othertri ------

depending onpatients’ clinical profiles, which not detailedwere generally size anddonot exclude distincteffects thatthesedrugshave thepossibility effective inmultiplesclerosis-associated peripheralfor painand refractory effective Δ tors andtheirendogenousligands. Oromucosal cannabinoids(2.7mg cannabinoid recep tigated in chronic pain after the discovery of inves cannabinoidshasbeenextensively The therapeuticpotential of Cannabinoids development. fibers are under on afferent sensory BTX-A activity with selective tions of large-scaletrialswiththiscompoundfor inperipheralNP. Novel prepara thresholds warm [44].Thesedata indicateaneed was thepreservationof found that a possibleeffects. predictor One study for response to BTX-A pain during injectionand no systemicprofile; side patients only reported similar. was remarkably (3 months) effects Thedrughadanexcellent safety of (approximately efficacy  week)andduration two studies, theonsetof in post-herpetic [48].Itisinteresting tonote neuralgiawasnegative thatin zoster [46]) and patients with diabetic PPN [47], but one unpublished study area amongpatientswithmononeuropathies (traumaticorrelated toherpes BTX-A (from00 to200units)injectedintothepainful ous injectionsof R single-center peripheral NP.mechanisms may be involved in some cases of Several on bymuscle tone, acting possibly on neurogenic inflammation [45]. Such itsaction muscle hyperactivity, independent of may analgesiceffects have focal A (BTX-A), a potent neurotoxin the treatment used for of commonly investigation suggested have that botulinum toxin type Several lines of toxin type A Botulinum More recently, three drug classes been studied in have Newer drugtreatments for neuropathic pain effective. incompletely whenmonotherapy is therapy particularly withtheseagentsmay beuseful, no effects.significant difference in side These trials suggest that combination andsleep life outcomes, andsecondary of includingon primary quality of combination therapy andmonotherapy athighdosages similar efficacy duloxetine) showed [44]. The study pregabalin or20mg of (ie, 600 mgof thesamedrugsinmonotherapy at similardosagesorincreased dosagesof both drugs randomized toreceive eitherthecombination of subsequently orduloxetine pregabalin (300mgdaily) were (60mgdaily) ate dosagesof gabapentin alone[43].Inalarge-scalestudy, tomoder patientsunresponsive in diabeticNP, gabapentinincombination withoxycodone wassuperiorto compared withmonotherapy withoutanincrease insideeffects.Similarly, with lowerThe combinationdemonstratedbetterefficacy dosages drugarms patientswithdiabeticPPNandPHN[39,42, 43]. therapy inamixed of group ormorphinecomparedcombined withnortriptyline withgabapentinmono at baseline. -9-tetrahydrocannabinol/2.5 mg cannabidiol) have been found tobe beenfound -9-tetrahydrocannabinol/2.5 mgcannabidiol)have Several placebo-controlled trials confirmed the benefit of gabapentin placebo-controlledSeveral trialsconfirmedthebenefit CTs reported the long-term efficacy of a series of subcutane of aseries CTs efficacy reportedthelong-term R CTs involving NP. ------

89 Chapter 9. Neuropathic Pain

90 Chapter 9. Neuropathic Pain United States, but they are in Canada. available NPinthe thetreatment for of notcannabinoids areavailable currently tolerance treatment anddependence afterlong-term [49].Oromucosal patientswithpsychiatricfor disorders. There iscontroversy withregard to exacerbate psychiatric conditions, socannabinoidsare not recommended cognition orpsychoactivewere effects noted inthese trials, cannabismay of gastrointestinal Althoughnoimpairment effects,andoraldiscomfort. mouth,sedation,fatigue, include events dizziness, Adverse dry negative. unpublishedtrialsare [7,0, ], butseveral NP associated withallodynia increase treatment responses the positive [8, 53, 6]. couldand groups reduce heterogeneity within study ogy pathophysiologic profiles basedonspecific NP questionnairessory and QSTratherthanetiol a betteroutcome patientswithsen withtopicaltherapy. Classificationof therapeutic studies. evokedfor differentiating patientswithandwithout pain of the importance systemic sodiumchannel blockers orpregabalin [53].Thesestudiessuggest with mechanical (static were allodynia or dynamic) better responders to thatpatients For reportedinposthocanalyses example,somestudieshave theclinical examination, such asQST[6]‌ tionnaires andanextensionof withspecific assessmentques and signsinclinical trialsisbestperformed symptoms linked todistinctmechanisms [8,53, 54].ably Theassessmentof shocks, brush-evoked pain)andsymptom combinations thatare presum pain,electric symptoms (ie,burning syndromes, which of include avariety NP because they did not takemostly into account the heterogeneity of toidentifyresponder profiles inNPmay totherapy failed have performed thetrials. Inparticular, R of relatesissue probably tothemethodology tend tobeassociated withapoorresponse todrugs. Themostimportant coping inNP[52].Itispossiblethatmaladaptive andcatastrophizingity) painsever [5] andinthepredicted pain-related (independentof disability pain in P that catastrophizingfound plays a role in the persistence of taken into insufficiently account inR generally thatpsychologicalson may berelated comorbid tothefact conditions are inthese findingsisthelargeplacebo effects recent trials[50].Another rea gabapentin, SNRIs,peripheralNP[].Onecontributor andopioidsfor to pregabalin, pared withplacebo) ranges from 3to6inrecent clinical trialsof totreat patientsnecessary toobtainoneresponder com (the numberof modest.Thenumberneededtotreat50%painrelief for NP isgenerally may improve therapeuticresponse, theresponse tomosttreatments for that rationalpolypharmacy drugsandtheincreasedDespite newer useof neuropathic pain Improving therapeutic outcome in In addition, preservation of thermal sensation has been associated thermal with In addition, preservation of CTs. For example,ithasbeen CTs HN ------.

2. . 0. References the improved management of NP. cific painquestionnaires. drugtreatmentscontribute to New willundoubtedly examinationandspe symptoms andsignsusingsensory characterization of responder profiles basedonadetailed conditions, andtheidentificationof rarerNP andoftenneglected and combination therapy trials,of thestudy studies comparative NP include the implementation of in the management of also proposed asfirst-line NP agentsin certain conditions. Clinicaladvances line) asfirst-line therapy; SNRIs(duloxetine) andlidocaine5%plastersare pregabalin) suggestantiepilepticsandTCAs (notably amitripty ally (notably NPgener Consensus recommendations thepharmacologictreatment for of 9. 8. 7. haanpää M, Attal N,Backonja M,et al. NeuPsig NeuPSIG guidelines on neuro 6. 5. 4. 3. 2. . Conclusions

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JAMA 2005; 293:3043–3052. of meta-analysis and review nonmalignantorigin: systematic neuropathic painof treatment of of opioid agonists in the Eisenberg E,McNicol ED, DB.andsafety Carr Efficacy 25:663–676. two-stage R open-label, non-inferiority sus pregabalin inpost-herpetic neuralgiaanddiabeticpolyneuropathy: an Baron R,Mayoral V, 5%lidocainemedicatedplasterver LeijonG,et al. neuralgia. Cochrane Database Syst Khaliq W, PuriN.Topicalpostherpetic AlamS, thetreatment lidocainefor of 25:85–92. double-blind, randomized, placebo-controlled clinical trial. Clin J Pain 2009; a results of postherpeticneuralgia: thetreatmentgabapentin for of November, 204. wiley.com/doi/0.002/465858.CD005452.pub2/pdf pain. Cochrane DatabaseSyst R 3:448–454. doses. DiabetesCare 2008; randomized controlled trialsaccross arangeof diabeticperipheralneuropathy: findings from balin treatmentpainful seven for in 23,983 subjects. Med Curr etine safety ev 2009; 60:267–277. ev R , Durso-Decruz E, Emir B. Efficacy, safety and tolerability of prega R, Durso-Decruz E, Emir B. Efficacy, and tolerability safety es Ther 2005; 7:R046–05. R ev ev J, Edwards JE, et al. Gabapentin for acute and Gabapentinchronic for HJ, Edwards JE, et al. Rheumatol 200; 6:9–97. ev 2009.Availableev at R R ev 2007; 8:CD004846. ev ecent and advances setbacks. Brain R CT study. Med R Curr HIV neuropathy. 2008; Neurology R es Opin 2007; 23:75–84. http://onlinelibrary. . Accessed 27 es Opin2009; ehabilitation. es ------45. 44. Prolonged-release hannaM,O’Brien Wilson MC. C, oxycodone enhances the 43. 42. 4. 40. 39. 38. 37. 36. 35. 34. 33. 32. 3. 30. 29. R teers. J Pain 200; :579–587. volun function inhealthy andsensory fiberdensity nerve patch, onepidermal study. Ann Neurol 2008; 64:274–283. in chronicanalgesic effects neuropathic pain: a double blind placebo controlled peripheral neuropathic pain. Pain 203; 54:266–2625. inpatientswithdiabetic study tional, randomized, double-blind,parallel-group multina monotherapy ortheircombination? The“COMBO-DN study”—a Tesfaye Duloxetine Lledo A, et al. and pregabalin: high-dose Wilhelm S, S, Eur J Pain 2008; 2:804–83. patients. diabeticneuropathy existinggabapentintherapy inpainful of effects neuropathic J Med 2005; 352:324–334. pain. N Engl Gilron I,Bailey JM,Tu D, et al. Morphine,gabapentin,ortheircombination for neuropathy. Diabet Med 2007; 24:377–383. diabetic of lamotrigine inpainful andamitriptyline andsafety ing theefficacy Jose VM,BhansaliA,Hota D, R et al. 2009; 26:09–026. randomized doubleblindclinical trial.DiabetMed diabeticneuropathy: a ful Bansal D, BhansaliA,Hota D, et al. versus Amitriptyline vs. pregabalin inpain over trial. Lancet 2009; 374:252–26. double-blind, randomisedcontrolled cross neuropathicbination for pain: a Gilron I,Baley JM,Tu D, et al. Nortritpyline andgabapentin, alone and in com 30:66–75. bination vs. placebo inpatientswithchronic lumbarroot pain.Pain 2007; andtheircom Morphine,nortriptyline Khoromi CuiL,Nackers S, L,et al. 74:43–20. randomized, double-blind,placebo-controlled 200; trial.Neurology thy: a HIVneuropaSimpson DM,Schifitto G,Clifford DB. forpainful Pregabalin Eur J Neurol 200; 7:082–089. post-traumatic randomized double-blind trial.peripheral neuropathic pain: a van Seventer R, Bach FW, Toth Pregabalin in the treatment of CC, et al. study. Pain 2008; 38:255–266. pain: a randomized, double-blind,placebo-controlled, cross-over, multi-center injury GordhGabapentin in traumatic nerve et al. TE, Stubhaug A, Jensen TS, a flexible-dose regimen. Pain 200; 52:267–273. trial of arandomized, double-blind,placebo-controlledcentral neuropathic pain: a Vranken J,HollmannMW, vanderVegt M H, et al. Duloxetine inpatientswith patients with central post-stroke pain. Pain 20; 52:08–023. of pregabalin in andefficacy Safety TK,et al. BashfordG,Murphy Kim JS, flexible-dose regimen. Pain 2008; 36:50–57. a randomized, double-blind,placebo-controlledneuropathic trialof pain: a Pregabalin MG,KruisMR,et al. inpatients with central Vranken JH,Dijkgraaf NICEguidance. BrMedJ200;340:c079. non-specialist settings: summary of Tan T, P, Barry R neuropathic pain. Eur J Neurol 2006; 3:53–69. treatment of Attal N, Cruccu G, pain. J Pain Symptom Manage 200; 39:053–064. high-concentration capsaicin patch, in patients with peripheral neuropathic NGX-400, a of safety Long-term BrownSimpson DM, Gazda S, et al. S, anoux D, Attal N,MorainF, direct Botulinum toxin aA induces type et al. eken S. Pharmacological management of neuropathic painin eken Pharmacologicalmanagementof S. aanpää M, et al. EFNS guidelines on pharmacological Haanpää M, et al. andomized double-blind study comparandomized double-blindstudy ------

93 Chapter 9. Neuropathic Pain 94 Chapter 9. Neuropathic Pain 50. 49. 48. 47. 46. 54. 53. 52. 5.

Pain coping JA,ClarkM R, Pappagalloaythornthwaite strategies M,et al. H Katz J,FinnerupNB, RH.Clinicaltrialoutcome Dworkin inneuropathic Manzanares J,JulianM,CarrascosaA.R 9 622-066: A Multicenter, Double-Blind,R Yuan R botulinum toxin ais Xiao L,Mackey Hui,et al. Subcutaneous injectionof S, Seattle, WA: IASP Press; 2004. States: A Primer Clinicians. for ProgressinPain Research andManagement L, Dickenson A,OllatH,eds. Bouhassira D, Attal N.Novel neuropathic strategiesfor pain.In: Villanueva 5:44–443. canitimprove outcome? EurJPainropathic painclinical trials: Can 20; Attal N, Bouhassira D, Baron R conditions. Pain 2005; 3:30–35. ciated withpainexperience inpatientswithneuropathic anddisability pain catastrophicasso thinking MJ,Lynch ME,ClarkAJ.Dimensionsof Sullivan 06:453–460. paininpost-herpetic neuralgia.Pain 2003;play arole inthepersistence of pain: relationship characteristics. 2008; 70:263–272. to study Neurology pain episodes. Neuropharmacol Curr 2006; 4:239–257. acute andchronic control themanagementof andtherapeuticimplicationsfor R Available at: Purified Neurotoxin Complex inSubjectswith Postherpetic Neuralgia(PHN). of BOTOX andEfficacy (Botulinum theSafety Parallel of Study Toxin TypeA) randomized double-blind crossover trial. Neurol 2009; 72:473–478. beneficial in postherpetic neuralgia. Pain Med 200; :827–833. esults_Web_Posting9622-066.pdf Y, SheuJJ,Yu JM,et al. Botulinum toxin diabeticneuropathic for pain: a http://www.allerganclinicaltrials.com/pdfs/neuroscience/ The Pain andPathological System inNormal , et al. Assessing symptom profiles in neu , et al. . Accessed 22 May 204. ole of thecannabinoidsystem inpain ole of andomized, Placebo-Controlled, . Vol. . - -

seem to have potential utility in heterogeneous painful conditions andhave inheterogeneous potentialseem tohave utility painful studies in other populations and clinical experience [5] ondataobtained fromcancer pain,andtheirusehasbeenbasedlargely theadjuvant analgesicsinpopulationswith studiesof There been few have the patient and family. and the values and preferences of treatment, salientmedicalandpsychiatric comorbidities, psychosocial factors, disease,andits theunderlying thepain,statusof thenature of standing of thepainandpatient[4]‌ ment of a comprehensive assess responsiveness must be based on the findings of to address this scenario [3]strategy ‌ oneormore adjuvantanalgesicsisacommon administration, andatrialof responsive” tothespecificterizes opioidand the painas“poorly route of analgesiaoccurs charac beforesatisfactory troublesome effects adverse of optimize thebalance between effects.Theoccurrence analgesicandadverse are addedtoopioidtherapyally aftertheopioiddosehas beentitratedto undertreatment. and effects reduce the impact of additive when opioidsare provided, they may becombined withtheseagents toyield pains, and Nonopioid analgesicsare first-linetypes of treatmentsforsome ered tobeasecond-line approach thosewithlimitedorabsentdisease. for erate orsevere chronic cancer, painduetoactive consid anditisusually acceptedfor mod Opioid-based therapy asthefirst-line iswidely strategy oped to provide guidance on appropriate cancer-related pain management. beendevel guidelineshave evidence-based undertreatment [2],several defined inthispopulation.Althoughnumerousmay barriers contribute to isyet poorly butitsepidemiology survivors, and heterogeneousof group illness[] ‌ those withadvanced therapy andapproximately active thosereceiving two-thirds of one-third of Pain prevalentinthecancer population,occurring inapproximately ishighly Paul N. Luong andRussell K. Portenoy Cancer-related Pain Chapter 9.2 Types ofadjuvant analgesics Introduction The decision to offer a trial of anadjuvantanalgesictoaddress pooropioid atrialof The decision tooffer cancer,pain related to active In the treatment adjuvant analgesics of usu . Cancer-related painalsooccurs inthelarge . . Rational decisions require. Rational anunder ‌. Some drug classes ------

9595 96 Chapter 9.2 Cancer-related Pain [Table 9.2.] [5]. musculoskeletal pain,orpainandother symptoms inbowel obstruction for specific conditions,used specifically such asneuropathic pain,bone been described as“multipurpose” adjuvantanalgesics. been Othershave (adapted from Lussier, Huskey, andPortenoy [6]‌ Table 9.2. Multipurpose Use Conventional Based on Category pain neuropathic Used for analgesics

Adjuvant Analgesics Used for CancerPain blockers Sodium channel Anticonvulsants analgesics All multipurpose Topical analgesics Cannabinoids α Corticosteroids Antidepressants Class receptor antagonists N 2 -Methyl- -Adrenergic agonists D -aspartate -aspartate – – – – Other SSRIs SNRIs Tricyclics Subclass – blocker Sodium channel modulator Sodium channel – See above antidepressants, capsaicin, tricyclic local anesthetics, nabiximols dronabinol, nabilone, tizanidine, clonidine methylprednisone prednisone, dexamethasone, buproprion citalopram paroxetine, desvenlafaxine venlafaxine, minalcipran, duloxetine, nortriptyline desipramine, amitriptyline, Drugs amantadine dextromethorphan, memantine, ketamine, IV lidocaine mexiletine, lacosamide lamotrigine, topiramate, oxcarbazepine, carbamazepine, phenytoin, divalproex, pregabalin, gabapentin, see above NSAIDs, others )

( continued )

ary amine tricyclic drugs, such as desipramine, have fewer side effects than aminetricyclic side effects drugs, such fewer ary as desipramine,have pain that may benefit fromeffects, specific side such assedation. The second illpatients, somepatientsmay symptoms inmedically have cern other than con associated withthetricyclic drugsmayAlthough thesideeffects beof amitriptyline [9] and one randomizedtrolled controlled trials [7, 8] trial of con few partially ina someanalgesicefficacy beensuggested tohave have cancer-related limited,however. painisvery Thetricyclic antidepressants reuptake inhibitors (SNRIs) [Table 9.2.]. thetricyclic compounds andthe serotonin-norepinephrine someof for antidepressants,Among many available isbestestablished analgesicefficacy Analgesic antidepressants opioid. to an responsive usual indication is neuropathic pain that has been poorly In practice, opioid-responsive. the pain that is poorly of any type pies for considered thesedrugsare cancer, asadd-onthera typically active allof topical therapies, are considered first-line approaches. For those with themultipurposeadjuvantanalgesics, such astheantidepressants and of rable withother populationswithchronic pain.For thesepatients, some isbestconsidered cancer tobecompa survivors noted, thepopulationof steroids, The so-calledmultipurposeanalgesicsinclude antidepressants, cortico SNRI, serotonin-norepinephrine reuptake serotonin SSRI,selective reuptake inhibitor; inhibitor. Abbreviations: IV, NSAIDs, drugs; intravenous; nonsteroidal anti-inflammatory Table 9.2. pain bone Used for Use Conventional Based on Category obstruction bowelUsed for Multipurpose analgesics Multipurpose α 2 -adrenergic agonists, cannabinoids, and topical therapies. As Continued Plus: Corticosteroids Somatostatin analogue Anticholinergic drugs corticosteroids Plus: NSAIDs, Radiopharmaceuticals Osteoclast inhibitors GABA agonists Class – – – – Bisphosphonates GABA GABA Subclass E vidence of analgesic efficacy in vidence of b a agonists agonists octreotide glycopyrrolate atropine, scopolamine, samarium-53 strontium-89, calcitonin ibandronate zolendronate, pamidronate, baclofen clonazepam Drugs ------‌.

97 Chapter 9.2 Cancer-related Pain

98 Chapter 9.2 Cancer-related Pain randomized controlled trial [4]. chemotherapy-induced wasalsoshown inarecent peripheralneuropathy of ate it [2], as well as in patients who did not tolerate pregabalin [3]. Relief patientswithcolon cancer whocould toler in63%of peripheral neuropathy Duloxetine in pain fromrelieving was effective chronic oxaliplatin-induced andadministeredtwo weeks for []. when initiatedthenightbeforesurgery chemotherapy [0].Itcanalsoprevent chronic postmastectomy pain of chronic oxaliplatin neurotoxicity whenadministered during2-week course conditions. Venlafaxine candecrease symptoms acute neurosensory and than tricyclics and beenhave shown cancer-related to be analgesic in a few preferred when pain is the target symptom. agentsare usually aminedrugssuch andformer asamitriptyline, the tertiary are lacking. ment withacorticosteroid alternatives shouldnot beundertaken unlesssafer mustbe long, thesepotential effects considered; adverse open-endedtreat or is relatively indeterminate expectancy When life is short. expectancy life sion, psychotomimetichypoadrenalism, are effects,andless when relevant treatment, long-term which includes myopathy, immunosuppres The risksof opioid therapy atalow dose,with nointenttotaperordiscontinue therapy. alternatives. various drugsinthis class. Prednisoneare andmethylprednisolone acceptable the low mineralocorticoid effects,thererelatively are trialsof no comparative effects, and direct on nociceptive neural effects systems. peritumoraledema,anti-inflammatory but itmay relate tothereduction of actionisunknown, by increased intracranial pressure [6].Themechanism of from bowel andheadache caused obstruction,paincausedby lymphedema, bone pain,painassociated withcapsularexpansionorductobstruction,pain cancer,active including neuropathic painresulting from compression, nerve clinicalfor varied pain experiencesyndromes thatsuggestsbenefit related to from[5]. Although evidence life clinical trialsis limited, there is extensive of poorappetite,malaise,andoverall such quality aspain,nausea,fatigue, usedtotreat cancer-relatedCorticosteroids beenwidely have symptoms Corticosteroids chronic noncancer pain syndromes. These are described in Chapter 3. scribed usingthesamedosesandprotocols appliedinthetreatment of be used to address these symptoms [5]. shown toimprove sleep, anxiety, anddepression incancer patients, anditcan painrelief,hasbeen which of hasnoevidence Mirtazapine, tion orfatigue. cancergood option patientswhoalsoare for experiencing distressing seda nolence thaneitherthetricyclicbea drugsortheSNRIs, mightnevertheless cancer-related andsom pain.Bupropion, which isassociated withlessfatigue In the setting of advanced cancer, advanced is added to a corticosteroidIn the setting of typically its becauseof dexamethasone,presumably Although many clinicians favor When usedtotreat cancer-related pain,antidepressants shouldbepre of all otherantidepressants in analgesicefficacy There of isnoevidence Serotonin-norepinephrine reuptake bettertolerated inhibitorsare usually ------

corticosteroid therapy cancer. inthosewithadvanced Typically, dexametha reduce neuropathic responding pain in patients with severe cancer pain partly chronic pain;intraspinalclonidine hasbeenshown to of types in diverse Clonidine and tizanidine are α blockade) is used to treat the pain. other (eg, radiotherapy intervention such orapain intervention as neural timesdaily,2–24 mgfour which istapered over assome –3weeks, usually may befollowed by 50–00 mgintravenously methasone loadingdoseof severe andescalatingpain(sometimescalled“painemergencies”). A dexa sion [7],ahigh-dosedexamethasoneregimen hasbeenusedtotreat very 0–20 mg. men may be initiated with a larger loading dose of orparenterally, orally Dexamethasone canbegiven andthelow-dose regi sone –2mg/day orprednisone 5–0mg/day isadministered [Table 9.2.2]. analgesics Multipurpose Use Conventional Based on Category Portenoy [6]‌) Adjuvant Analgesics (adapted from Lussier, Huskey, and Table 9.2.2 night atbedtime;tid,three times a day. Abbreviations: bid, twice aday; IV, PO, intravenously; q,each; qd,once aday; orally; qhs, every obstruction bowelUsed for pain bone Used for pain neuropathic Used for 2 -Adrenergic agonists There are no data that adequately inform dose selection for long-term long-term doseselectionfor There inform are nodatathatadequately Based on experience in the treatment of emergent spinal cordBased on experience compres in the treatment of

Therapeutic DoseRanges for Commonly Used analog Somatostatin drugs Anticholinergic inhibitors Osteoclast see Chapter 9. agonists α Corticosteroids Antidepressants Class 2 -Adrenergic α 2 -adrenergic agonists. Clonidine has been used dexamethasone (Chapter 3) chronicDoses similar to use for noncancer pain Drugs octreotide glycopyrrolate calcitonin pamidronate tizanidine prednisone qd-bid –2 mg Dose Starting Usual Varies 0. mg qd – – qhs –2 mg 0–20 mg dose of loading or larger PO or IV. –2 mg qd-bid, Dose Range Usual Effective 0.–0.3 mg bid 0.–0.2 mg tid  unit/kg per day qmonth 60–90 mg 2–8 mg bid 5–0 mg qd-bid (see text) emergencies pain used for dose can be Higher - - - -

99 Chapter 9.2 Cancer-related Pain

100 Chapter 9.2 Cancer-related Pain and adverse effects. and adverse escalatedwhilemonitoringanalgesia night, andthedoseisthengradually neuropathicwith opioid-refractory pain.Itmay beinitiatedat–2mg andmayeffects bepreferred overfor atrialincancer patientsclonidine hypotensive provedadjuvant analgesicshave Tizanidine hasless ineffective. consideredafterother thesedrugsisusually only oneof of sion. A trial hypoten mouth,somnolence, andorthostatic effects, which include dry pathways in the spinal cord and brain. in monoamine-dependent, endogenous pain modulating to increased activity clonidine, relate headache. Presumably, theseanalgesiceffects,like thoseof pain insyndrome has demonstratedanalgesicefficacy andmyofascial chronic spasticity,to opioids[8].Tizanidine, which isapproved thetreatment for of pain in cancer survivors. Inthelatter context,pain incancer thesepatientsare survivors. treated like oid regimen, and they are considered commonly first-linefor neuropathic totheopi responsive diseasewhen painispoorly populations with active pain. Asdiscussed above, usedasadd-ontherapy they are in empirically Adjuvant analgesicsare usedtotreat commonly cancer-related neuropathic on the approach used to manage chronic noncancer pain (see Chapter 8). pain hasalimiteddistribution.Sequentialtrialsshouldbeconsidered, based when formulation to identify a useful justifies the effort these formulations of risk profilesfavorable for cancer-related pain,butthe tested specifically racotomy, not postamputation)[20].Othertopicalanalgesicshave been mononeuropathies (postmastectomy, after cancer ful surgery posttho mononeuropathies andpolyneuropathies,including peripheralpain painful tion. Low-dose topicalcapsaicin (0.%)wasshown torelieve pain from orincombinaare commercially ormay available becompounded, singly drugs,nonsteroidal tricyclic anti-inflammatory compounds, or other drugs Creams andpatches containing localanesthetics, capsaicin preparations, Topical analgesics tolerated. low initialdoseatnightandtitratedupif atarelatively should bestarted thesecompounds toother relative adjuvants. Allcannabinoids positioning of nabiximolsmay alterthe appropriate adjuvantanalgesics. of Theadvent considered inthosepatientswhoare toopioidsandother refractory only drug(eg,dronabinolcommercially available [THC] ornabilone)istypically a several countries of opioid-refractory pain for due to cancer [9]. A trial andhasalreadybeenapprovedis undergoing development worldwide in other compounds), known asnabiximols, diol (andsmallerconcentrations of An oromucosal spray containing tetrahydrocannabinol (T Cannabinoids neuropathic pain Adjuvant analgesics used for The use of The useof α 2 agonists asadjuvantanalgesicsislimitedby theirside H C) plus cannabi ------

Chapter 9.). those populationswithchronic neuropathic painunrelated tocancer (see continuous intravenous or subcutaneous infusion. A broad range of doses rangeof A broad continuous orsubcutaneous intravenous infusion. tostandard administered therapy asa adequately [28].The drugisusually should beconsidered patients withcancer painthathasnot for responded randomized five controlled trialsthatthis drug concluded onthebasisof of ketamine, a recent review controlled trial[27]didnot confirm theefficacy theopioidreceptor. of rons Althoughalargerandomized andthefunctioning continuous or long-term subcutaneous administration [26].venous infusion intra sidered neuropathic insevere refractory cancer pain,eitherasabrief toshow analgesicefficacy.cancer failed painhave Nevertheless, itcanbe con noncancer neuropathic pain,butalltrialsin types of to diverse relieve effective lidocainehasbeenshown tobe of infusion intravenous decades.for A brief blockers and cancer-relatedrefractory neuropathic pain.Theseinclude sodiumchannel drugclassesas tizanidineoracannabinoid—several alsoare considered for In addition to the other drugs categorized as multipurpose analgesics—such Other drugsused for neuropathic pain topiramate, and sodium divalproex. may be considered. These include oxcarbazepine, lamotrigine, lacosamide, ropathic pain,other anticonvulsants(andother drugclasses described below) neu refractory one or more analgesic antidepressant drugs. In this setting of thegabapentinoidsand benefitfrom both of patient demonstrateslack of other drugsshouldbeconsidered aftera neuropathic cancer pain,trials of of otheranticonvulsants in analgesicefficacy for evidence thelack of Given and prevented chronic pain after mastectomy [25]. combined withtopicalEMLAcream, gabapentinalsodecreased acute pain better toleratedthanhigh-dosegabapentin400mgbidalone)[24].When gabapentin 200mgbidandimipramine0were and more effective alone [22,23].Italsoworked incombination withimipramine(low-dose gabapentin and an opioid was shown tothan be the more opioid effective neuropathic cancer pain [9]. Combination of of types and diverse ropathy in chemotherapy-induceddemonstrated itsanalgesicefficacy peripheralneu gabapentinhave motherapy-induced [2].Studiesof peripheralneuropathy [9]‌ than gabapentinoramitriptyline neuropathic cancer pain in a randomized controlled trial, and it was better related pregabalin. neuropathic isbestfor Thisdrugrelieved pain,evidence the gabapentinoids are well established. In cancer- The analgesic of effects Anticonvulsant analgesics comorbid depression exists. if aregabapentinoids (seebelow). considered Theantidepressants typically first analgesics—the analgesicantidepressants andthetopicalagents—and The NMDA receptor is involved in both the sensitization of central neu The NMDA receptor isinvolved inboth thesensitization of Sodium channel blockade hasbeenrecognized asananalgesicmechanism Patients may respond toeitherpregabalin, gabapentin,orboth drugs. themultipurpose First-line neuropathic therapiesfor paininclude two of N -methyl- D -aspartate (NMDA)-aspartate receptor antagonists. . It also reduced the symptoms of che . Italsoreduced thesymptoms of ------

101 Chapter 9.2 Cancer-related Pain

102 Chapter 9.2 Cancer-related Pain cancer-related neuropathic painthathasnot responded toother therapies. pain, butresults beenmixed. have They areconsidered rarely trialsin for neuropathic of types dextromethorphan, alsobeenstudiedindiverse have side effects. A benzodiazepine or neuroleptic drug is coadministered. is used.Thistitratedhigher, withtolerable ananalgesiceffect againseeking doses 0.5mg/kgintwo orthree divided clinical doseof experience, astarting psychotomimetic effects.Oral ketamine hasalsobeenused,andbasedon of ment withabenzodiazepine donetoreduce orneuroleptic therisk isusually increased, oftenuntilbenefitoccurs appear. orsideeffects Concurrent treat 0.2–0.5mg/kgperhour. isgradually Theinfusion doseof astarting to favor mostclinicianshas beenused,beginningaslow seem as0.05mg/kgperhour; dence that oral trauma and dental infections increase the risk of osteonecrosis, increasedence thatoral traumaanddentalinfections theriskof fractures. the evi femoral [30]andatypical Given thejaw osteonecrosis of cally a bisphosphonate has beenassociated withmore serious complications, specifi of with renal or levels. insufficiency low-serum calcium Repeatedadministration screening beforetreatment isimportant toexcludetory orlimitdosingin those A labora and symptomatica transient decline in hypocalcemia. renal function, based on experience, cost,ally and convenience. aspecific drugisusu limited,andtheselectionof data are very Comparative ibandronate, and clodronate, andoralibandronate andclodronate [29]. theparenteral drugs, including pamidronate, zolendronate, allof potential of and causingosteoclast apoptosis. Substantialresearch theanalgesic supports clast activity, stimulatingosteoblaststoproduce osteoclast-inhibiting factor, cer patientswithbonemetastases[29].They inhibitingosteo actby directly in can life events, including fracture andpain, may improve of the quality inpreventing skeletal-related beenshownBisphosphonates have tobeuseful Osteoclast inhibitors which bone pain is one. skeletal-related events, of approved thetreatment intheUnitedStatesfor of nuclear factor so-called receptor of activator [Table humanmonoclonal antibodies(mAbs)thatinhibitthe 9.2.].New setting include bisphosphonates, radionuclides calcitonin, andbone-seeking tion toacorticosteroid, such asdexamethasone,drugstoconsider inthis for bonepain.In addi drug, opioid,andadjuvantanalgesicsusedspecifically managedwithanonsteroidal painareanti-inflammatory multifocal usually tion therapy orsurgery. such oranintervention askyphoplasty Patients with a patient with bone pain may radia suggest the need for The assessment of GABA cancer-related neuropathic pain.TheGABA with a neuropathic component can be considered treatment-refractory for Drugs used for bone pain Bisphosphonate administrationmay beaccompanied by flu-like symptoms, Other drugsthatarenoncancer painsyndromes sometimesusedfor Other NMDA receptor antagonists, such asmemantine,amantadine,and B agonist, baclofen, are agonist, baclofen, two such agents. A agonist, clonazepam, andthe κ B ligand(RANKL)are also ------

very poor dentition, jaw infection, or recent infection, poor dentition, jaw substantial dental procedures.very bonepainshouldbeconsidered for patients with for strategy an alternative tinal secretions and reduces motility. Thisdrugmay alsorelieve painandother Octreotide pancreatic, andintes isasomatostatin analogthatinhibitsgastric, Octreotide ranted in those who are predisposed to these side effects. glycopyrrolate may bewar bowel obstruction,atrialof thesymptoms of for the blood-brainbarrier. asatreatment evaluated systematically Althoughnever macological profile similartoscopolamine buthasminimalpenetrationthrough tem sideeffects,such Glycopyrrolate assomnolence and hasaphar confusion. salt, which crosses andmay theblood-brainbarrier produce central sys nervous In many countries, as the hydrobromide [33, 34]. scopolamine only is available mal patch, aconvenient routethosewithlimited gastrointestinal for absorption decrease intraluminalsecretions. Scopolamine canbeadministered by a transder Anticholinergic drugsreduce gutmotility and andnonpropulsive propulsive Anticholinergic drugs secretions and peristaltic movements (anticholinergic drugs and octreotide). by lesseningperitumoraledema(corticosteroids) ordiminishingintraluminal analgesics may directonpainor have effects reduce painand other symptoms andpaincontrolhydration, usingopioidsandadjuvantanalgesics. Adjuvant gastriccontents (viaoralornasogastricsuction,venting gastrostomy), of vomiting) considers becomes Management important. usually removal very control symptoms (eg,distention,nausea,and painandother obstructive When malignantbowel remediable, theneedto obstructionisnot surgically future. bone pain in the profiles and may contribute to the management of [32]. This and other mAb compounds are their analgesic being studied for spinal cord compression, inmenwithbonemetastasesfrom prostate skeletal-related complications, including pathologicfractures and prevention of human mAbagainstRANKL,wasshown tobebetterthanzoledronic acid for In arecent randomized, comparative, double-blindedstudy, denosumab, a Human monoclonalantibodies however, and treatment requires specialized and facilities. skills bonepain[3]‌ multifocal treatmentrefractory for bonemetastases andcanbeauseful up atthesiteof radiationsourceshort-lived toabisphosphonatemolecule. Thedrugistaken radionuclides,Bone-seeking such asstrontium-89 andsamarium-53,linka Radionuclides ments are or are not available ineffective. considered when other this treatmenttreat is generally only empirical trial of citonin toreduce an thelimitedevidence, metastaticbonepain[3].Given Drugs used for thepainofbowel obstruction There is conflicting information about the potential for subcutaneousThere aboutthepotentialcal isconflicting information . Bonemarrow suppression isasignificant concern, cancer ------

103 Chapter 9.2 Cancer-related Pain

104 Chapter 9.2 Cancer-related Pain decades has been very rapid,andthere nowdecades hasbeenvery are numerous drugsinmany thesedrugsduringrecent community. in thesurvivor of Thedevelopment cancer andoftenareto active first-linefor cancer-related strategies pain Adjuvant analgesicsareadditionstoopioidtherapy important inpainrelated much higher levels. Cost may however. be prohibitive, twice daily, at00mcg subcutaneously starts butitcanbetitratedto usually Dosing A long-acting isalsoavailable. subcutaneousous infusion. formulation and may beadministered asrepeated subcutaneous bolusesorasacontinu symptoms in bowel obstruction [33, 34]. Octreotide profile has a good safety 0. 3. References needed. badly thesedrugsinvariousindicationsare of compare andeffectiveness thesafety based ondataobtained inother populations andexperience. Studies that these drugs in populations with cancer empirical, remains largely more of oneor classes. Theclinical approach totheselectionandadministrationof 5. 8. 7. 6. 4. 2. . 9. Conclusions prevention and relief of oxaliplatin-induced acute neurotoxicity: results of oxaliplatin-induced acute neurotoxicity: results of of prevention andrelief Durand JP, forthe of venlafaxine DeplanqueG,MontheilV, Efficacy et al. double-blind placebo-controlled study. Am J gabapentin, andpregabalin inneuropathic cancer pain: a randomized prospective of amitriptyline, efficacy Acomparative Goyal BhatnagarS, GN,et al. Mishra S, cancer.to advanced Proc Am Soc Clin Oncol 986; 5:237. Walsh imipramineandmorphinein chronic paindue TD. Controlledof study and amitriptyline trazodone. Ital J Neurol Sci 987; 8:579–587. syndromes withdeafferentation and other painful component: comparison of Ventafridda V, Antidepressantscancer pain for Caraceni A,et al. BonezziC, agement. Oncologist 2004; 9:57–59. Lussier D, 4th ed. Oxford, N,et al, NI,Christakis G, Cherny eds. Lussier D, Portenoy RK.Adjuvantanalgesics inpainmanagement.In: 32:237–25. recommendations. Pain 2007; neuropathic pain: evidence-based ment of Pharmacologicmanage RH,O’ConnorDworkin AB, Backonja M,et al. Manage 200; 2:338–354. strategiestoimprove opioidresponsiveness. JPain SymptomPart 3: Clinical Mercadante Portenoy S, responsive cancer RK. Opioid poorly pain. 9:985–99. publishedliterature. AnnOncol 2008; of ment incancer pain.A review undertreat G.Prevalence of Deandrea MontanariM,MojaL,Apolone S, Oncol 2007; 8:437–449. Ann thepast40 years. of systematic review paininpatientswithcaner: a of van den Beuken-van Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain man ngland: Oxford University Press; 200: pp.England: Oxford University 706–734. Everdingen MH, de Rijke JM, Kessels AG, et al. Prevalence xodTxbo fPalliative Medicine Oxford Textbook of Hosp Pall Care 202; 29:77–82. Hanks - - - - . 26. 25. 24. 23. 22. 2. 20. 9. DuPenisenach JC, intrac Epidural clonidine analgesiafor DuboisM,et al. S, 8. E 7. 6. 5. 4. 3. 2. . Phase III placebo-controlled trial of llison N, Loprinzi CL, Kugler J, et al. E

Oncol 202; 23:200–205. EFFOX, arandomized, double-blind,placebo-controlled phaseIIItrial.Ann cancer pain. Pain 99; 45:45–48. neuropathic Brose WG, treatment CousinsMJ.Subcutaneous lidocainefor of cancer. for breast surgery Anesth Analg 2005; 0:427–432. with gabapentin andlocal anesthetics prevents acute andchronic pain after A,TrigaFassoulaki Multimodalanalgesia A,MelemeniSarantopoulosC. mine. J Anesthesiol 200; 24:407–40. neuropathicto opioids for cancer pain when combined with low-dose imipra Arai YC, MatsubaraT, adjuvant ShimoK,et al. Low-dose gabapentinasuseful ized open trial. J Pain Symptom Manage 2007; 34:83–89. random neuropathic cancer pain: a the management of sus opioidalonefor Keskinbora K,Pekel AF, Aydinli I.Gabapentinandanopioidcombination ver Group. J Clin Oncol 2004; 22:2909–297. randomized controlled trialfrom theGabapentinCancerpain: a Pain Study neuropathic Gabapentinfor cancer Caraceni A,Zecca et al. E,BonezziC, oxaliplatin-induced neuropathy. sensory Anticancer Res 200; 30:2927–2933. pregabalin intreatment MW, of I.Role Syrigos of K,KaleySaif K,Isufi patients. J Clin Oncol 997; 5:2974–2980. surgicalneuropathic painincancer capsaicin cream in the managementof 2007; 4:729–743. acannabis-based medicine. ChemBiodivers Sativex, peutic clinical trialsof Russo EB, GuyGW, Robson PJ.Cannabis, pain,andsleep: lessons from thera table cancer pain: the J Clin Oncol 2005; 23:2028–2037. Ontario Practice GuidelinesInitiative’s DiseaseSiteGroup. Neuro-Oncology malignantextraduralspinalcord Cancer Care compression: the agement of thediagnosis and man DA,Loblaw Perry J,ChambersA.Systematicof review patients. Am J corticosteroids as adjuvant drugs to opioids in advanced cancer of study Mercadante SL,Berchovich randomized Aprospective M,Casuccio A,et al. Supp Care Cancer 2008; 6:29–298. lowers anddepression anxiety incancer patients: superiority over imipramine. improves Mirtazapine sleepand Ozalp E, Soygur ES, Cankurtaran H, et al. 309:359–367. randomized clinical trial. JAMA 203; peripheral neuropathy: a painful amongpatientswithchemotherapy-induced life of andquality function, duloxetine on pain, of Effect Smith EM,Pang et al. C, H,Cirrincione Res 202; 32:805–809. cer patientswithneuropathic topregabalin. painnon-responsive Anticancer duloxetine can Koyama for C, Matsuoka H,Makimura of Pilot A,et al. study Care Cancer 202; 20:49–497. in patients with colorectalneuropathy open-label pilot cancer: an study. Supp Yang Duloxetine improves et al. YH,LinJK,ChenWS, oxaliplatin-induced pain syndrome. J Pain Symptom Manage 2004; 27:33–39. postmastectomy theprevention of XLfor venlafaxine administrationof ative Makari-Judson G, Lurie SD.Reuben SS, Hosp Palliat Care 2007; 24:3–9. pidural Clonidine Study Group.Epidural Clonidine Study Pain 995; 6:39–399. valuation of efficacy of the perioper efficacy Evaluation of ------

105 Chapter 9.2 Cancer-related Pain 106 Chapter 9.2 Cancer-related Pain 3. 30. 29. 28. 27. 34. 33. 32.

H Martinez-Zapata MJ, Roque M, Alonso-Coello P. Calcitonin metastatic for Woo SB, HellsteinJW, and Kalmar JR.Systematic review: bisphosphonates malignancy-related bone disease: current JJ. Bisphosphonates for Body status, Bredlau AL, Thakur R, Korones DN, RH. Dworkin Ketamine pain in adults for nant inoperable bowel obstruction. Supp Care Cancer 2000; 8:88–9. butylbromide incontrollinghyoscine gastrointestinal symptoms duetomalig octreotide and CasuccioMercadante RipamontiC, A,et al. S, Comparisonof J Pain Symptom Manage 2000; 9:23–34. randomized prospective trial. bowel obstructionandnasogastrictubes: a patientswithinoperable insymptombutylbromide, control andhydration of octreotide, scopolamine Role of L, et al. MercadanteRipamonti C, Groff S, cer: a randomized, double-blind study. Lancet 20; 377:83–822. bonemetastasesinmenwithcastration-resistant prostate can treatment of Denosumabversus zoledronicFizazi K,Carducci acid for M,Smithet al. bone pain. Cochrane 2006; (3):CD003223. Rev the jaw. Med 2006; 44:753–76. Ann Intern osteonecrosis of Care developments. Support Cancerfuture 2006; 4:408–48. Pain Med 203; 4:505–57. theliterature. andsynthesis of systematic review and children withcancer: a 30:36–367. cancer pain.JClinOncol 202; neous ketamine inthemanagementof of subcuta placebo-controlled and toassesstheefficacy study toxicity ardy J, Quinn S, Fazekas B, et al. Randomized, double-blind, al. Randomized, Fazekasardy J, Quinn B, S, et - - -

tion, without peripheral tissue abnormality that maytion, be without present peripheral tissue abnormality as aunique andbone. Fibromyalgiain cartilage incontrast based condi isa neurologically inthesynovial changes changes predominantly tissueandsecondary matory egorized as OA, or IA with inflam originating in the cartilage, with pathology intothosecat jointsmay Conditionsaffecting bedivided some timeinlife. Pain arising in these tissues will be experienced by at almost all individuals tions, andbursaeisthemost prevalentreasonmusculoskeletal for pain. Soft-tissue rheumatism comprises conditionstendons, affecting theirinser Rheumatic painmay ariseinthesoft tissues, thejoints, ormuscles andbones. low back and OAalso approved pain [3, 4]. treatment for of FMare pregabalin, duloxetine,treatment andmilnacipran, withduloxetine of Adjuvant agentswithUSFood andDrugAdministration(FDA) approval for rheumaticpainconditions. awiderspectrumof inmanagementof be useful management. WithpromisinginFM,adjuvantagentsmayeventually effect neuropathic for pain,inrheumaticpain usedonly medications, previously adjuvant Therefore,will bemore alogicalstepistoexplore diverse. useof pain mechanisms, treatment options directed to pain management tion of (NSAIDs) andopioidswere appropriate choices. apprecia Withthisnew the peripheralprocess drugs that included nonsteroidal anti-inflammatory nociceptive, treatments tobepurely (IA) wasbelieved directed towards between FM and defined rheumatic conditions. softtissueabnormality, andthatthere isconsiderable overlapcondition of syndrome withpathogenesiscentered system, inthenervous rather thana due to the recognitionknowledge is partly that fibromyalgia (FM) is a pain This new by[, 2]. nociceptive to be driven mechanisms believed only nally logical mechanisms contribute tothepainexperience inrheumaticpain,origi overconsiderably thepastdecade.There that neuro isemergingevidence painprocesses inrheumaticconditions haschanged The understandingof Fitzcharles Mary-Ann Fibromyalgia Rheumatic Pain and Chapter 9.3 Rheumatic conditionscausing pain Introduction When the pain due to osteoarthritis (OA)When thepainduetoosteoarthritis arthritis andinflammatory ------

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108 Chapter 9.3 Rheumatic Pain and Fibromyalgia via the descending inhibitory system [5]‌ via thedescending inhibitory mediated effects cord inthebrain,andfinally andbrainstem,altered function the pain message by plastic changes in the spinal the periphery, modulation of at localfactors Pain duetoarheumaticprocess isacomplex interactionof pain pathways and centrally. both in the periphery sensitization of are patientswitharthritis now recognized symptoms of tobemanifesting of orassociated withsomeotherentity rheumaticdisease.Increasing numbers of gabapentin and pregabalin in FM, there was reductionstrong for evidence of treatment effects of Inameta-analysis FM[4, 5]. inthetreatmentcacy of sified assecond-generation anticonvulsants, andthey shown have clinical effi gabapentinoids( Anticonvulsant drugsintheclass of Analgesic anticonvulsant drugs FMandrheumaticpainalongwithrecommended doses. thetreatmentfor of forvariousadjuvantanalgesics analgesicefficacy of theevidence of summary pain such asanxiety, depression, andsleepdisturbance. Table 9.3.provides a the common accompaniments to someof affecting of the addedadvantage serotonin andnorepinephrine mechanisms [2, 3]. Adjuvantsmay alsohave pathwaysdescending paininhibitory inthebrainstemandspinalcord via on sensitization, whereasgroup with effect the antidepressantability affects studied in FM. Anticonvulsant agents dampen neuronalsively hyperexcit anticonvulsantsandantidepressants,medications, beenexten namely have interest. adjuvant adjuvanttreatmentsTwo broad is of categories of of effect as well astheconsiderable overlap withFMinmany rheumaticconditions, the neurogenic mechanisms in rheumaticpain, the contribution of In thelightof size after joint replacementnormal [8–]. thalamusto jointand(2) return of lidocaineinto thepainful administration of after activation of OA, inpatientswithpainful observed with() reversal andstructure been have norepinephrine [5–7].Changesinbrainfunction the painmessageare theendogenousopioids, cannabinoids, serotonin, and P, andcalcitonin gene-related dampen peptide, whereas thosethatmostly [5]‌ pain inperpetuationof response tovariousstimuli,andisafactor geration of continued pain,neuronal peripheralandcentral sensitizationleadstoanexag rheumatic conditions. In the setting of in the pain experience of genic factors structural changes and even within the system.nervous neurophysiologic ongoing pain,thisinitialresponse isfollowed by response. Inthesettingof neuron and account somatosensory the initial nociceptive for the primary of Adjuvant treatments rheumatic conditions Neurogenic mechanisms in Several lines of evidence strengthen the hypothesis of interplay of neuro interplay of of strengthen evidence thehypothesis lines of Several . Molecules augmenting the pain message include glutamate, substance. Molecules augmentingthepainmessageinclude glutamate, . Local tissue changes cause activation . Localtissuechanges causeactivation

α 2 δ liganddrugs)are clas ------Table 9.3. Adjuvant Pharmacotherapy for Fibromyalgia and Rheumatic Pain Drug Class Fibromyalgia Suggested Daily Rheumatic Pain Suggested Dose Daily Dose Anticonvulsants Gabapentin + 00–300 mg HS No studies N/A Pregabalin + 25–00 mg HS No studies N/A Antidepressants TCAs + 0–25 mg HS No studies N/A SSRIs + / − Variable No studies N/A SNRIs duloxetine + 30–60 mg + 30–60 mg milnacipran + 00–200 mg − N/A Topical agents NSAIDs No studies N/A + TID/QID Capsaicin No studies N/A + TID Cannabinoids Herbal No studies N/A No studies N/A Nabilone + 0.5– mg No studies N/A Sativex No studies N/A + 2–8 puffs Abbreviations: HS, at bedtime; N/A, data not available; NSAIDs, nonsteroidal anti-inflammatory drugs; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; TID, 3 times a day; QID, 4 times a day; +, evidence supports analgesic efficacy; −, evidence suggests does not have analgesic efficacy; +/−, conflicting evidence on analgesic efficacy.

109 Chapter 9.3 Rheumatic Pain and Fibromyalgia

110 Chapter 9.3 Rheumatic Pain and Fibromyalgia drugs, thereby attenuating side effects. A single study hasbetter study reported drugs, thereby attenuatingsideeffects.A single individual usedinclinical practice andmaymonly lower allow for dosesof patients.disturbance inarthritis Combinationdrugtreatment isalsocom disease,theseagentsarearthritic usedoff-labeltotreat both pain and sleep the hip [7]. of of pregabalin in OA hasreportedbeneficial effects post hocclinical study reduced by pregabalin administrationinanOA onesmall ratmodel[6].Only gabapentinoids inhumanrheumaticdiseases,were althoughpainbehaviors tice, in contrast to the higher doses used in clinical trials [3, 4]. toreduceweight ledphysicians gain,andedemahave dosesinclinical prac drowsiness, [4].Troublesome andanxiety impact onfatigue of sideeffects pain,improved andsome sleep, life, andimprovedof health-related of quality mood, and even fatigue have been reported. The ideal dosing of theseagents beenreported.Theidealdosing of have fatigue mood, andeven onpainrelief,improvementsthese studieshas focused healthstatus, in global 60 mg/day. outcome most of for Although the primary dose of with a daily duloxetineing for seen islower depression,mostly thanthatfor witheffect chronic painincluding low back pain.However, thetreatmentfor of dos FM, and duloxetineby the FDA has anadded indication treatment for of up to one year [24–30]. Both duloxetine and milnacipran been approved have consistent improvement in FM, with sustained response in pain and function agents with a onbalanced serotonin effect and norepinephrine, shown have shownand have promise inpainmanagement.Duloxetine andmilnacipran, serotonin norepinephrine reuptake inhibitors, mayimproved offer tolerability serotonin andnorepinephrine, termed depressants thatinhibitreuptake of anti rheumaticpain.Newer profile holdspromiseforthemanagementof in patients with chronic lowfunction back pain [23]. nine trials, antidepressants intheTCA andSSRIclasses improved painbutnot of not(SSRIs) have shown consistent[22].In ameta-analysis analgesiceffect over time[2].However,wear off serotonin the selective reuptake inhibitors effect thattendsto of FMbutwithmodest inthe shown efficacy treatment antidepressants (TCAs). have anditsmetabolitenortriptyline Amitriptyline group are [20].Thebeststudiedinthis theoldertricyclic effective ciently other rheumaticconditions inwhich analgesicsandNSAIDsare not suffi in human synovial membrane cultures [9]. cytokines inflammatory disease progression andalso inhibited production of (RA),both citalopram rheumatoidarthritis andfluoxetine inhibited model of N antidepressants may animpactonopioid mechanisms, alsohave ionchannels, in the brain stem and spinal cord, mediated by norepinephrine and serotonin, pathways recognized ondescending paininhibitory effect Although mostly for Pain modulators affecting descendingpathways inhibitory pain [8]. inhibitor, back wasusedcompared withmonotherapy thetreatment for of pregabalin and celecoxib,cyclooxygenase-2 whena a effect combination of -methyl- The development of new antidepressant new agentswithreduced side-effect of The development in effect inFM,thereAlthough clinical for studiesareisevidence mostly To date,there beennocontrolled have studiesexaminingtheuseof D -aspartate (NMDA)-aspartate channels, inflammation.Inamouse andeven E xtrapolating from experience in FM,in but without study - - - - -

will probably be somewhat flexible [3]. be somewhat will probably become be clarifiedwill as likely physicians more with use but comfortable With considerable limitations of studies with small sample sizes, short study studieswith smallsamplesizes, study short With considerable limitationsof [4]. andnine, respectively reportedasfour with numbersneeded toharm drowsinessimprovements, and wereconfusion common but of side effects 28 patientswithmusculoskeletal disease,painscores showed statistical is required.additional study rheumatic disease suggests a possiblean inflammatory therapeutic role, but cannabinoid treatment in group.and sleep in the active of This first study orplacebo overSativex a5-week period,withsignificantimprovement inpain RApatients trial were[36]. Fifty-eight treated with the oromucosal spray questionable value. cannabinoid use in FM remains of 36 H asmeasured Form by theShort patients butwithnoimpactuponfunction study, painscores were reduced two hoursafterherbalcannabisusein28FM studies reported more inthose usingnabilone.Inanuncontrolled sideeffects Both of life. oneither painorquality on sleepbutwithout significant effect effect for nabiloneandamitriptyline of second reportedequivalency study study, nabilonewasassociated withimproved whereas the painandfunction, small randomized controlled In the first trials in patients with FM [37, 38]. patients who use medicinal professional cannabis.caring for exists between useandabusehasmedicolegalany healthcare implications for must discriminate between recreational andmedicinal use.Thefinelinethat thatpersonsusingmedicinal cannabisagement. Inaddition, it isnecessary symptom man for the purpose of be made specifically cannabis use can only professionals needtoclarify topatientsthatany recommendation herbal for recreational andmedicinal cannabinoiduse.Healthcare ies istheoverlap of issue raised by both the population stud A concerning tis pain [33, 34, 39]. arthri treatmentin theUnitedKingdom andAustraliareportingusefor of personsintwo populationstudies pain,anduptoonethirdmyofascial of usersinapainclinic intheUnitedStatesreporting nal cannabis, with80%of clinical trials: two three formal in FM only and one in RA [33–38]. preclinical science, populationsurveys, anecdotal reports, andtheresults of paininmusculoskeletal conditionsfrom isavailable managementof noids for cannabi regarding jointdamage[32].Information theuseof tion andeven systemthe nervous andpainpathways, butthey animpact on inflamma have areconfined to thecannabinoideffects not only topopularbelief, Contrary The cannabinoids agents in older patients. these inpatientswithotherof comorbidities,ability theeffect andespecially toler druginteractions,reason cautionistheconcern for problems for of clinical practice, other thanFM,isstillpreliminary.ogy Themostcommon In a systematic review and meta-analysis thatincluded 4studieswith and meta-analysis In asystematic review randomized controlled beenstudiedinRAasingle Cannabinoids have nabilone,a synthetic cannabinoid,hasbeenstudied intwo of The effect medici musculoskeletal painisacommonTreatment reasonuseof for of antidepressant painmodulationinrheumatol medicationsfor The useof ealth Survey or the FIQ [40]. Therefore, on the strength of evidence, ealth Survey or the FIQ [40]. Therefore, onthe strength of ------

111 Chapter 9.3 Rheumatic Pain and Fibromyalgia

112 Chapter 9.3 Rheumatic Pain and Fibromyalgia demonstrated in the rat model by the application of amitriptyline, an agent demonstrated in the rat model by the application of mediators. Prolongedperipheral inflammatory cutaneous analgesiahasbeen painmodulation,andNSAIDsinhibit gatemechanisms of tants make useof endings afterrepeatedapproximately applicationfor 3weeks, counterirri action[42–46]: capsaicin depletessubstance Pfrom nerve ent mechanisms of thetic agentssuch asketamine, topicalTCAs, andcapsaicin, each withdiffer treatments may besimplecounterirritantssuch asmenthol,NSAIDs, anes interest in the recent comment. past deserves Topicalthe resurgence of beenusedtotreat decades,Although topicalagentshave rheumaticpainfor Topical treatments andintra-articular tenuous and require further study. sizes noted tobemodestatbest,anyduration, andeffect conclusions remain change in chondrocyte cell function and cartilage metabolism.Thistreatment andcartilage change cell inchondrocyte function actionisa from thejointwithin 24hours, thepostulated mechanism of knee OA in selected patients [57, 58]. acid may hyaluronic arolethetic agent.Intra-articular have inthetreatment of botulinum toxin, alocalanes orsimply but withsomeinterest intheuse of applied treatments [55].Corticosteroid areusedagent, themostcommonly location over a one-year period. injectionstothreeeach for dotal recommendations tolimitthenumberof [56]. Repeated treatments may berequired months, afterseveral withanec turesof symptomsare more efficacious in initiating prolonged improvement corticosteroids intosofttissuesstruc disease [55].Incontrast, injectionsof of on pain ornatural history effect long-term for duration, withnoevidence rare which are occurrences. mostly sheath is injected, both of thetendonratherthan atendonwheninadvertently ture of intoatissuespace and(2) rup infection concerns are() introduction for of acceptable, andimportantly, therisksare Thetwo minimal[53, 54]. greatest corticosteroid success ismodestandalmostwithoutsystemic effect, rateis localinjectionsisthatthedoseof rheumatic conditions. of Theadvantage for andenduringtreatment strategy sheaths, andjointshasbeenauseful treatment, with thereafter [52].less obvious effect weeks of topicalNSAIDsisapparent withinthefirst two of that theanalgesiceffect in chronicmuscle injuriesbutnoeffect low back painorFM[5].Italsoseems joint asingle OA oracute thanplacebo in managementof a bettereffect administered treatment. anorally Topical thanfor favorable NSAIDshave of atopicalagentismore Thereforeprofile theside-effect be high[49, 50]. drugare low, whereas localtissueconcentrations of plasmalevels can ally used,butgener dependingupon theformulation temic absorption canvary reduced [48].Localand sys systemic effects of with theaddedadvantage nociception and onperipheralmechanisms of increasing effects for evidence sodium channels and thereforethat affects the pain response [47]. Intra-articular orintralesionalinjections mayIntra-articular beconsidered aslocally short corticosteroids,of ismostly theeffect jointinjectionsof In studiesof corticosteroidsFor intobursae,tendon thelasthalf-century, injectionof toThese oral agents treatments provide with alternative an attractive Even acid is clearedthough hyaluronic ------

effects within the first three months of treatment [59]. within the first threeeffects months favorable and well tolerated,withmost safe, has beenshown tobeeffective, preliminary. matic painconditions, inFMmust still be andeffects considered tobe profile [69].Oncea good safety again,there are nostudiesin other rheu significant reduction inpainintensity compared withplacebo andshowed three monthsresulted in over aperiodof monthly FM, dolasetron infused patients with usedas antiemetic drugs. In a recentbeen primarily of study in musculoskeletalthis treatment pain [68]. strategy able inpatientswithchronic pain.However, there are nostudiesexamining thisreceptor desir would behighly chronic painisperpetuated,blockade of although use is tempered by frequent gastrointestinal side effects [67]. pain, pramipexole inFMimprovementreported in symptoms of of the effect thatexamined accompaniment study torheumaticpainconditions. A small treatmentfor restlesslegs,augment dopamineare afrequent aneffective 5-hydroxytryptamine-3 receptor antagonists. Anti-Parkinsonian drugsthat included are thedopaminergic agents, NMDA receptor antagonists, and drugs exists.rheumatic diseasesother thanFMhardly Thecategories of which may in someuseinpainmanagement, althoughevidence have action, agents, each withuniquemechanisms of There are anumberof Other agents the patient to improve health. of on the part other treatment effort options as a positive the exploration of may view even productscomplementary speakstoatrustingdoctor-patientrelationship and useof care professionalshouldacknowledge thatdisclosure by thepatientof pain orjointspace narrowing whencompared withplacebo [66].Thehealth patients withOA, althougharecent indicatesnoreduction in meta-analysis byRA [65].Both glucosamineandchondroitin sulphateare usedextensively NSAIDs in ties and has been associated with reduction in consumption of properalpha linolenicacid) hasbeenshown topossessanti-inflammatory cised regarding interaction with other prescribed medications. cautionneedstobeexer safe, effects, andherbalagentsseemtobe relatively not Althoughstudieshave reportedseverepatients withOA side [63, 64]. tum), and avocado/soya on pain in some been effect reported to have have ing phytodolor, primrose capsaisin,evening oil,devil’s (harpargophy claw OA, agentsinclud several thetreatment herbalmedicine for of the useof 4hadbeentestedincontrolled of only trials[62].Inasystematic review treatment arthritis inJapan, productsfor the260complementary available of A recent Japanthat [60, 6]. review from reported efficacy for out evidence not prescribed andoftenwith with rheumaticdisease,mostly by physicians manipulationsareusedbyHerbal treatments patients commonly anddietary Herbal and Diet The 5-hydroxytryptamine-3 receptor antagonists are agents thathave the NMDA receptor is a mechanism by which of Because activation acids (eg, fatty supplementationwithomega3polyunsaturated Dietary ------

113 Chapter 9.3 Rheumatic Pain and Fibromyalgia

114 Chapter 9.3 Rheumatic Pain and Fibromyalgia vants can be universally recommended routine for pain management. vants can be universally weighed againstpotential risksbeforeadju population, needtobecarefully for theolder oralagents, especially FM.Benefits related touseof treatment of for beusedmoreinrheumaticdiseases andnot only commonly eventually the adjuvant agents, with impact on sleep, they may fatigue, mood, and even of some of effects usedinclinical practice. Inlinewiththediverse been tentatively studiednot in rheumaticbeen adequately conditions,mostly but they have pain inrheumaticdisease.Theseagents,from apart topicalapplications, have FMtype neurogenic mechanisms inFMandtheoverlap of the knowledge of The notion toconsider adjuvantagentuseinrheumaticconditions stemsfrom 4. 3. 2. . 0. References 9. 8. 7. 6. 5. 4. 3. 2. . Summary auser W, fibromyalgia K,Uçeyler Treatment H Bernardy N,SommerC. of controlled trials. Pain 2009; 45:69–8. randomized syndrome of withgabapentinandpregabalin—a meta-analysis 992; 49:205–29. 39placebo-controlled studies. Pain of meta-analysis non-malignant pain: a Onghena P, Van nonepileptic conditions. Nat Med 2004; 0:685–692. treatment of the antiepileptic drugs for MA,Loscher W.Rogawski of Theneurobiology patients. Rheum 2009; 6:226–234. osteoarthritis Arthritis central sensitizationinacohortof thepresence supporting ing evidence of SE, KeltnerGwilym JR, Warnaby CE, et al. imag Psychophysical and functional voxel-based morphometric study. Rheum 200; 62:2930–2940. Arthritis longitudinal thehipisreversible afterarthroplasty: a of osteoarthritis painful associated with Thalamicatrophy SE,FilippiniN,DouaudG,et al. Gwilym treatment in chronic back pain and knee osteoarthritis. Mol Pain 2008; 4:47. analgesic MN, Geha PY,Baliki of fMRI study A preliminary R, et al. Jabakhanji concerned with emotions and fear. Rheum 2007; 56:345–354. Arthritis Kulkarni B, Bentley DE, 87:3–. pain. BrJAnaesth 200; inflammatory Kidd BL,Urban LA. Mechanisms of 33–38, 277–279. tion andpaininarthritis.Novartis Found Symp 2004;260:22–33;discussion mediatorsonnocicep inflammatory JJ.TheroleKidd BL,Photiou A,Inglis of Ther 2006; 8:220–220. Res jointpain.Arthritis and pain. NeurogenicMcDougall JJ.Arthritis originof fibromyalgia. Rheumatol 2009; 5:9–99. Nat Rev management of CroffordBoomershine CS, LJ.A symptom-based approach topharmacologic 4:39–34. therheumaticdiseases.Rheum20; SeminArthritis and painmanagementof conceptsGoldenberg DL,Clauw DJ,Fitzcharles MA.New inpainresearch Rheum 2005; 52:3685–3692. rheumatologist. Arthritis Fitzcharles MA, Almahrezi A, Shir Y. Pain: understanding the and challenges for Rheum 2009; 60:32–324. Clauw DJ,WitterJ.Pain andrheumatology: thinking outsidethejoint.Arthritis Houdenhove B. Antidepressant-induced analgesia in chronic Elliott R, et al. pain is processed Arthritic in brain areas - - - 5. 32. 3. 30. 29. 28. 27. 26. 25. 24. 23. 22. 2. 20. 9. 8. 7. 6.

treatment of fibromyalgia: a systematic review and a meta-analysis. JClin andameta-analysis. systematic review fibromyalgia: a treatment of Tzellos, TG, Toulis Gabapentinandpregabalin inthe KA,GoulisDG,et al. 63:569–6. Pertwee RG. Cannabinoidreceptors andpain.Prog Neurobiol 200; J Rheumatol 200; 37:2578–2786. randomized, double-blind, placebo-controlled fibromyalgia: a trial. ment of LM,ClauwD,Arnold Wang F, Flexibledosedduloxetine et al. inthetreat :80–94. ized, double-blind,monotherapy 6-monthextensionstudy. Pain Med200; response a random to milnacipran treatment fibromyalgia. for Results of Goldenberg DL, Clauw DJ, Palmer R patients with fibromyalgia. J Rheumatol 2005; 32:975–985. of milnacipran in Gendreau MD, RM,Thorn Efficacy Gendreau JF, et al. in Clin Ther.[Erratum 2009 Feb;3:446] placebo-controlled, multiple-doseclinical trial.ClinTher2008;30:988–2004. 5-week, multicenter,fibromyalgia inadults: a randomized, double-blind, Clauw DJ, Mease P, Palmer R myalgia with disorder.or without major depressive Pain 2005; 9:5–5. women withfibro duloxetine inthetreatmentplacebo-controlled of trialof al.Arandomized, double-blind, LM, RosenArnold A, Pritchett YL, et disorder.without major depressive Rheum 2004; 50:2974–2984. Arthritis fibromyalgiaing duloxetine patientswithor withplacebo inthetreatment of LM,LuY,Arnold Crofford LJ,etal.Adouble-blind,multicenter trial compar 70:99–08. fibromyalgia. Drugs200; PL.Milnacipran: in Chwieduk CM,McCormack duloxetine in patients with fibromyalgia. Clin J of Pain 2009; 25:365–375. LittlejohnG,KajdaszChappell AS, DK,et al. study andefficacy A-year safety chronic back pain: a Arch meta-analysis. Med 2002; 62:9–24. Intern antidepressant treatment on SM,Browning of Salerno JL.Theeffect R,Jackson 2:384–389. chronic Med997; pain.JGenIntern themanagement of inhibitors for serotoninof selective reuptakeJung AC,StaigerT, M.Theefficacy Sullivan pain. Ann Acad Med Singapore 2009; 38:974–979. chronic Chan HN,FamJ,NgBY. antidepressants inthetreatment of Useof 2008; 47:7–23. pharmacological and clinical studies. Rheumatology rheumatologicalconditions? Systematicof anti-depressants review inpainful Perrot M,et al. RM,Marty Isthere theuseof Javier any tosupport evidence S, and inhibit toll-likearthritis receptors. Rheum 200; 62:683–693. Arthritis rheumatoid in human and murine models of activity potent antiinflammatory FluoxetineSacre Medghalchi B, M,Gregory S, et al. andcitalopram exhibit 2009; 0:85–9. chronic low-back Traumatol pain.JOrthop combination treatment for of Romano CL,Romanò D, MineoG.Pregabalin, BonoraC, celecoxib, andtheir 43:S337. thehip. Rheum2000; Arthritis pregabalin of inpatientswithosteoarthritis M,Iacobelis Jaffe D, Young JP,et al. of Post-hoc results showeffects beneficial pain. Mol Pain 2009; 5:45. osteoarthritic pregabalin inaratmodelof of and theantinociceptive effects W,Rahman Descending BannisterK,et al. serotonergic BauerCS, facilitation Ther 200; 35:639–656. Pharm H , et al. Milnacipran for the treatment of Milnacipran the treatment for of , et al. H , et al. Durability of therapeutic al. Durability of , et - - - -

115 Chapter 9.3 Rheumatic Pain and Fibromyalgia 116 Chapter 9.3 Rheumatic Pain and Fibromyalgia 38. 37. 36. 35. 34. 33. 52. haroutiunian Drennan S, DA, LipmanAG. Topical 5. NSAID therapy muscu for 50. 49. 48. 47. arvey WF,injections in analgesics and intra-articular Hunter DJ. The role of 46. H 45. 44. 43. 42. 4. 40. 39.

Walleyneman CA,Lawless-LidayC, Oralversus topicalNSAIDsin GC. H Skrabek RQ, Galimova L,EthansK,Perry D. thetreatment Nabilonefor of Ware MA, Fitzcharles MA, Joseph L, Shir Y. nabilone on sleep of The effects Blake DR,Robson P, theefficacy, toler HoM,et al. assessment of Preliminary Ware MA, Gamsa A, Persson J, Fitzcharles chronic MA. Cannabis for pain: case Ware cannabisinthe MA,AdamsH,GuyGW. Themedicinal useof Swift W, GatesP, DillonP. medical Australiansusingcannabisfor Survey of randomised controlled trials. BMJ 2004; 329:324. of osteoarthritis: meta-analysis drugsinthetreatment of anti-inflammatory topicalnon-steroidal of Lin J,ZhangW, M.Efficacy Jones A,Doherty loskeletal pain. Pain Med 200; :535–549. rheumatic diseases: a comparison. Drugs 2000; 60:555–574. 996; 46:38–43. ibuprofenafter oralandtopicaladministration.Arzneimittelforschung of levels tissueandplasma Dominkus M,NicolakisKotz Comparisonof R,et al. 55:–20. J.TopicalSawynok actinganalgesics. 2003; PharmacolRev andperipherally 2002; 96:09–6. analgesia in the rat. Anesthesiology P,Khan MA,Gerner Kuo Wang prolonged for cutaneous G.Amitriptyline disease management. Rheum Dis Clin N Am 2008; 34:777–788. BMJ 2004; 328:995–995. acute andchronic pain. thetreatment containingfor of salicylates rubefacients of topical efficacy Systematic of review et al. S, Mason L, Moore RA, Derry 2004; 5:28–28. skeletal pain: systematic BMCMusculoskelet andmeta-analysis. Disord review Mason L,Moore RA,E ized controlled trial. CMAJ 2004; 7:333–338. random theknee: a of osteoarthritis primary relievingsymptoms of tion for solu atopicaldiclofenac of ShainhouseJZ.Effect Bookman AA,WilliamsKS, in neuropathic pain syndromes: an open-label study. J Pain 2005; 6:644–649. MJ.TopicalLynch J,Sullivan ME,ClarkAJ,Sawynok andketamine amitriptyline 20; 38:7. JRheumatol musculoskeletal and meta-analysis. systematic review diseases: a Kung T, forpainin of cannabinoids Hochman J,SunY,et al. andsafety Efficacy 20; 6:e8440. PLoS One life. and health-related of quality on symptoms relief gia: effect CannabisuseinpatientswithfibromyalFiz J,DuránM,CapellàD, et al. J Opioid Manag 2009; 5:257–286. chronic painaccessing treatment withmedical cannabisinWashington State. GT, patientswith Aggarwal SK,Carter MD, Characteristicsof Sullivan et al. pain in fibromyalgia. J Pain 2008; 9:64–73. 0:604–60. arandomized controlled trial.AnesthAnalg200; of in fibromyalgia: results 2006; 45:50–52. pain caused by rheumatoid arthritis. Rheumatology inthetreatment acannabis-basedmedicine of (Sativex) of andsafety ability clinicians.series and implications for Pain Res Manag 2002; 7:95–99. survey. a nationwide Int J Clin Pract UK: results2005; 59:29–295. of purposes. arm Reduct J 2005; 2:8.Harm , et al. Topicaldwards JE,et al. chronic NSAIDs for musculo ------53. 69. 68. 67. 66. 65. 64. ernst 63. 62. treatments inrheumaticdiseases. E. Complementary Rheum DisClinN ernst 6. 60. 59. 58. 57. 56. 55. 54.

olman AJ,Myers RR.Arandomized, double-blind,placebo-controlled trial H injections and other injections for management of tendinopathy: a systematic tendinopathy: a managementof injections andother injectionsfor of corticosteroid Coombes BK,BissetL,Vicenzino B. andsafety Efficacy 3 receptor antagonist, in patients with fibromyalgia. dolasetron,double-blind, a 5-hydroxytryptamine placebo-controlled trial of Vergne-Salle al. Arandomised, P, et Dufauret-Lombard BonnetC, C, to oral ketamine. J Pain Symptom Manage 2002; 23:65–70. foradjuvant indifficult painconversion syndromes: afrom parenteral strategy Fitzgibbon EJ,HallP, Low doseketamine asananalgesic Schroder et al. C, concomitant medications. Rheum 2005; 52:2495–505. Arthritis pramipexole, adopamineagonist, inpatientswithfibromyalgia receiving of 200; 34:c4675. hiporknee: network BMJ meta-analysis. of cebo inpatientswithosteoarthritis Wandel JüniP, S, glucosamine, chondroitin, orpla Tendal of E ffects B, et al. 29:20–223. jointpain. inflammatory Pain 2007; acid supplementation for unsaturated fatty omega-3 poly of theanalgesiceffects of Goldberg RJ,Katz J.Ameta-analysis tis: a systematic review. 200; 40:779–793. Rheumatology osteoarthri thetreatmentLong L,SoekenE.Herbalmedicines for of K,Ernst Best Pract Res Clin Rheumatol 2004; 8:539–556. arthritis. Geriatr Gerontol Int 2009; 9:29–40. andrheumatoid osteoarthritis medicines for alternative complementary Kikuchi M,MatsuuraK,Matsumoto Y, of investigation Bibliographical et al. Am 2008; 34:455–467. health care in setting.a universal J Rheumatol 994; 2:48–52. patients medicine useby rheumatology Boisset M,Fitzcharles MA.Alternative nans. Med Res Opin 2008; 24:3307–3322. Curr Brzusek D, Petron D. Treating hyaluro withintra-articular kneeosteoarthritis Rheum 2007; 57:40–48. Arthritis and meta-analysis. systematic review the knee: a of osteoarthritis Reichenbach Rutjes AW, Blank S, S, H et al. 9;(2):CD00532. theknee.Cochrane DatabaseSyst 2006Apr Rev of osteoarthritis ment of Bellamy N,CampbellJ,Robinson V, et al. Viscosupplementation thetreat for trolled trials. Ann Rheumatic Dis 2009; 68:843–849. randomised con of meta-analysis shoulderandelbow tendonitis: a tions for of steroid injec andsafety Gaujoux-Viala DougadosM,GossecL.Efficacy C, Opin Rheum 999; :47–42. Creamer P. corticosteroid Intra-articular treatment inosteoarthritis.Curr 9;(2):CD005328. Apr Syst 2006 Rev the knee.Cochrane Databaseof of osteoarthritis treatment of Bellamy N,CampbellJ,Robinson V, corticosteroid Intraarticular for et al. randomised controlled trials. Lancet 200; 376:75–767. of review . Musculoskeletal conditions and complementary/alternative medicine.E. Musculoskeletal conditions and complementary/alternative ylan versus acid hyaluronic for Eur J Pain 200; 5:509–4. ------

117 Chapter 9.3 Rheumatic Pain and Fibromyalgia

chronic posttraumatic pain [9] ‌ andperhapsto contributes hyperalgesia likely to referredpainandsecondary Inaddition,centralwhen patients’ sensitization painisgreatest. postoperative andperipheralsensitization aresurgery, profound afferentactivation primary after basic scienceor opioiduse[].Furthermore, dataindicatethat early incisionpainat didnot theskin affect rest themagnitudeof whereas varying decreases painatrest deeptissueinjury andopioidconsumption, amount of unique indicates thatdifferenttissueshave responses toincision: reducing the ways andguarding painwere model reportedafterincision. Thispostoperative innociceptive path using theratplantarincision [0],spontaneousactivity experiments other clinical neurophysiology painconditions [].Afterinvivo painproduced are by differentfrom surgery andtreatment of The etiology acutepain [46]. severe postoperative [28].A recentlife hasidentifiedstrongfor study predictorsfor patientsatrisk pain thatconstitutes adistressing healthcare problem andreduces of quality chronic 0surgicalpatients willdevelop postoperative recognized thatoneof surgical patients is crucial [8]. Finally, it has now been involved inthe care of allpersons for educationalprograms most importantly, of thedevelopment abilities. Acute mustbeestablished,and, painservices the patient’sfunctional outcomes, adverse and to maintain pain management, to reduce the risk of acute of andeffectiveness thesafety theseguidelinesisto facilitate pose of setting. acute painmanagementintheperioperative The pur guidelines for go [8]‌ specialists recently inthefieldstatedthatthereand even isstillalongway to painisarealHowever, acute challenge, postoperative themanagementof beendeveloped. analgesiahave provisionsic agentsandtechniques for of pain, postoperative and innovations in both analge of the pathophysiology year beenmadein [49].Many have worldwide advances undertaken every majorsurgicalprocedures are[50]. Ithasbeenestimatedthat234 million healthcare painisanimportant issue acute postoperative The treatment of BeaulieuPierre Acute Postoperative Pain Chapter 9.4 Pathophysiology ofpostoperative pain Introduction . The American Society of Anesthesiologists[]hasjustpublishedtheir of . TheAmericanSociety . - - -

119119

120 Chapter 9.4 Acute Postoperative Pain [8]‌ patientsundergoing surgicalprocedures resources alargenumber of for healthcare andconsumption life of ing consequences of thequality for reach butalsobecausesubstandard acute painmanagementhasfar gery) humanitarian reasons (to decrease after sur immediately pain suffering for not only painisimportant, postoperative The optimal managementof manythen moderate or severe days for weeks later. or even such ascoughingissevereactivities, duringthefirst2to3 days orwalking, implemented a multidisciplinary team or acute pain service [7]implemented a multidisciplinary ‌ academicinstitutionshave was introduced in988[4]. Nowadays, 90%of clinical research pain, inpostoperative of educationandthefacilitation formal approach pain,whichinterdisciplinary included tomanagingpostoperative acollaborative, pain.Theconcept postoperative of improved managementof Acute pain management servicesevolved inresponse to the desire for General management: acute painservice 9.4.) [38]. Surgery • Anesthesia • Concurrent • Concurrent • Genetics • Biological Cognitive • Prior • Locus • Vulnerability • Depression • Anxiety • Psychological Family • Income • Educational • Ethnicity • Sociocultural Gender • Age • Demographic Perception (from [38]) Table 9.4. Management ofpostoperative pain In general,painatrest resolves withinthefirst week aftersurgery. P . Many factors can influence the perception of postoperative pain (Table postoperative caninfluence theperception. Many factors of experience/expectations of background

control components

level disease medications Variables ThatMay Affect Postoperative Pain . ain with - -

Pharmacological management ofpostoperative pain tially serious side effects that serioussideeffects restrain theirutilization inthepostoperative tially depressionrespiratory [36, 37]. pruritus,retention, or urinary ontheincidenceless sedation,butnoeffect of lessnauseaand vomiting, 29% 50% andwithareduction inside effects: 30% 30%– of NSAIDs withmorphineisassociated withamorphine-sparingeffect pain.Theadministrationof postoperative NSAIDs inthemanagementof cyclooxygenase-2Selective antagonists (coxibs) asstandard are aseffective Nonsteroidal anti-inflammatory drugs patients’[37, 42]. satisfaction thefirst24hours,20% for butwithoutany difference inside-effect profileor aminophen with opioids was associatedof witha morphine-sparing effect acet other theadministrationof analgesicsby 36%–50%[43].Furthermore, acetaminophen intravenous reduces theuseof period. Theadministrationof in patientsnilby mouthasisoftenthecaseinimmediatepostoperative in theUnitedStates, P now kg inchildren. existsinmostcountries (Ofirmev form Anintravenous is pain, timesuch aspostoperative periodof ashort dose,whenusedfor daily multimodal analgesia [35]. The maximal of analgesic as part background tive efit ratio, mightjustifyaforacetaminophen asanear-routinerole postopera The Acetaminophen Analgesics acetaminophen, NSAIDs, and opioids. the multimodal analgesia, including use of of overview also provide a brief pain, we postoperative the management of adjuvant analgesics for the use of [37].R will be associated withlesssideeffects more severe sideeffects.Itisthenhopedthatusing lessopioids,forexample, thedrugswithpotentially smaller dosesof time allows theadministrationof andatthesame synergistic effects oreven bined drugsmay additive have antidepressants.possibly Theideabehindmultimodalanalgesiaisthatcom anesthetics, and, more recently, anticonvulsant analgesics, ketamine, and aminophen, nonsteroidal drugs (NSAIDs), anti-inflammatory opioids, local regarding composition the various surgical procedures [27]. and duration for treatment. However, theoptimal combination therapy needstobeevaluated side effects compared single-modality withmore intensive reducing the risk of inasmuch asanalgesicpower isenhanced togetherwithanexpectedgainby ferent mechanisms toprovideseemedadvantageous, analgesia.Thisstrategy two ormore drugsactingviadif pain managementastheadministrationof Anesthesiologists[]‌ of American Society paintreatment wasproposederative in993by Kehlet andDahl[27].The “multimodal” or“balanced analgesia” inpostop The definitionandvalueof analgesia Multimodal 4 Nonsteroidal anti-inflammatory drugsand Nonsteroidalcoxibs anti-inflammatory are associated with poten Today, acet multimodalanalgesiaincludes thecombined administrationof g very in adults, low risk 3 g of in

acetaminophen elderly erfalgan inEurope) thatallows anadministrationeven erfalgan or patients therapy, weighing defines multimodal techniques for definesmultimodaltechniques with ather than simply focusing on focusing ather thansimply less a highly than favorable 50 kg, and risk/ben 60 mg/ ------

121 Chapter 9.4 Acute Postoperative Pain

122 Chapter 9.4 Acute Postoperative Pain tinal and cardiovascular problems [48]. NSAIDshasbeenproposedpatientswithgastrointes for the prescription of ment atthelowest recommended. for efficacious doseishighly Analgorithm treat diabetes,sion, dyslipidemia, andinsmokers. Finally, course ashort of hyperten from shouldbeusedwithcautioninpatientssuffering particular or cerebrovascular disease(transientischemic orstroke). events Coxibs in cated inpatientswithgastrointestinal, renal, cardiac (angina,cardiac failure), patients are, the more are deleterious effects reported. longertheadministration,biggerdose;andolder effects: the thepatientare crucial inproducing unwanted administered, andtheageof treatment, thedose torememberperiod. Itisimportant thatthedurationof the understanding of the pathophysiology of OIH has led to the administration OIH hasledtotheadministration of thepathophysiology the understanding of involves the effect preexisting pain.Thisparadoxical andmay aggravate heightened painsensitivity analgesia [3]‌ to pain) rather than (increasedcan be associated sensitivity with hyperalgesia opioids years, thattheadministrationof In thelastfew ithasbeenobserved Opioid-induced hyperalgesia between twointerval each doses) patient. must be set up for theopioidandlockout (minimal interval loading dose,thebolusdoseof are used,buthydromorphoneorfentanyl other options.is usually Aftera Morphine [20, 39]. opioidspostoperatively theadministrationof nique for P Patient-controlled analgesia ing effects [24]. periodwithvary hasbeenusedinthepostoperative fentanyl administration of lessthanhour. Theintranasalroute analgesiaof minutes withadurationof on the ate effect central nervous system. The onset time via this route is 6–8 enter thecerebrospinal mucosae, resulting inanimmedi fluidviatheolfactorial gastrointestinal andhepaticpresystemic elimination.Italsoallows to fentanyl Itsadministrationprevents hasbeendeveloped. fentanyl administrationof of stillneeded.Inarecent study, theintranasalroute are if administered orally Whenthepatient cantolerateoralmedications,gesia (PCA)device. opioids atregularby anurseorviapatient-controlled intervals subcutaneously anal addiction. (OIH);(3) tions, opioid-induced hyperalgesia pruritus, nausea and vomiting, depression, respiratory Common: () lowing: routes. the under opioidsisdiscussed association withother analgesics. Spinaladministrationof painin moderate-to-severe postoperative Opioids are themaintreatment of Opioids atient-controlled analgesia administration isnow the recommended tech In the immediate postoperative period,opioidsare administeredIn theimmediatepostoperative either fol acute paininclude the opioidsinthetreatment of of Side effects drugs,Nonsteroidal including anti-inflammatory coxibs, are contraindi oral, “Local intravenous, urinary . Indeed,opioidtherapy, inhighdoses, may cause particularly and Regional retention, N -methyl- subcutaneous/intramuscular, techniques”. D ileus, -aspartate (NMDA)-aspartate receptors [45].Therefore, sedation; Systemic (2) Less opioids R are: physical dependence, are: physical transmucosal, are common: hallucina delivered or through nasal ------

tion or treatment. The use of multimodal analgesia is also beneficial to try multimodalanalgesiaisalsobeneficial totry tion ortreatment. Theuseof NMDA ketamine, anonselective itspreven antagonist, for smalldosesof of pain scores inhospital orat6 months withinthecontext afterhiparthroplasty doesnot reduce morphineconsumption orpostoperatively or preoperatively nausea and vomiting [9]. postoperative visual disturbances, but it decreased the occurrence of and of dizziness or light-headedness effects. Pregabalinadverse increased theriskof additional provides butatthecost term of additionalanalgesia intheshort tration greater. visual disturbance was such as effects vomiting, but the risk of doses≥300mg).Pregabalinand 3.4mgfor reduced opioid-related adverse pregabalin <300mg decreased withpregabalin (8.8mgreductiondosesof for was significantly opioidconsumptioncumulative at 24 hours aftersurgery isnot reduced painintensity als, postoperative by pregabalin [5].However,  randomizedAccording controlled to atri recent systematic of review gabapentinandpregabalin. macological propertiesof andpharmacokinetic pain andopioidconsumption. Chapter 4provides onphar more information make period,toreduce theminteresting analgesicstouseintheperioperative gabapentinandpregabalin propertiesof Theanti-hyperalgesic mon [6, 7]. isbecomingsuch more asgabapentinorpregabalin com (gabapentinoids) painusinganalgesicanticonvulsivants postoperative Multimodal treatment of Gabapentinoids opioid exposure [32].operative ance afteracute intra andthatitreduces wound hyperalgesia postoperative OIH or analgesic toler low-dose ketamine might modulate the expression of vomiting was less frequent in the ketamine group. nausea and for pain, postoperative subgroups. When ketamine was effective surgical upperabdominal,andmajororthopedic thoracic, for wasfound cacy greatest effi The rescue analgesic. tion, anddelays thetimetofirst request of upto48hours, painintensity decreasespostoperative total opioidconsump ketamine during administeredanesthesia in adults decreases intravenously analgesics such as opioids [47].perioperative central sensitizationinduced both by theincision andtissuedamage andby ketamine exerts aspecific NMDA and,hence, blockade modulates effect transdermal, [4, 40]. R been shown todecrease painandopioidrequirements postoperative inadults Ketamine, properties, acompoundhas withanalgesicandantihyperalgesic Ketamine NMDA in Chapter 7. antagonists pain can be to found treat postoperative OIHandtheuseof on doserequirements detaileddiscussion [3].A more of distinctphenomenaandshareOIH arethesameneteffect pharmacologically tonote thattolerance OIH.Itisimportant and of thedevelopment to avoid For gabapentin, Clarke et al [3] reported that a single 600 mg dose given For gabapentin, Clarke 600mgdosegiven et al [3]reported thatasingle Another recent on pregabalin meta-analysis reported that the adminis There administrationof toshow issomeevidence thatperioperative According [8]andarecent [29], toameta-analysis systematic review of outes of administrationinclude intravenous, subcutaneous, epidural, outes of

225–300 and intra-articular. mg/day pregabalin At low subanesthetic during a short doses perioperative (0.5–0.5 mg/kg), period ------

123 Chapter 9.4 Acute Postoperative Pain

124 Chapter 9.4 Acute Postoperative Pain Antidepressant analgesics, inasimilarmannertogabapentinoids, may a have Antidepressants recommended [23]. pentin ± the current trend istoadministergabapentinoidshourpreoperatively However, they are surgery effective. in acute pain setting,which of type ing, improves recovery functional following total knee arthroplasty [4]. reportedthatgabapentindecreasessame group morphineconsumption and spinalanesthesiaandarobust multimodalanalgesiaregimen. However,of the thetic infiltration is effective in major abdominal and orthopedic surgery [5]. in major abdominal and thetic infiltration is effective painby localanes postoperative of postoperatively.thetics are Therelief infused space throughthe surgeonin subcutaneous orsubfascial which localanes A perforated catheter may by infection. be inserted skin nor is it with the risk of patient[22].Itisnot associated withwound dehiscencemended inalmostevery in opioid use is noted with perineural analgesia [5]‌ pruritus alloccurred morewithopioidanalgesia,andareduction commonly all catheterlocationsandtimeperiods. Nauseaandvomiting, sedation,and oids. Indeed,perineuralcathetersprovide superioranalgesia toopioidsfor lower general, and plastic surgery. limb surgeries including orthopedic, [26].Thesetechniqueshours ordays are upperand used for aftersurgery afew localanesthetics for of catheterswillallow indwelling theinfusion of are pain.The use butalso to treat oftenusedtoallow postoperative surgery some advantages (Tableepidural technique [2] offer 9.4.3) [6]‌ common with spinal opioids. When compared with depression. respiratory Pruritus,ing thistimefor nausea,andvomiting are approximatelyfor 24hoursaftersurgery. P to provide painrelief.Intrathecalmorphineprovides postoperative analgesia administered and opioids arewithlocalanestheticstoallow surgery usually infiltrations intra-articular (Table 9.4.2). techniques, orplexusblocks, nerve approaches: neuroaxial incisional and chronic pain syndromes. postsurgery as possibleimproved rehabilitation anddecreased incidence of are seenwithcontinuous blocks, peripheralnerve patient satisfaction aswell thatblocks evokedity pain.Decreased nauseaandvomiting andincreased modal medium- to long-term available blockadeContinuous nerve is the only Local and regional techniques ment [2, 25]. available Therefore,currently pain their manage role in postoperative pain.However, postoperative two studiesare only role inthemanagement of 2 The infiltration of thesurgical wound withlocalanestheticsisnow recom The infiltrationof blocksContinuous peripheralnerve provide betterpaincontrol thanopi echography, orplexusblocks peripheralnerve of With thedevelopment spinalandepiduralanesthesia.Spinal Neuroaxial techniques include mainly indifferenttechniques and localanesthetics can bedivided The useof trialsare neededtodelineatetheoptimal dose,tim Therefore, further and and/or hours or duration of later.

for 300 the A dose mg of prevention

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of efficacy, but this concept is not necessarily applicable to all types of surgery. efficacy, butthis concept types applicableto all is not necessarily of a valuable overview analgesic can give a particular needed-to-treat (NNT) of reliable, analgesic treatment. comprehensive, The number- individualized approachan evidence-based to There of the development is a need for treatment pain Specific local anesthetic delivery [2]. method of new localanestheticsprolongs analgesicdurationandisanattractive tions of liposomal formula results compared blocks with nerve [3]. The use of localanestheticswithgood of toallow theinfusion shoulder) aftersurgery Postoperative Pain Relief Table 9.4.2 • • • R • • • • • Side effects • • P Patient-Controlled Analgesia (from [6]‌ Table 9.4.3 and intrabursal blocksIntraarticular Incisional blocks: subcutaneous, subfascial transversus • paravertebral • intercostal • proximal • plexus • P caudal • combined • spinal • epidural • Neuroaxial blocks eripheral nerve and plexus blockseripheral nerve ain control eduction in postoperative morbidity eduction in postoperative Intra-articular cathetersarewithinmajorjoints(hip,Intra-articular alsoinserted knee, nurses respiratory cardiovascular sedation urinary nausea/vomiting postoperative ileus hypotension on at rest mobilization blocks: brachial workload retention and spinal/epidural

abdominis Different Regional Techniques to Provide Comparison ofEpiduralAnalgesia vsOpioid distal nerves plane and lumbosacral block + + + – + – shortening – ++ +++ Anesthetics) Analgesia (Local Epidural ) + – – + + ++ prolongation + ± ++ Analgesia Patient-Controlled Opioid -

125 Chapter 9.4 Acute Postoperative Pain

126 Chapter 9.4 Acute Postoperative Pain Management in the Management AnesthesiologistsTask Force of and (3)theAmericanSociety onAcute P R European of Society postoppain.org the lines arefrom available varioussources, themainonesare () asfollows: sequences may beprocedure-related [47].Such procedure-specific guide anditscon becausethepainintensity management guidelinesmay behelpful proposedTherefore, have thatprocedure-specific somegroups acute pain effects. Therefore, multimodalanalgesiaisthe rule. Table 9.4.4provides abalance and betweenacceptable efficacy side best treatment is thatof patients. Theadequately, isassociated with chronic painin 0%–40% of pain,ie,pain not treatedthe cases.severe postoperative Furthermore, painin20%of severe postoperative of pain ispredictive Preoperative ies are proceduresneeded to validate the approach in individual [28, 46, 50]. attempt inan hasbeendeveloped anxiety pain,obesity, preoperative of andlevel of surgery, extent bined scoring systemanddurationof basedonage,sex,type clues topredict which patientswillgochronic on todevelop pain[44].Acom andthetransitionalmechanisms involved may revealgenetic factors important tion, orchemotherapy theincreasing [30,33].Inthefuture, understandingof approach, moderate to severe acute pain, postoperative depression, radia painandanxiety,tive repeat surgery, catastrophizing,gender, female surgical beenidentified: preopera have chronic aftertissueinjury paindevelopment involved in riskfactors important [30,44].Several reviewed been recently patients [28].Theprogressionfrom acute tochronic painhas postoperative these itcanbesevere inapproximately bypass surgery; 2%–0%of artery repair, hernia groin breast andthoracic surgery, legamputation,andcoronary aftercommon operations, individuals such as persistent painin0%–50%of apreexistent condition. painisfollowed by Acute postoperative erbation of excluded orchronic and(4)painisnot (malignancy duetoanexac infection); been painshouldhave atleast2monthsduration; (3)other causesof is of afterasurgical procedure;to beestablished[34]:()paindevelops (2)pain paintobeclassified as chronicfollowingfor postsurgicalpain,the criteria have operationswere associated withchronic painsyndromes. Inorder of variety years whenitwasrealized topicuntilthelastfew thatawidea neglected healthcare. hasbeen Indeed,chronic painaftersurgery of quality indicator of interest, anditsprevention now represents achallenge asan of major focus pain after surgical procedure or traumaThe has persistencebecome a of Future andconclusions Chronic painafter surgery PROSPECT to predict with ), a group of European anesthesiologistsandsurgeons;(2)the of ), agroup (procedure the its P erioperative Setting []‌ erioperative updated severity egional Anaesthesia(ESRA) specific of report

early pain on postoperative treatment) Practice . Guidelines Working pain. www.esraeurope.org Large for Group cohort Acute ( www. stud Pain ain ); ); ------

References andcurrent literature. evidence-based surgery of basedonthetype program center,in place inevery patientsanalgesicoptions anda offering rehabilitation postoperative pain. usedadjuvant analgesics in themost commonly dosing guidelines for Postoperative Period Table 9.4.4 *Based on one clinical study for each drug. for *Based ononeclinical study • • • Local Ketamine • • Antidepressants* • • Gabapentinoids • • drugs anti-inflammatory Nonsteroidal Acetaminophen Drugs . 5. 4. 3. 2. A hospital program for the management of postoperative painshouldbe postoperative themanagementof for A hospitalprogram

ropivacaine levobupivacaine bupivacaine duloxetine venlafaxine pregabalin gabapentin celecoxib naproxen 04:872–880. AP Boezaart 2007; 54:48–485. Beaulieu P review. 2006; 04:570–587. Anesthesiology systematic qualitative ClarkD.Angst MS, Opioid-induced hyperalgesia: a Clin J orgabapentinonacute andchronic venlafaxine postmastectomy pain. tion of administra of theperioperative efficacy AA.Evaluationof Amr YM,Yousef 6:248–273. 202; setting.pain managementintheperioperative Anesthesiology Anesthesiologists. acute Practice guidelinesfor American Society of anesthetics P ain 200; 26:38–385. . Non-opioid strategies for acute painmanagement. CanJAnesth . Non-opioidstrategiesfor

Summary ofNonopioidDrugsUsed inthe Summary . P erineural infusion of local anesthetics. Anesthesiology 2006; localanesthetics. Anesthesiology of erineural infusion 2 2–3 mg/kg 2–3 mg/kg Maximal dose per min 0–5 μg/kg 0.5 mg/kg 60 mg 37.5 mg 300 mg 600 mg 00 mg 500 mg  g 650 mg Dose mg/kg intraarticular epidural, perineural, topical, subfascial, Subcutaneous, infusion intravenous Continuous Intravenous Oral Oral Oral Oral Oral Oral Intravenous Oral Administration Route of 4 hourly P P and at 24 h 2 h preoperatively postoperatively. 0 days for Daily  h preoperatively  h preoperatively 2 hourly 2 hourly 6 hourly 4 hourly Administration Frequency of eroperatively eroperatively -

127 Chapter 9.4 Acute Postoperative Pain 128 Chapter 9.4 Acute Postoperative Pain . 0. 25. 24. 23. 22. 2. 20. 9. lia N,Tramer system quantitative M R. Ketamine pain: a 8. E andpostoperative 7. 6. 5. 4. 3. 2. 9. 8. 7. 6.

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a for formulations rat anaesthesia. postopera P early the ain 2009; model acute post pain. con Clin of ------

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apse isreferred to asserotonin toxicity orserotonin syndrome. Thisis serotonin excess atthe syn italicized. of Themostacute manifestation [28].Serotonergic been analgesicsinTable 0.3 have tonergic activity serotonin in the synapse. Table 0.3 illustrates drugs enhancing sero the neurotransmitter of the effect medications involves potentiation of serotonergic themostsignificantdrug-druginteractionsinvolving One of Serotonin toxicity analgesic (Table 0.2).adjuvant analgesic with another class of interactions occurring between two adjuvantanalgesics(Table 0.)oran Tables 0.and0.2illustratethemostcommon drug-drug andimportant other classes. adjuvant analgesics or drugs of adjuvantanalgesicswithother chapter willpresent drug-druginteractionsof cytochrome specific P450isozymes). This metabolizers of poor vsextensive actions, centers around genetic-based differences in drug metabolism(eg, cases, pharmacogenetics. Pharmacogenetics, asappliedtodrug-druginter theinteraction,drugdoses, and,insome applicable tothemechanism of to therapeuticconcentrations ordoses),age-related changes inphysiology toxic the drugs (ie, the ratio of including the therapeutic indicesfactors of drug-druginteractionsisinfluenced by several result. of turn, Theseverity oneorboth drugsinvolved. reaction Anadverse may,good andbad)of in tribution, metabolism,andexcretion) (ie,responses orpharmacodynamics (ie,absorption, dis thepharmacokinetics Drug-drug interactionscanaffect thischapter, drug-druginteractionswillbepresented.For only purposesof large-volume parenteral solutions, foodstuffs,nutrients, etc. components of Drugs caninteractwithother drugs, excipients inthedosageformulation, R. P. GuayDavid Adjuvant Analgesics Interactionsof Drug-Drug Chapter 0 medications prescription andover-the-counter Drug-Drug interactions involving Introduction - - - -

131131 132 Chapter 0 Drug-drug Interactions

Table 0. Interactions Between Diverse Adjuvant Analgesics Adjuvant Other Adjuvant Interactions Mechanism Evidence Recommendations TCAs []‌ SSRIs, SNRIs ↑ serotonergic effects • Additive serotonergic effects at Reported with • Avoid this combination synapse • Amitriptyline + sertraline if possible • Inhibition of TCA drug metabolism • Imipramine/desipramine + • If must use a TCA, by SSRIs/SNRIs (inhibition of fluvoxamine avoid clomipramine CYP450 isosymes 2D6, A2, 2C9, as it is the most • Clomipramine + fluvoxamine 2C9, 3A4. Note: range of number serotonergic TCA • TCAs + fluvoxamine of isozymes inhibited and potency • If must use a SSRI, of inhibition vary between SSRIs) • TCAs + venlafaxine use citalopram or → ↑ TCA (parent +/− active escitalopram because metabolite) serum concentrations these interact least with → serotonergic effects at synapse CYP450 isozymes TCAs []‌ Phenytoin ↑ plasma phenytoin Unknown • Case report with imipramine Use TCA other than concentrations • No interaction in case imipramine series with nortriptyline and amitriptyline CBZ [2]‌ Valproate • Variable effects • Valproate inhibits CBZ metabolism, • Pharmacokinetic studies Careful monitoring of on plasma CBZ displaces it from plasma protein toxicity/loss of efficacy concentrations binding sites, inhibits CBZ epoxide and therapeutic drug • ↑ plasma CBZ epoxide metabolism monitoring are necessary concentrations • CBZ induces valproate metabolism whenever regimen of either agent is altered • ↓ plasma valproate concentrations

CBZ [2, 3] Phenytoin • ↓ plasma CBZ • Each induces the hepatic • Pharmacokinetic studies Careful monitoring of concentrations metabolism of the other toxicity/loss of efficacy • Variable effect on • Compete for metabolic enzymes in and therapeutic drug plasma phenytoin the liver (substrate inhibitors) and monitoring are necessary concentrations thus function as “enzyme inhibitors” whenever regimen of either agent is altered CBZ [2, 4] Lamotrigine • ↓ lamotrigine plasma • Lamotrigine impairs CBZ epoxide • Case series Careful monitoring of concentration clearance • Pharmacokinetic studies toxicity/loss of efficacy • ↑ CBZ epoxide plasma • CBZ induces lamotrigine and therapeutic drug concentrations metabolism monitoring are necessary whenever regimen of either agent is altered CBZ [, TCAs • ↓ plasma TCA • Induction of TCA • Therapeutic drug monitoring • Avoid combination if 2, 5] concentrations CYP450-mediated metabolism by retrospective studies possible. CBZ • Pharmacokinetic studies • Monitor carefully if CBZ regimen is changed. • May require therapeutic drug monitoring of both drugs. • Beware TCA toxicity if CBZ dose is reduced or CBZ therapy is stopped without a reduction in TCA dose. Table 0. Interactions Between Diverse Adjuvant Analgesics Adjuvant Other Adjuvant Interactions Mechanism Evidence Recommendations TCAs []‌ SSRIs, SNRIs ↑ serotonergic effects • Additive serotonergic effects at Reported with • Avoid this combination synapse • Amitriptyline + sertraline if possible • Inhibition of TCA drug metabolism • Imipramine/desipramine + • If must use a TCA, by SSRIs/SNRIs (inhibition of fluvoxamine avoid clomipramine CYP450 isosymes 2D6, A2, 2C9, as it is the most • Clomipramine + fluvoxamine 2C9, 3A4. Note: range of number serotonergic TCA • TCAs + fluvoxamine of isozymes inhibited and potency • If must use a SSRI, of inhibition vary between SSRIs) • TCAs + venlafaxine use citalopram or → ↑ TCA (parent +/− active escitalopram because metabolite) serum concentrations these interact least with → serotonergic effects at synapse CYP450 isozymes TCAs []‌ Phenytoin ↑ plasma phenytoin Unknown • Case report with imipramine Use TCA other than concentrations • No interaction in case imipramine series with nortriptyline and amitriptyline CBZ [2]‌ Valproate • Variable effects • Valproate inhibits CBZ metabolism, • Pharmacokinetic studies Careful monitoring of on plasma CBZ displaces it from plasma protein toxicity/loss of efficacy concentrations binding sites, inhibits CBZ epoxide and therapeutic drug • ↑ plasma CBZ epoxide metabolism monitoring are necessary concentrations • CBZ induces valproate metabolism whenever regimen of either agent is altered • ↓ plasma valproate concentrations

(continued)

133 Chapter 0 Drug-drug Interactions 134 Chapter 0 Drug-drug Interactions

Table 0. Continued Adjuvant Other Adjuvant Interactions Mechanism Evidence Recommendations Lamotrigine Phenytoin • ↓ lamotrigine plasma • Induction of lamotrigine metabolism • Pharmacokinetic studies • Dramatic ↓ lamotrigine [6]‌ concentrations by phenytoin concentration is unlikely • Following lamotrigine plasma concentrations during phenytoin dose titration and subsequent phenytoin dose adjustments is reasonable TCA [7]‌ Venlafaxine • ↑ plasma TCA • Venlafaxine- or duloxetine- • Pharmacokinetic studies Avoid the combination Duloxetine concentrations associated inhibition of by substituting an SSRI CYP2D6-mediated metabolism with minimal CYP450 of TCA. Should preferentially isozyme 2D6—inhibiting affect desipramine, imipramine, potential (eg. citalopram) amitriptyline and doxepin. for venlafaxine/duloxetine and/or substituting a TCA not dependent on CYP450 isozyme 2D6 for its metabolism (eg, nortriptyline). Abbreviations: CBZ, carbamazepine; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. Table 0.2 Interactions Between Adjuvant Analgesics and Other Analgesics Adjuvant Other Analgesic Interactions Mechanism Evidence Recommendations Imipramine [8]‌ ASA • ↑ adverse effects of ASA ↑unbound (free) One case series Transient effect, so monitor for ↑ adverse imipramine, transient plasma concentrations via effects of imipramine at initiation of ASA if adequate renal/ plasma protein displacement hepatic function TCAs [9, 0] NSAIDs ↑ risk of upper Unknown. Possible • Population-based, • Replace TCA by another antidepressant gastrointestinal additive/synergistic case-cohort study with minimal or no serotonergic bleeding antiplatelet effects of TCAs reported ↑ bleeding activity or and NSAIDs risk; however, lower • Replace NSAID by nonacetylated than with SSRI-NSAID salicylate, celecoxib or acetaminophen combinations • If must use a TCA and NSAID, • Another study did not use desipramine, trimipramine, or observe interaction nortriptyline because these are minimally serotonergic CBZ [] Methadone • ↓ methadone plasma • CBZ induces hepatic • Case series of patients • Avoid combination if possible concentrations metabolism of on methadone • If not possible, careful monitoring when • Withdrawal of CBZ methadone maintenance therapy dose of CBZ is altered who experienced → ↑ methadone • Removal of CBZ • Monitor for necessary adjustment opioid withdrawal plasma concentration causes deinduction of of methadone dose after CBZ symptoms after unless methadone methadone metabolism discontinuation dose is decreased back to baseline level introduction of CBZ • Case report of methadone-associated respiratory depression after discontinuation of CBZ

(continued)

135 Chapter 0 Drug-drug Interactions 136 Chapter 0 Drug-drug Interactions

Table 0.2 Continued Adjuvant Other Analgesic Interactions Mechanism Evidence Recommendations CBZ [2] Codeine • ↑ production of • ↑ N-demethylation • Case series of Clinical relevance unknown active codeine pathways of codeine by epileptic patients metabolite, hepatic enzyme-inducing normorphine effects of CBZ→ ↑ urinary excretion of norcodeine while urinary excretion of normorphine is unchanged Lamotrigine [3] Acetaminophen • ↓ lamotrigine plasma • Unknown • Pharmacokinetic • Unclear clinical relevance concentrations studies in eight • Likely clinically relevant only with with initiation of healthy volunteers chronic acetaminophen usage acetaminophen Corticosteroids Phenytoin • ↓ plasma • Phenytoin-associated • Case series • Avoid this combination if possible [4] corticosteroid enhancement of • Pharmacokinetic • May need to ↑ corticosteroid dose by and phenytoin corticosteroid metabolism studies ≥2-fold and phenytoin dose, too, to concentrations (eg, 6--hydroxylation) and compensate for this interaction • Corticosteroid-associated enhancement of phenytoin metabolism (primarily seen with dexamethasone).

Prednisone NSAIDs • ↑ incidence/severity • Additive gastrointestinal • Theoretical • Use local corticosteroids where of NSAID-associated mucosal injury interaction. Few data applicable (topical skin, nasal cavity, and/or corticosteroid- available rectum, lung, eye) and/or associated peptic ulcer • Add peptic ulcer disease prophylaxis disease, gastritis, etc (misoprostol 400–800 mcg/day, standard-dose proton pump inhibitor, double-dose histamine 2 blocker) Duloxetine NSAIDs • ↑ risk of upper • Unknown • Large • Such combination therapy should be Venlafaxine gastrointestinal • Possibly additive platelet population-based, avoided bleeding cohort study SSRIs [9, 0, function inhibition • If cannot be avoided, replace one or 5, 6] • Nested both of the interacting agents: NSAID case-control study with acetaminophen or celecoxib and/ • Meta-analysis of or SSRI/SNRI with noradrenergic TCA observational studies (desipramine, nortriptyline) Bisphosphonates NSAIDs • ↑ risk of gastric ulcer • Additive irritative effects • Open-label study in • Use alternatives for  or both agents. (oral only) on gastric mucosa 26 healthy volunteers • Monitor for gastrointestinal adverse [7, 8] • Retrospective effects. case-control study did • No data supporting efficacy of not find interaction misoprostol, proton pump inhibitor, and histamine H2 blocker prophylaxis with this combination. However, the American Gastroenterological Association does recommend prophylaxis with one of these agents if oral bisphophonate-NSAID therapy must be used concurrently. Adjuvant Other Analgesic Interactions Mechanism Evidence Recommendations CBZ [2] Codeine • ↑ production of • ↑ N-demethylation • Case series of Clinical relevance unknown active codeine pathways of codeine by epileptic patients metabolite, hepatic enzyme-inducing normorphine effects of CBZ→ ↑ urinary excretion of norcodeine while urinary excretion of normorphine is unchanged Lamotrigine [3] Acetaminophen • ↓ lamotrigine plasma • Unknown • Pharmacokinetic • Unclear clinical relevance concentrations studies in eight • Likely clinically relevant only with with initiation of healthy volunteers chronic acetaminophen usage acetaminophen Corticosteroids Phenytoin • ↓ plasma • Phenytoin-associated • Case series • Avoid this combination if possible [4] corticosteroid enhancement of • Pharmacokinetic • May need to ↑ corticosteroid dose by and phenytoin corticosteroid metabolism studies ≥2-fold and phenytoin dose, too, to concentrations (eg, 6--hydroxylation) and compensate for this interaction • Corticosteroid-associated enhancement of phenytoin metabolism (primarily seen with dexamethasone).

(continued)

137 Chapter 0 Drug-drug Interactions 138 Chapter 0 Drug-drug Interactions

Table 0.2 Continued Adjuvant Other Analgesic Interactions Mechanism Evidence Recommendations Serotonergic Tramadol [9–23] • Precipitation of • Additive effects • Several case reports, Substitute a minimal or nonserotonergic antidepressant Tapentadol serotonin syndrome on serotonergic including lethal antidepressant and/or nonserotonergic (SSRIs, (possibly same neurotransmission interaction analgesic. venlafaxine, liabilities as mirtazapine, tramadol) [24] trazodone, Methadone imipramine, [25, 26] clomipramine) Paroxetine and Tramadol • ↓ tramadol efficacy • ↓ generation of active • pharmacokinetic Use antidepressant other inhibitors O-desmethyl metabolite studies that does not inhibit CYP2D6 of CYP2D6 [27] Abbreviations: ASA, aspirin; CBZ, carbamazepine; NSAIDs, nonsteroidal anti-inflammatory drugs; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants. Table 0.3 thorphan Dextrome Fentanyl Methadone Meperidine Tapentadol Tramadol Opioids Nefazodone Trazodone Other ADs Desipramine Doxepin Clomipramine Imipramine Amitriptyline TCAs Duloxetine Venlafaxine SNRIs Citalopram Fluvoxamine Sertraline Paroxetine Fluoxetine SSRIs Release of 5-HT Inhibition d a c

Drugs WhichIncrease Serotonergic Activity Metabolism of 5-HT Inhibition Wort St. John’s Phenelzine promine Tranylcy R Selegiline Moclobemide MAOIs asagiline c Pathway Receptor Postsynaptic Stimulation of Sumatriptan 5-HT Lithium Carbamazepine  agonists 5-HT Release Stimulation of Phenelzine Tranylcypromine R Selegiline Moclobemide MAOIs Cocaine Fenfluramine (ecstacy) MDMA Amphetamine asagiline c b tryptophan 5-Hydroxy Synthesis of 5-HT Stimulation L-tryptophan ( continued

)

139 Chapter 0 Drug-drug Interactions 140 Chapter 0 Drug-drug Interactions fluoxetine metabolite norfluoxetine anditsactive can longproduce very toxicity. such as dispositionhalf-lives agents withlong-terminal Thisiswhy serotonin of may totheonsetbutalso intensity contribute not only to produce serotonin excess, which factors, one mustadd pharmacokinetic tonin toxicity [28]. orsynergistic serotonergictime may leadtoadditive effects, resulting insero administeringtwo serotonergicmacodynamic perspective, drugsatthesame becoming morecontributors important toserotonin toxicity. From aphar addition, theserotonergictramadolandmethadone—are opioids—especially serotonin-active compounds, which are also analgesic compounds. In class of these two classes. The tricyclic antidepressants are the next most important andduloxetine view, venlafaxine only are represented in an analgesicpointof inhibitors andserotonin norepinephrine reuptake inhibitors. Althoughfrom serotonin cases involve selective reuptake tonin syndrome, of the majority in serotonin activity) [28]. amodestconcurrent increase (withonly decreased dopaminergicactivity thepostsynaptic response, and(possibly) of tors, increased sensitivity serotonin recep monoamineoxidase), direct stimulationof inhibition of serotonin inthesynaptic cleft (ie, themetabolismof porter, inhibitionof the serotonin reuptakesis, increased trans serotonin release, inhibition of mechanisms canproduce serotonin syndrome: increased serotonin synthe serotonin-active drugs. Seven system, resulting from theadministrationof a Table 0.3 [Modified from Ref. 28.] d similarities. c b a serotonin norepinephrine reuptake inhibitors;TCAs, tricyclic antidepressants. serotoninMDMA, methylenedioxymethamphetamine; SSRI,selective reuptake SNRIs, inhibitor; Abbreviations: ADs, antidepressants; 5-HT, serotonin; MAOIs, monoamineoxidase inhibitors; Wort St. John’s Cocaine Amphetamine Others Release of 5-HT Inhibition Presumably similar to immediately preceding agentbasedonstructuralandpharmacological similartoimmediately Presumably From synapse. And congeners andalfentanil. such assufentanil From terminals. nerve predictable In addition to the pharmacodynamic mechanisms thatcausetheseagents In additiontothepharmacodynamic sero beenimplicatedintheprecipitationAlthough many drugshave of a Continued consequence Metabolism of 5-HT Inhibition of Pathway Receptor Postsynaptic Stimulation of

serotonergic excess 5-HT Release Stimulation of in the central b Synthesis of 5-HT Stimulation nervous ------

serotonin-active drug be started. This is also why the addition of adruginhib theadditionof Thisisalsowhy serotonin-active drugbestarted. serotonin excess shouldanother afterdrugcessation, risk,even of periods of their pharmacology/pharmacokinetics/pharmacodynamics, which, inturn, their pharmacology/pharmacokinetics/pharmacodynamics, oversight regulatory withrespect to with thelattermedications isthelack of or drugswith herbal ever-increasing interest isthe interactionof An area of metabolites. CYP450 isozyme 2D6. Finally, both are desmethyl metabolized to active and norepinephrine. metabolismvia Fourth,both undergo enantioselective serotonin (nausea, headache, dizziness).Third, both inhibitthereuptake of lar orientations).Second, they thesameprominent have effects adverse may assume near-superimposableintermolecu (groups clohexyl groups hasmethoxyphenyl, are great: each may explainthefindingsjustdescribed. First,thestructuralsimilarities venlafaxine [9]. serotonergicfor combinations, eithertramadolor thoseinvolving especially remainder (≤.47).Thedatafrom thisreportsubstantiatethelethal potential Tramadol scored 0.5followed by ecstasy (4.57),fluoxetine (3.02),andthe theseagentsinAustralia over the2002–2008datacollection period. tion of in the23caseswere calculated annualdrugconsump by adjustingfor theseserotonergic agents respectively. prevalences Inaddition,therelative of plusatricyclic antidepressant present, (amitriptyline) andvenlafaxine four) plusanopioid(tramadolinone, methadonein one subjecthadvenlafaxine were involved recipients, in six cases each. Among the six and venlafaxine five two or more potential analgesic agents were Tramadol found. and venlafaxine drome contributed tohave andbelieved tothesubjects’ death.Incases, serotonin syn of whichsigns orsymptoms was suggestive antemortem, (ecstasy). Although 23 such deaths were in 28 cases there found, were madol, serotonergic thefollowing drugswere atautopsy: tra found one ormore of Tables 0.relevant sections of and 0.2. response may leadtoenhanced drugmetabolism andareduction indrug(ie,analgesic) an“enzymestimulant” tramadol, codeine). Inother cases, theadditionof metabolite (eg, anactive it results in reduced generation of if analgesic effect supervenes.ity In other cases, enzyme inhibition will lead to a reduction in other (serotonergic) drug,causing drugaccumulation untilserotonin toxic the these“enzymeinhibitors” willleadtoareduction inmetabolismof one of drug-metabolizingenzymes. Additionof of P450family thecytochrome of tonin toxicity. There are many agentsthatcaninhibitoneormore isozymes precipitate a serotonin-active drug may sero actually iting the metabolism of complementary andalternativecomplementary medications Drug-drug interactions involving herbalsor

There that aresimilaritiesbetween tramadolandvenlafaxine striking deaths from 2002 to 2008, wherein A survey was conducted in Australia of complementary venlafaxine,

[28].

More fluoxetine, and details alternative

regarding sertraline, medications N,N serotonin citalopram, -dimethylamino, andhydroxycy (CAMs). toxicity paroxetine,

are

A major available and problem MDMA

the ------

141 Chapter 0 Drug-drug Interactions 142 Chapter 0 Drug-drug Interactions

Table 0.4 Interactions Between Herbals and Analgesics Herbal Analgesic Interactions Mechanism Evidence Recommendations Garlic [29] Acetaminophen ↑ exposure to acetaminophen and its Unknown Pharmacokinetic study Unlikely to be clinically glucuronide metabolite significant Garlic [30] NSAIDs Possible ↑ bleeding risk Garlic ↓ platelet Theoretical assumption without clinical Likely clinically relevant aggregation as do data of effect of combination of only with excessive NSAIDs garlic-NSAIDs on bleeding risk doses of garlic Gingko [3] Aspirin No additive effects occur for the combination Randomized controlled trial No interaction of ginkgo 300 mg daily and aspirin 325 mg daily over 2 weeks in terms of clotting time or platelet aggregation. Gingko [32] Ibuprofen Possible ↑ bleeding risk One case report of fatal intracerebral No clear evidence of bleed interaction Gingko [33] Anticonvulsants ↓ plasma concentrations of anticonvulsants CYP2C9 One case report of fatal seizure in one No clear evidence of metabolised by induction by patient on stable doses of phenytoin interaction CYP2C9 gingko and valproate who started gingko St. John’s Amitriptyline ↓ systemic exposure to amitriptyline and its Induction of Crossover trial evaluating plasma Monitor therapeutic Wort [34] active metabolite nortriptyline CYP3A4 and/or concentrations of amitriptyline and response P-gp by St. John’s nortriptyline with/without concurrent Wort St. John’s Wort St. John’s Venlafaxine Precipitation of serotonin syndrome Unknown. Case report of serotonin syndrome No clear interaction or Wort [35] No causality in patient on venlafaxine who started causality established. St. John’s Wort, resolved after discontinuation St. John’s Methadone ↓ plasma concentrations of methadone Induction of Pharmacokinetic study in 4 patients Monitor therapeutic Wort [36] CYP3A4 and/or response. Beware P-gp by St. John’s opioid withdrawal Wort signs/symptoms Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; P-gp, P-glycoprotein.

potential. It is only through thecasereportmechanismpotential. thatdrug-druginter Itisonly drug-druginteraction may not allow thepractitionertomake predictions of 5. 4. Malminiemi 3. 2. Ramsey . References relevant, to increasedavoid clinically toxicity or decreased efficacy. takealways into account potential the most drug-drug interactions, especially When CYP450 • carbamazepine • two • oral • tricyclic • significance.following: These include the highpotential clinical Tables 0., aretobeof likely afew 0.2,and0.4,only in adjuvant analgesicsreviewed alldrug-druginteractions involving Of [29–36]. effects important cally can seefrom clini Table 0.4, thesedrug-druginteractionscanhave someof miology investigate capitalized themechanisms to andepide not sufficiently generally theseproducts are actions may of come tolight.Inaddition,manufacturers Summary

Psychopharmacol 99; :33–38. pine on serum antidepressant concentrations in psychiatric patients. J Clin Leinonen E,LillsundeP, LaukkanenV, YlitaloP. carbamaze of Effects 2000; 38:540–545. carbamazepine. IntJClin Pharmacol Ther treatment of onpharmacokinetics 38:46–50. serum concentration andreduces clearance. 988; phenytoin Neurology Carbamazepine increasesBrowne phenytoin TR, Szabo Evans GK, J E, et al. 2:235–24. humans: effect actions updated. Br J Pharmacol 2007; 5:737–748. Gilman PK.Tricyclic andtherapeutics: drug antidepressant pharmacology inter tramadol is initiated or discontinued CYP 450hepaticenzymes: variable plasmaconcentrations whenonedrug serotonin syndrome and its congeners): riskfentanyl of and serotonergic opioids(tramadol/tapentadol,methadone,meperidine, nergic analgesicssuch astricyclic antidepressants, duloxetine, venlafaxine, biphosphonate aluminium): malabsorption of antiplatelet effects tinal bleeding due to additive uppergastrointes drugs: increased riskof nonsteroidal anti-inflammatory adding bisphosphonates or of more RE,

antidepressants/venlafaxine/duloxetine/oral drug-drug isozyme an K, McManus drug Keranen adjuvant of or

concurrent combinations phenytoin 2D6 interactions DQ, + T, analgesic multivalent inhibitors Kerrtula Gutterman anticonvulsant + with other to of T,

a cations serotonergic + et al. their A, pharmaceutical rmdl decreased tramadol: analgesics/agents et al. Effects herbal/CAM therapy. (eg, Carbamazepine calcium, of agents,

Ther short-term regimen, bisphosphonates products. Drug magnesium, including metabolized metabolism Monit efficacy one lamotrigine seroto As should 990; iron, one by of + in ------

143 Chapter 0 Drug-drug Interactions 144 Chapter 0 Drug-drug Interactions 0. De 9. Dalton Patroneva 7. 6. Wolf 23. Ripple 22. 2. 20. Mittino 9. 8. Etminan 7. Graham 6. Loke 5. 4. Wong 3. Depot 2. Yue . Benitez-Rosario 8. interactions with traditional antiepileptic drugs. J oulihan DJ. Serotonin syndrome resulting from coadministration of trama oulihan DJ.Serotonin syndrome resulting from coadministration of H , Flores-Perez J, Asseff IL. Clinical evidence of Juarez-Olguinevidence of IL.Clinical H,Jung-CookFlores-Perez J,Asseff 2:370–374. dol J Am serotonin syndromedepressants going undetected? andopioidanalgesics: is Gnanadesigan N,Espinoza R Ann Pharmacother 2004; 38:4–43. and mirtazapine. dol, venlafaxine, combination.tramadol-sertraline Clin Neuropharmacol 2004; 27:50–5. drugs. Forensic Sci Int 200; 98:0–7. JL,Gerostamoulos D,Pilgrim serotonergic DrummerOH.Deathsinvolving drugs: a case-control study. Aliment Pharmacol Ther 2009; 29:88–92. tinal bleedingwithoralbisphosphonatesandnonsteroidal anti-inflammatory opment drugs. Aliment Pharmacol Ther 2008; 27:3–40. anti-inflammatory serotonininteraction between selective reuptake inhibitorsandnon-steroidal acid-suppressing agents. Arch Gen Psychiatry 2008; 65:795–803. of therapy: drugsandeffect interactionwithnonsteroidal anti-inflammatory serotonining associated withselective reuptake inhibitorsandvenlafaxine deAbajo FJ, Garcia- possible Ther 990; 48:346–355. lamotrigine. ClinPharmacol oraldoseof acetaminophen onasingle doses of 4:93–98. codeine inman.Pharmacogenetics994; themetabolismof differentially pine Methadone-induced ing: population-based serotonintive reuptake inhibitorsanduppergastrointestinal tractbleed population-based a uppergastrointestinal tractbleeding: reuptake inhibitorsandriskof in depressed patients. Clin Neuropharmacol 2002; 25:32–36. an interaction between acid imipramine on and proteinacetylsalicylic binding 2008; 36:2484–249. of andduloxetine desvenlafaxine onthepharmacokinetics of effect actions: the

the Abajo

and

P. QY, administration. Med YK, Lamotrigine: preliminary DD, CYP MG, M, SO, multiple of drug-drug DY, M, D, Tomson Trivedi Powell Dir FJ,

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32:99–00. Risk discontinuing cigarette 39:06–09. on are of combination effects 63:59–64. pharmacokinetics of

synergistic Drug selective

of upper Med associated

drug-drug smoking bleeding of between E, Metab

Pathol multiple carbamaze gastrointes Feria serotonin for of

Dispos trama induce due devel selec 2000; inter with oral and M. to ------

24. 36. Eich-Hochli 35. 34. 33. 32. Meisel 3. 30. 29. Gwilt 28. 27. 26. 25.

Ortho-McNeil Anonymous. Tapentadol R prescribing (Nucynta) information. and St. John’s wort: a case report. Pharmacopsychiatry 2003; 36:35–37. Presse Prost N,Tichadou L,R ( anditsmetabolitesoncomedicationtyline withanextractfrom St.John’s wort amitrip Johne A,Schmider J,Brockmoller Decreased J,et al. of plasmalevels Ginkgo biloba. J Anal Toxicol 2005; 29:755–758. Kupiec T, R Ginkgo biloba and ibuprofen. Atherosclerosis 2003; 67:367. 2007; 8:787–793. Coagul Fibrinolysis randomized clinical trial.Blood cardiovascularadults atriskfor disease: a aspirin amongon platelet older and aggregation platelet function 76) and Ginkgo biloba(EGb of Effect Gardner CD, Zehnder JL,Rigby AJ,et al. drug Borrelli F, CapassoR,Izzo AA.Garlic( 3:55–60. acetaminophen. Cancer E metabolism of Med drug metabolism,response, interactions, effects. andadverse Forensic Sci on serotonergiccytochrome P450polymorphisms of theeffect aspects of JL,Gerostamoulos D,Pilgrim DrummerOH.R tramadol. Clin Pharmacol Ther 2005; 77:32–323. of effect the hypoalgesic 2D6 inhibitor, diminishesthestereoselective EnggaardLaugesen S, TP, Pedersen Paroxetine, et al. RS, P450 acytochrome human hepatic cytochrome p450 3a4. Toxicologystrates of 997; 7:3–23. Dreano C, Y, methadonewithsub Iribarne Interactionof Bardou LG, et al. lizers. J Clin Psychopharmacol 2002; 22:2–25. butnot poormetabo extensive (r)—methadone incyp2d6 concentrations of von Bardeleben S, U,Begre D, Ladewig et al. Paroxetine increases steady-state Hypericum perforatum Pathol interactions PR, Med C, Lear Johne 20; aj V. Fatalseizures duetopotential herb-druginteractionswith D, 2000; Oppliger Janssen; CL, A, in 7:62–84. 29:285–286. Tempero Roots humans. ). J Clin Psychopharmacol 2002; 22:46–54. July 20. odor F. St.Johnswort-venlafaxine interaction. et al. R, I. Golay Fatal Mol MA, Nutr KP, intracerebral et al. et al. Food Allium sativum The Methadone pidemiol Biomarkers Prev 994; effect Res O mass -demethylation andreduces-demethylation 2007; of ve: pharmacogenetic eview: bleeding

L.): adverse effects and effects L.): adverse garlic maintenance 5:386–397. extract associated aritan, NJ; on treatment human with - - -

145 Chapter 0 Drug-drug Interactions

α Adjuvant medicine(s), Adjuvant drug(s), definition Adjuvant analgesic(s) Acute 20 pain service, Acetaminophen, 9 A Note: Page numbers followed by 2 -Adrenergic agonists, 7 dosage and administration cancer pain, for 96 and side effects adverse on WHO analgesic/pain and other analgesics, neuropathicfor pain, 7, 7 musculoskeletalfor pain, multipurpose, 7, 7 5 definition of, classification of, by clinical bowelfor obstruction, bone pain, 7, 7 for pain, 2 postoperative for and opioids, combination in multimodal analgesia, toxicity 3 liver of, lamotrigine and, drug-drug intravenous, 2 indications for, 3, 6, 6 garlic and, interactions dosage and administration and side effects adverse dosage and of, 99 of, 99–00 00 of, effects 5 definition of, 5 of, ladder, 2, 2 35 interactions, drug-drug 7, 7 efficacy, 7, 7 7, 7 27 administration of, therapy with, 2 2 interactions, 36 between, 42 3, 2 of, 3 of, effects Index t t t t –38 t t t t t f t , 6, 6 , t t t , 8 t t t t t American Society of American Society of Amantadine , 79 Allodynia, Allergic reaction(s), 6, 8 α α Amitriptyline,  Amitriptyline, f 2  and -Adrenergic receptor(s), -Adrenergic receptor(s), mechanism of action mechanism of cancer-relatedfor cancer pain, for 96 opioids intraoperative 59–60 definition of, 55 to methylparabene, 55 to local anesthetic, action mechanism of for postmastectomy for neurotransmitter profile neuropathicfor pain, 4, action mechanism of lowfor back pain, 6 headache, 5–7 for 2 of, half-life fibromyalgia,for 5, 7, of, 4 efficacy dosage and administration cancer pain, for 88, 96 pain, 6 arthritis for and side effects adverse placebo-controlled t indicate figures and tables, respectively. in perioperative in perioperative pain management acute guidelines for Anesthesiologists, 63 of, 02 neuropathic pain, and, 60–6 as drug targets, 9 as drug targets, 9 0 of, pain, 88 2 of, 3 trials of, 7, 80, 8 8 of, 0 2 of, 97–98 2 of, effects setting, 9, 26 t t t t t , 8, 80, 8 t , 88 t t t , 8 t , t t t t Analgesic(s) Amphetamines, and Anticholinergics, 7 Antibiotic(s), drug 7 Antiarrhythmics, Anorexia, AIDS-related, Ankylosing spondylitis, pain Anandamide, 35 mechanistic taxonomy of, classification of and, drug-drug venlafaxine topical, 2 drug-drug and sertraline, and serotonergic activity, St. John's and, wort precautions with, 8 for cancer pain, for 97 drug interactions with, 8 topical. serotonergic, 3–4, cancer multipurpose, for by therapeutic class, by pain severity, 5–6, 6 mechanistic approaches by clinical efficacy, 5, dosage and 5, 6 8 for, 5, 6 6 activity, 39 serotonergic interactions, 4 interactions, 32 39 between, 42 interactions of, 99 of, administration 8 interactions with, for, 34 cannabinoids 6 of, treatmentof, analgesics 39 97–00, 99 pain, 95–96, 96 8, 9 See t t –9 , 7, 7 Topical t t t t –0 , 7 t t f t t t t t , 7–8, t t t –40 t t t , t t t

147 148 Index Antidepressant(s), 5–7, 7 Anticonvulsant(s), 5–7. Anticholinergics serotonergic rheumatic pain, 09 for precautions with,  pain, postoperative for patient education about, neuropathicfor pain, therapy monitoring of action of, mechanism of lowfor back pain, 6 indications for, 8 headache, 5–6 for fibromyalgia,for 5, 08, drug interactions with, 8 dosage and administration contraindications to, in combination therapy, 9 chronicfor noncancer pain cancer pain, for 96 baseline tests with, 8 effects anti-inflammatory of, analgesic effects and side effects adverse rheumatic pain, 09 for neuropathicfor pain, 86 action mechanism of indications for, 8 fibromyalgia,for 08–0, cancer pain, for 96 of, 2 analgesic efficacy cancer-relatedfor bowel and methadone, dosage and cancer-related, 0 6–7 selection of, randomized controlled cancer-related, 0 interactions, 38 drug-drug 0 27 administration of, 24 8 4–5 with, 8–9 0 09 8–9 of, 7–8 –7 trials of, 97–98, 99 0 of, 3–4 action of, mechanism of 2 of, effects also 2 of, 09 also obstruction, 03

t t t specific drug specific drug (Cont.) t t t t t , t t See , 6 . See See t t , t Atropine, cancer pain, for pain, . Arthritis local Arrhythmia(s), Anxiety, improvement Antispasmodics, indications Antiretrovirals, drug Antipsychotics, drug Anti-Parkinsonian drugs, 3 Antinociceptive analgesics, 9 9 Antihyperalgesics, drug interactions Antifungals, Bisphosphonates, 5–6, 7 7 Baclofen, B treatment 6–7 of, for,mirtazapine 98 drugs for, 8 and modulators of oral action of, mechanism of cancer-relatedfor bone cancer pain, for 97 and effects adverse cancer-relatedfor cancer pain, for 97 and tramadol, and tapentadol, and NSAIDs, drug-drug and multivalent arthritis (RA) arthritis Rheumatoid Osteoarthritis; arthritis; Inflammatory induced, 53–55 anesthetic- for, 8 8 interactions with, 8 interactions with, mixed, 0 excitation, inhibition/ descending with, 8 interactions, 38 drug-drug interactions, 38 drug-drug 43 interactions, 37 interactions, 43 cations, drug-drug 0 pain, 02–03 02–03 of, side effects 02 neuropathic pain, 97 t t t , 02 t t –82 See also t t t

t t

t t t , t Botulinum toxin A type Bone pain Bupivacaine, 52 Bupivacaine, Bowel obstruction pain for rheumatic pain, 2 for neuropathicfor pain, 89 treatment 7, 7 of, cancer-related adjuvant analgesics for, precautions with, for postoperative pain, postoperative for 50, of, pharmacology action, 52 onset of molecular structure of, dose maximum daily action, 52 duration of 52 of, analgesic potency treatment 7, 7 of, cancer-related analgesics used for, 97 zolendronate for, treatment 02–03 of, strontium-89 for, 97 samarium-53 for, 97 radiopharmaceuticals pamidronate for, osteoclast inhibitor for, monoclonal antibody ibandronate for, corticosteroids for, clodronate for, dosage and calcitonin for, 97 bisphosphonates for, analgesics used for, 97 treatment 03–04 of, corticosteroids for, analgesics used for, 97 dosage and 02–03 7, 7 02–03 of, 27 of, administration dosage and 52 50–5, 5 55 of, 98–99 99 of, administration 02–03 03 03 for, 97 02–03 02–03 for, 02–03 02–03 98–99 02–03 99 of, administration t , 54 t t t t t f t , 03 t t f t t , 03 t t

t , t t t t , Bupropion Cancer pain Camphor, 76 Calcium channels, as N-type, Calcium-channel blockers, Calcium channel Calcitonin, 7 C Bursa block, 48 for cancer pain, for 96 clonazepam for, 97 citalopram for, 96 carbamazepine for, 96 cannabinoids for, 34 bupropion for, 96 bisphosphonates for, 97 for,baclofen 97 atropine for, 97 antidepressants for, 96 anticonvulsants for, 96 anticholinergics for, 97 for,amitriptyline 88, 96 amantadine for, 96 α adjuvant analgesics precautions with, 82 neuropathicfor pain, action of, mechanism of dosage and administration and side effects adverse action mechanism of cancer-relatedfor bone neuropathicfor pain, 4 contraindications to, 6 2 -adrenergic agonists for, dosage and dosage and dosage and dosage and of, 00 of, administration 96 97–98, 99 99 of, administration 97–98 99 of, administration 96 96 used for, 95–96, drug targets, 9 with, 8 drug interactions 82 82 82 of, 82 of, effects 0 of, 99 of, administration pain, 97 t t t t t t , 99–00 –97 , 84 , 84 , 00 t t t t t t , 84 α t t t t 2 , 03 d t t t ligands , 98 t t t , 98 t t t , 39, t t t t t t , , t mexiletine for, 96 for,methylprednisone 96 for,methylprednisolone memantine for, 96 local anesthetics for, 96 lamotrigine for, 96 lacosamide for, 96 ketamine for, 65, 96 lidocaine intravenous ibandronate for, 97 glycopyrrolate for, 97 gabapentin for, 96 GABA agonists for, 97 duloxetine for, 96 dronabinol for, 39, 96 for,divalproex 96 dextromethorphan for, dexamethasone for, 96 for,desvenlafaxine 96 desipramine for, 96 corticosteroids for, clonidine for, 96 oxcarbazepine for, 96 osteoclast inhibitors for, opioids for, 95 octreotide for, 97 NSAIDs for, 97 for,nortriptyline 96 NMDA receptor blockers neuropathic. nabiximols for, 96 nabilone for, 96 multipurpose analgesics milnacipran for, 96 dosage and dosage and dosage and dosage and dosage and 98–99 for, 96 99 of, administration 00 96 99, 99 administration of, 98–99 97–98 99, 99 administration of, 96 of, 99 of, administration 97 99 of, administration for, 96 (antagonists) cancer-related Neuropathic pain, 97–00, 99 for, 95–96, 96 t t t –97 See t t t t t t t t t , 98–99 t t , 00

, 99–00 t t t t t t t t t , 00 t t t t t t , t t t t t t , , t t , t Cannabinoids, 7 Cannabinoid receptor, Cannabigerol, 33 Cannabidiol, 33. Cannabichromene, 33 Cancer treatment, local topical tricyclic topical NSAIDs for, 96 topical capsaicin for, 96 topical analgesics for, 96 tizanidine for, 96 SSRIs for, 96 somatostatin analog for, sodium channel sodium channel blockers SNRIs for, 96 scopolamine for, 97 95 prevalence of, pregabalin for, 96 prednisone for, 96 for,phenytoin 96 paroxetine for, 96 pamidronate for, 97 for AIDS-relatedfor and side effects adverse as adjuvant analgesics, acute pain, 36 for zolendronate for, 97 for,venlafaxine 96 95 undertreatment of, tricyclic antidepressants treatment 2–3, 2 of, topiramate for, 96 dosage and dosage and dosage and dosage and for, 96 antidepressants 00 00 99 of, administration 99 of, administration 97 96 modulators for, for, 96 99, 99 administration of, 98–99 99 of, administration anorexia, 34 4 39–40, of, effects 40–42 33–36, 35 Cannabinoids 49 anesthetics and, for, 96 t t t , 90,  t t t t t t t , 97–98 t t t , 9 See also , 97–98 t t t , 99–00 t f t t t t , 98 , t t t f t , 95

t t , t ,

149 Index 150 Index Cannabinoids Capsaicin Cannabis. Cannabinol, 33 Cannabinoid system, 33–36, patch, 75 9 molecular target of, action of, mechanism of spinal cordfor injury, 37 and sleep quality, 37–38 rheumatoid arthritis, for rheumatic pain, 09 for precautions with, 90 oromucosal, for and opioids neuropathicfor pain, 5, nausea and vomiting,for musculoskeletalfor pain, multiple sclerosis,for 34 action of, mechanism of indications for, 8 HIV-relatedfor fibromyalgia,for 38–39, dependence, 40, 4 chronicfor pain, 34 cancer pain, for 34 medical for available 37 of, effects anxiolytic of, antispasmodic effects of, analgesic efficacy dosage and and side effects adverse 40 interactions of, combination therapy dosage and of, 83 of, administration 83 of, effects 2 0 cannabis) (marijuana, 35 38,  89–90 neuropathic pain, with, 40 34 chemotherapy, 34 in cancer 38,  37–38  36–37 neuropathy, 09 36–39 00 of, administration 96 practice, 33, 34 37–38 40–42 See t f t t , 75, 83 , 36–37 , 00 Marihuana t (Cont.) ,  t t t t , 85, , 39, t t , , 90 t t t t t , t Carbamazepine, 23, 86 Central sensitization, 8, Celecoxib, postoperative for Causalgia, 8 Cauda equina syndrome, Catastrophizing, and Cardiac arrest, local and phenytoin, drug-drug and phenytoin, 9 molecular target of, and methadone, action of, mechanism of and lamotrigine, drug-drug dosage and administration contraindications to, 24 and codeine, drug-drug cancer pain, for 96 of, 2 analgesic efficacy and side effects adverse topical, 75–76 and valproate, drug-drug trigeminal neuralgia, for and TCAs, drug-drug and serotonergic activity, precautions with, 24 for rheumatic pain, for HIV-relatedfor in combination therapy, cancer pain, for 96 and effects adverse neuropathicfor pain, HIV-relatedfor interactions, 33 interactions, 35 drug-drug 0 interactions, 33 24 of, interactions, 36 23, 24 of, effects 09 75–76, 85–86 neuropathy, 76 00 75–76, 86 of, side effects 7, 83 83 neuropathy, 9 27 administration of, pain, dosage and induced, 53–55 local anesthetic- pain, 90 neuropathic induced, 53–55 anesthetic- interactions, 32 23, 86 interactions, 33 39 t t , 9 t t , 24 , 88 t t t , 2 t t t , 85–86 t

t t t , t t t t t t t t

Clomipramine Clodronate, for Citalopram Cisplatin neuropathy, 4–5 Cisapride, drug interactions 3 Chondroitin sulfate, Chloroprocaine Chemotherapy Cesamet. Clonazepam, 28 adverse effects and side effects adverse and serotonin syndrome, and serotonergic activity, neuropathicfor pain, 4 fibromyalgia,for 5 cancer pain, for 96 effects anti-inflammatory 50, 52 of, pharmacology action, 52 onset of action, 52 duration of 52 of, analgesic potency caused byneuropathy nausea and vomiting opioids intraoperative 59–60 of, evaluation for cancer pain, for 97 and tramadol, drug-drug and tapentadol, and serotonergic activity, neurotransmitter profile neuropathicfor pain, and methadone, 2 of, half-life and fluvoxamine, dosage and administration pregabalin for, 0 80, 98 management of, gabapentin for, 0 for, 34 cannabinoids related to, and, 60–6 interactions, 38 interactions, 38 drug-drug 39 2 of, 3 of, controlled trials placebo- interactions, 38 drug-drug interactions, 32 drug-drug 2 of, 2 of, effects 02–03 bone pain, cancer-related 4 39 0 of, with, 8 See Nabilone t t t t t t t t t t t t t t t t t t Counterirritants Corticosteroid(s), 7 Constipation, drugs causing, Complex regional pain and Complementary Cognitive-behavioral Coeliac block, 2 Codeine, 6, 6 Cocaine Coanalgesics, 6 Clonidine for cancer-relatedfor for rheumatic pain, 2 for action of, mechanism of soft-tissue injections, 2 and phenytoin, and opioids, combination local injection, for joint injections, 2 intralesional injections, injections,intra-articular cancer pain, for 96 and side effects adverse rheumaticdisease,3 for and analgesics, carbamazepine and, and serotonergic activity, 50 of, pharmacology dose maximum daily 5 definition of, 9 molecular target of, cancer pain, for 96 and side effects adverse dosage and 2 interactions, 36 drug-drug therapy with, 98 2 rheumatic pain, 2 2 99, 99 administration of, 98–99 98 of, effects 2 treatment 22 of, syndrome, 4–43, 42 between, interactions medicine (CAM) alternative therapy,  interactions, 36 drug-drug 39 55 of, 99–00 00 of, effects 02 neuropathic pain, t , 8 t t –40 t t t t t t –97 , t t t , t t D Cytochrome P450 Cystitis, 8 Cymbalta. Cyclooxygenase-2 (CO Coxibs, 9 Desipramine,  Depression Denosumab, prevention for and drug-drug and drug-drug CYP2D6 CYP2C9, anticonvulsants pain, postoperative for indications for, 3 contraindications to, 22 and effects adverse for neuropathicfor pain, action mechanism of 2 of, half-life and fluvoxamine, of, 4 efficacy dosage and administration cancer pain, for 96 and side effects adverse for,mirtazapine 98 drugs for, 8 and venlafaxine and venlafaxine and tramadol inhibitors and tramadol, and TCAs, drug-drug t t 43 interactions, 4, metabolism, 4 metabolism, 4 43 interactions, 38 drug-drug interactions, 34 gingko, 42 interactions with metabolized by, 2–22 2–22 of, side effects inhibitors, 9 (CO Cyclooxygenase-2 See also 4, 8 8 of, interactions, 32 drug-drug 2 of, 97–98 2 of, effects Antidepressant(s) 03 prostate cancer, complications in skeletal of , 2–22. See Duloxetine X2) inhibitors t . t t t t , 8 See also

t t t t , t X2) , 8

t t t , t Diabetic neuropathy, painful, Dextromethorphan, 63 Dexamethasone cancer for Desvenlafaxine, Divalproex. Divalproex. therapy,Dietary for Diclofenac drugs causing, 2 Diarrhea, treatment 22–23, 27, of, tramadol for, 83 topical lidocaine for, 74 topical capsaicin for, pregabalin for, 22, 82 opioid agonists for, 83 gabapentin for, 22, 82 duloxetine for, 8 combination therapy and serotonergic activity, 9 molecular target of, cancer-relatedfor cancer pain, for 96 pain emergencies,for 99 cancer pain, for 96 and serotonergic activity, precautions with, 8 neurotransmitter profile topical patch, 72 72 action of, mechanism of for,venlafaxine 8 tricyclic antidepressants dosage and placebo-controlled solution, with DMSO, gel, 72 and side effects adverse randomized randomized 75–76 85 for, 89 4–5, 7, 79–86 39 02 neuropathic pain, 99, 99 administration of, 98–99 pain, 96 39 2 of, 3 trials of, divalproex 3 rheumatic pain, 72–74, 73 of, controlled trials 72 72–74, 73 of, controlled trials 72–73 of, effects for, 8 86, 88–89 See also t t t t t t t , 84 Sodium t t t t t , t t t t t t t , t

151 Index 152 Index Doxepin Douleur Neuropathique Dopaminergic agents, 3 Dolasetron, fibromyalgia, for Duloxetine, 5,  mouth, drugs causing, Dry Drug-drug interactions. Drowsiness, drugs causing, 8 Dronabinol, 36 Divalproex Divalproex for neuropathicfor pain, 4, action mechanism of lowfor back pain, 07, 2 of, half-life fibromyalgia,for 5, 7, dosage and administration central neuropathicfor cancer pain, for 96 and side effects adverse factors of, severity 3 pharmacogenetics of, between herbals and with antidepressants, 8 between adjuvant MS-associated pain,38 for indications for, 34 fibromyalgia,for 38 dosage and administration chronicfor pain, 40 cancer pain, for 39, 96 and serotonergic activity, neurotransmitter profile lowfor back pain, 6 2 of, half-life dosage and administration and side effects adverse cancer pain, for 96 and other analgesics, 7, 80–84, 8 8 of, 0 07, 09 0 2 of, pain, 88 2 of, effects 2 3 affecting, 4–43, 42 analgesics, 35 32 analgesics, 3, also 34 of, 00 39 2 of, 2 of, 2 of, effects (DN4), 79 en 4 questions 3 (Cont.) t , 8

t t t specific drug –38 –34 t t t t t t t , 80, 8 t t t t t t t t , 8 t t See t , 86 , t , t Epidural block, 3, 24, 25 Endocannabinoid system, Effexor. E E E Fenfluramine, and Femoral block, nerve 48–49 Felbamate, 28 Failed back syndrome, 88 Facial pain, 4 F Exercise, in pan Excitation, descending, Regional European Society of 76 Eucalyptol, Etidocaine neuropathic Escitalopram, for ctopic discharge, 8, 9 cstasy (drug) and patient-controlled and serotonin syndrome, and serotonergic activity, and serotonin and serotonergic precautions with, 8 pain, postoperative for oxaliplatin-inducedfor and other serotonergic pain, osteoarthritis for and NSAIDs, drug-drug neurotransmitter profile pharmacology of, 52 of, pharmacology action, 52 onset of action, 52 duration of 52 of, analgesic potency See comparison of, analgesia, 33–36, 35 4 39 syndrome, 40 activity, 39 27 administration of, dosage and neuropathy, 98 peripheral interactions, 43 agents, drug-drug 07 43 interactions, 37 2 of, activity, 39 serotonergic management,  9 modulators of, Anaesthesia, 26 pain, 4 24, 25 Venlafaxine t t t

f t t t t t t t t t t t , Fibromyalgia, 8 Fentanyl Fluoxetine Flecainide, 49 nabilone for, 38, 09 monoamine oxidase moclobemide for, 5, 7 milnacipran for, 5, 7, gabapentinoids for, gabapentin for, 22, fluoxetinefor, 5 duloxetine for, 5, 7, dronabinol for, 38 dolasetron for, 3 citalopram for, 5 cannabinoids for, 38–39, antidepressants for, 5, anticonvulsants for, for,amitriptyline 5, 7, and serotonergic activity, in patient-controlled and other serotonergic intranasal administration indications for, 6, 6 and serotonin syndrome, and serotonergic activity, fibromyalgia,for 5 effects anti-inflammatory tricyclic antidepressants treatment 5, 7, of, SSRIs for, 5, 7, 09 SNRIs for, 5, 7, 09 pregabalin for, 22–23, pramipexole for, 3 pirindole for, 5, 7 of, pathophysiology paroxetine for, 5 for,nortriptyline 0 analgesia, 22 interactions, 43 agents, drug-drug 22 of, 40–4 39 0 of, for, 7, 09 2–23, 27, 07 0 07–0, 09 07–08  5, 7 (MAOIs) for, inhibitors 07, 09 08–0 08–0, 09 07, 09 09 08, 09 08–0, 09 0 39 t t t ,  t , , 4 t t t t t , 0 t t t t t , t , Fluvoxamine Gabapentin, 2–23, 74 G clomipramine and, immediate-release and imipramine, gastroretentive fibromyalgia,for 22, and dosage and administration diabetic neuropathy,for chronicfor noncancer cancer pain, for 96 of, 2 analgesic efficacy and side effects adverse tricyclic antidepressants and serotonergic activity, imipramine and, desipramine and, contraindications to, and side effects adverse precautions with, 24 postherpetic for action mechanism of dosage and contraindications to, and side effects adverse 24 perioperative, EMLA cream, 24 24 of, effects 0 neuropathic pain, cancer-related therapy with, for combination neuralgia, 22 24 of, 22, 24 administration of, 24 24 of, effects 22 of, formulation 08–0, 09 cancer-related, 0 neuropathic pain, therapy with, for combination 2–22, 82 of, 22, 82 pain, 7 23, 82 of, effects 34 interactions, 32 and, drug-drug 39 interactions, 32 drug-drug interactions, 32 drug-drug interactions, 32 drug-drug t t t t t t t t t t t t , 84 t t t t t t , Gabapentinoids, 5, 7 Gabapentin enacarbil, 22 for postherpetic neuralgia, for 2–22 of, pharmacology and oxycodone, and opioids, combination and nortriptyline, neuropathicfor pain, 5, and morphine, combination 9 molecular target of, action of, mechanism of indications for, 22 for chronicfor noncancer of, 2 analgesic efficacy and side effects adverse precautions with, 24 action mechanism of dosage and administration contraindications to, 24 and side effects adverse spinal cordfor precautions with, 82 pain, postoperative for in hemodialysis in hemodialysis cancer-related, 0 precautions with, 24 action mechanism of dosage and dosage and 22, 82 pain, 89 neuropathicfor therapy with, combination 0 neuropathic pain, cancer-related therapy with, for 88–89 neuropathic pain, therapy with, for combination patients, 23 84, 86, 88–89 7, 22–23, 82 pain, 89 neuropathic for therapy with, 2, 82 24 of, 24 of, administration pain, 7 0 of, effects 3, 2–23 24 of, 22, 24 of, 24 of, effects 82 pain, injury-related 27 administration of, 23–24 t , 86–88 t t t t t t , 84 t t , 9 t t t t t t , , t t Gingko Gastrointestinal distress, Garlic ablation, 2 Gamma knife acid Gamma-aminobutyric acidGamma-aminobutyric Headache,  H Guillain-Barré syndrome, Guarded receptor Guanethidine block, Glycopyrrolate Glucosamine, 3 and ibuprofen, and aspirin, interactions and anticonvulsants, and NSAIDs, interactions and acetaminophen, in cancer-related pain, postoperative for 23 use of, perioperative neuropathicfor pain, fibromyalgia,for 08–0 treatment 5–7 of, cancer-related, cancer-relatedfor bowel cancer pain, for 97 dosage and cancer-related, 0 dosage and between, 42 interactions between, 42 between, 42 interactions drugs causing, 2 between, 42 between, 42 interactions 97 cancer pain, for (GABA) agonists, 02 neuropathic pain, target, 9 (GABA), as drug 27 administration of, 23–24 5, 7 for, 98–99 corticosteroids 88 action, 53, 54 local anesthetic for hypothesis, 9 of, molecular target obstruction, 03 99 of, administration t t t t t t f t t t t t t

153 Index 154 Index Human immunodeficiency Human immunodeficiency Herpes zoster, acute, Herbal therapy patient(s), Hemodialysis Ibandronate I Hyponatremia, Hyperalgesia, 79 5-Hydroxytryptophan-3 5-Hydroxytryptophan- 5-Hydroxytryptophan, and Hydromorphone Hydrocodone, indications Hyaluronic acid, for cancer-relatedfor bone cancer pain, for 97 secondary, 9 primary, 59 60 postoperative, opioid-induced, 60–6, opioids intraoperative 59–60 definition of, in patient-controlled indications for, 6, 6 treatment 22, 27, 88 of, topical capsaicin for, capsaicin patch for, 83 cannabinoids for, 36–37 rheumatic pain, 3 for and analgesics, prevention, ketamine pain, 02–03 induced, 25 oxcarbazepine- and, 23 6 and, 60–6 antagonists, 3 receptor activity, 39 serotonergic antagonists, and receptor activity, 39 serotonergic analgesia, 22 for, 6, 6 knee, 2–3 in osteoarthritis injections, for intra-articular 75–76, 85–86 neuropathy, 4–5 virus (HIV) treatment 22 of, 4–43, 42 between, interactions treatment 23 of, in, neuropathy peripheral f , 85, 22–23 t t t t t t t t

Inflammatory arthritis Inflammatory Increased transmission Incision block, 48 Imipramine ID Pain, 79 Ketamine, 6 Keratinocytes, as drug K Joint replacement, 2 J bowel,Irritable 8 Intrathecal analgesia, 2 block,Intra-articular 2, 48 Intercostal block, nerve 49 Inhibition, descending, pain, 8 Inflammatory pathophysiology of, of, pathophysiology mechanisms of, pain of, and tramadol, drug-drug and tapentadol, drug-drug and serotonergic activity, drug-drug and phenytoin, neurotransmitter profile neuropathicfor pain, and methadone, 2 of, half-life and fluvoxamine, dosage and administration and aspirin, drug-drug pain, 6 arthritis for and side effects adverse anti-hyperalgesic effect of, of, effect anti-hyperalgesic and side effects adverse pain from, treatment topical analgesics for, 7 cannabinoids for, 36 placebo-controlled 07–08 07 mechanism, 8, 9 interactions, 38 interactions, 38 39 interactions, 32 2 of, 3 trials of, 4, 88 interactions, 38 drug-drug interactions, 32 drug-drug 2 of, interactions, 35 2 of, effects 6–63 63 of, effects target, 76–77 22 of, 9 modulators of, t t t t t t t t t t t t t t t t t t Lacosamide, 27–28, 86 L perioperative and opioids, in same opioid-induced for 9 molecular target of, action of, mechanism of intravenous, dosage and epidural, 62 on postoperative effects on postoperative effects dosage and administration chronicfor pain, 64–65 cancer-relatedfor cancer pain, for 65, 96 mechanism of action mechanism of dosage and administration cancer-relatedfor cancer pain, for 96 and side effects adverse S rheumatic pain, 2 for pain, postoperative for 6, of, pharmacology (+), 62 dosage and 6–63 benefits of, neuroleptic with, 02 dosage and benzodiazepine with, dosage and indications for, 63 0–02 administration of, 02 0–02 neuropathic pain, of, 26 of, 26 of, 0 neuropathic pain, 26 of, effects 27 administration of, 23 64–65 for, 62, 62 recommendations administration of, 63 PCA, solution for 22–23 hyperalgesia, 6, 23 for, 62, 62 recommendations administration of, pain, 6–63 6–62 consumption, opioid 64–65, 23 of, t t t t t t t t t Lamotrigine, 9 Laminectomy, 2 Lidocaine Levorphanol Levobupivacaine Levetiracetam, 9 Leukopenia, drugs causing, Leeds Assessment of duration of action, 52 duration of 52 of, analgesic potency precautions with, 83 neuropathicfor pain, action mechanism of dosage and administration and side effects adverse postoperative for 52 of, pharmacology action, 52 onset of dose maximum daily action, 52 duration of 52 of, analgesic potency action mechanism of dosage and administration and side effects adverse precautions with, 25 drug-drug and phenytoin, neuropathicfor pain, 88 9 molecular target of, action mechanism of HIV-relatedfor dosage and administration contraindications to, 25 carbamazepine and, cancer-relatedfor cancer pain, for 96 and side effects adverse and acetaminophen, 83 83 of, 83 of, 83 of, effects 27 of, and administration pain, dosage 55 of, 26 of, 26 of, 26 of, effects 23 Signs (LANSS), 79 Symptoms and Neuropathic interactions, 34 25 of, neuropathy, 88 25 of, interactions, 33 drug-drug 0 neuropathic pain, 25 of, effects interactions, 36 drug-drug t , 88 t , 27 t t t t t t t t t , 27

t t t t t t t

t t t t , 53 t t t t t t Local anesthetics, 6, 47. Lithium, and serotonergic topical, 74–75 subcutaneous, for plaster, 74 50, of, pharmacology patch, 49, 74 action, 52 onset of 9 molecular target of, action of, mechanism of dose maximum daily intravenous, 49, 53 in cancer treatment, 49 cancer pain, for 96 action anti-inflammatory of, anesthetic potency amino ester, 50 amino amide, 50 and side effects adverse administration of for postherpetic for 74 of, pharmacology and oral therapy, neuropathicfor pain, and lidocaine gel, indications for, 74–75 dosage and and side effects adverse neuropathicfor pain, cancer-relatedfor cancer pain, for 96 pharmacology of, 52 of, pharmacology 52 of, pharmacology class B, 53–55 class A, 53 ultrasound-guided, 47 topical, 47, 48 techniques for, 47, 48 47, 49 systemic, routes for, 47, 48 neuralgia, 74, 75 of, combination 82 mixture 49–50 of, 82 administration of, 82 of, effects 0 neuropathic pain, cancer-related 84 52 74, 82 55 of, 0 neuropathic pain, of, 49 of, 50–5 of effects also activity, 39 82 t t t t , 84 , 84 , 54 , 86

specific drug t t f t , 49–50 t t t t t t , 84 t See t t t Lumbar root pain, chronic, Lumbar radicular pain, Low back pain,  onset of action, 50–5 onset of octanol-buffer coefficient action of, mechanism of dose maximum daily liposomal formulations, infusion, intra-articular for infusions, systemic inadvertent 50–5, hydrophobicity of, guarded receptor eutectic mixture of, epidural analgesia with, action, duration of dosage and administration differential block of contraindications to, 50 treatment 6–7, 27, of, wound infiltration with, toxicity 53–56 of, 47 of, safety precautions with, 50 pain, postoperative for 50–52, of, pharmacology and toxicological management protocols lipid rescue therapy for, 55, 56 clinical signs of, and toxicological of, 53, 54 of, 0 55 of, 25 pain, 25 postoperative for pain, 24 postoperative 53 application of, 53, 54 53, 54 for,hypothesis 49–50 pain, 24, 25 postoperative for profile, 50, 53 50–5 5 of, 5–52 motor fibers, and sensory 4–5 treatment 27 of, 07, 0 24 for, 56 53, 55–56 27 administration of, dosage and 52 profile, 50, 53 t t , 47–49 t t f f f t t

155 Index 156 Index Magnesium Macrolides, drug interactions M Lymphedema, Lumbar spinal stenosis, pain Mepivacaine, 52–53 Mepivacaine, Meperidine Menthol, 76 Memantine MDMA Massage,  Marinol. Marihuana (marijuana, Maprotiline,  pharmacology of, 50, 52 of, pharmacology action, 52 onset of molecular structure of, action, 52 duration of 52 of, analgesic potency and serotonergic activity, and other serotonergic rheumatic pain, 2 for action mechanism of cancer-relatedfor cancer pain, for 96 and serotonin syndrome, and serotonergic activity, of, synthetic derivatives smoked 33,  medical use of, neuropathicfor pain, 4 pain and perioperative as NMDA receptor for neuropathicfor pain, HIV-relatedfor vs. recreational use, See 50–5, 5 39 interactions, 43 agents, drug-drug 63 of, 02 neuropathic pain, 4 39 33, 34 36–37 37, 88 neuropathy,  also cannabis), 34 63–64 management, blocker, 63–64 with, 8 for, 98–99 corticosteroids cancer-related, 22 of, treatmentof, Dronabinol Cannabinoids t t t f t t t . t See t t Methadone N- N- Methyl- Methyl- trazodone and, drug-drug SSRIs and, drug-drug and serotonin syndrome, and serotonergic activity, St. John's and, wort precautions with, 83 and other serotonergic neuropathicfor pain, and, mirtazapine action of, mechanism of indications for, 6, 6 imipramine and, drug interactions with, 8 dosage and administration clomipramine and, carbamazepine and, and side effects adverse for cancer-relatedfor cancer pain, for 96 and postoperative and µ-opioid receptors, in opioid-induced 60 of, activation and, drug-drug venlafaxine interactions, 38 40 39 between, 42 interactions 43 interactions, 38 agents, drug-drug 83 interactions, 38 drug-drug 63, 83 interactions, 38 drug-drug 83 of, interactions, 38 drug-drug interactions, 35 drug-drug 83 of, effects 0–02 neuropathic pain, 9 (antagonists), 7 receptor blockers (NMDA) D 60–6, 6 hyperalgesia, 6, 6 link between, 22 hyperalgesia, receptor(s) (NMDA) D 4 interactions, 38 interactions, 38 t -aspartate -aspartate -aspartate , 4, 3 t , 85 t t t f f t t t t t t , t t t t t t t t , , Moclobemide Mirtazapine in pan Mindfulness, interventions,  Mind-body Milnacipran,  treatment of, Migraine, Mexiletine for Methylprednisone, for Methylprednisolone, allergic Methylparabene, Morphine Monoclonal antibody(ies) Monoamine oxidase and serotonergic activity, fibromyalgia,for 5, 7 and tramadol, drug-drug and tapentadol, drug-drug and methadone, headache, 5–7 for cancer-relatedfor fibromyalgia,for 5, 7, cancer pain, for 96 oral, 49 9 molecular target of, cancer pain, for 96 pain, 59 postoperative for neuropathicfor pain, 59 chronicfor pain, 64–65 mechanism of action mechanism of administration, long-term intrathecal, 24 indications for, 6, 6 dosage and administration chronicfor noncancer and side effects adverse and serotonergic activity, fibromyalgia,for 5, 7 98–99 cancer pain, reactions to, 55 of, 83 of, by, 85 problems caused 83 of, pain, 7 83 of, effects 02–03 bone pain, cancer-related (mAb), for 39 (MAOIs) inhibitors 39 interactions, 38 interactions, 38 interactions, 38 drug-drug symptoms, 98 management,  07, 09 5–7 cancer pain, 96 t t t t t t t t t t t t t t Nerve block(s),Nerve 2–3, 47, 48 9 Nefopam, and Nefazodone, Nausea and vomiting Naproxen, postoperative for Nabiximols Nabilone, 36–37 N Musculoskeletal pain, 8 Muscle spasm(s),inspinalcord Muscle relaxant(s), 5–7 Multiple sclerosis (MS), pain Multimodal analgesia, 2 for neuropathicfor pain, 5, for postoperative pain, postoperative for differential, 52 and side effects adverse postoperative, drugs causing, 2 chemotherapy-related, indications for, 34 dosage and administration cancer pain, for 96 and side effects adverse musculoskeletalfor pain, indications for, 34 fibromyalgia,for 38, 09 dosage and administration cancer pain, for 96 and side effects adverse treatment 7, 7 of, cannabinoids for, 38,  treatment 22 of, cannabinoids for, 34 precautions with, 83 in patient-controlled 24–25, 25 55 of, effects activity, 39 serotonergic 23–24 prevention, for, 34 cannabinoids 27 administration of, pain, dosage and 34 of, 34 of, effects 38  34 of,  of, effects Rheumatic pain also for, 37 injury, cannabinoids 37–38 in, 27 analgesia, 22 83 t t , 85 Fibromyalgia; t t t t t t t t t t , 00 , 00 t t t t t , . t See t t , Neuropathic pain, 5, 8, block, 3 Neurolytic Neuraxial block(s), 48, 48 Neuralgia, 8 cancer-related, 4. calcium channel bupropion for, 4 botulinum toxin type antidepressants for, 4–5 anticonvulsants for, 86 for,amitriptyline 4, 7, adjuvant analgesics for, gabapentin and gabapentin for, 82 dextromethorphan corticosteroids for, clonazepam for, 02 for,baclofen 02 antidepressants for, 0 anticonvulsants for, 0 analgesics used for, for,amitriptyline 88 amantadine for, 02 placebo-controlled oxcarbazepine for, 0 NMDA receptor memantine for, 02 lamotrigine for, 0 lacosamide for, 0 ketamine for, 0–02 lidocaine intravenous gabapentinoids for, 0 gabapentin and opioids gabapentin and neuroleptic with, 02 dosage and benzodiazepine with, therapy with, 0 for, combination EMLA cream for, 02 98–99 96 also ligands for, 82 A for, 89 3 trials of, 80, 8 7, 7 8 24, 25 0–02 (antagonists) for, blockers 0–02 administration of, 02 for, 0 therapy with, 0 for, combination therapy with, 0 combination imipramine for, t ,  t t –97 Cancer pain t t , 88 t α t 2 δ t See

t , 0 t , 84 t , etiology of, 79 of, etiology escitalopram for, 4 duloxetine for, 4, 7, 79–80 diagnosis of, desipramine for, 4, 8 combination therapy for, clomipramine for, citalopram for, 4 79 characteristics of, central, 86–88 catastrophizing and, 90 capsaicin patch for, 7, cannabinoids for, 5, 34 in cancer survivors, levorphanol for,levorphanol 83 lamotrigine for, 88 79 intermittent, intensity, temporal imipramine for, 4, 88 gabapentinoids for, 5, 7 gabapentin for, 5, 7, evoked, 79, 90 placebo-controlled duloxetine for, 88 oromucosal, 89–90 tricyclic antidepressants treatment 22, of, topiramate for, 0 subcutaneous lidocaine for,sodium divalproex sodium channel pregabalin for, 0 placebo-controlled and oxycodone, and nortriptyline, and morphine, in hemodialysis 80–84, 8 3 trials of, 75–76, 88–89 3 of, controlled trials placebo- 83 36–37, 89–90 00–0 for, 8 00–02 for, 0 0 blockers for, 0 variations in, 79 3 trials of, therapy with, 89 combination 88–89 therapy with, combination therapy with, 89 combination patients, 23 86, 88–89 22–23, 82 t , 85–86 t t

t t , 84, , 86 t t t , 88 t t ,

157 Index 158 Index Neuropathic pain traumatic, 79 traumatic, tramadol for, 5, 83 topical lidocaine for, topical analgesics for, 7, therapeutic outcomes in, tetracyclic antidepressant tapentadol for, 85 SSRIs for, 4–5 spontaneous, 79 SNRIs for, 4–5, 7, smoked cannabis for, screening tools for, 79–80 psychological comorbidity 79 prevalence of, pregabalin for, 5, 7, peripheral, 80–86 pathophysiologic paroxetine for, 4 oxycodone for, 5,83 opioids for, 5 opioid agonists for, 83 for,nortriptyline 4, 7, NMDA receptor blockers morphine for, 5, 83 methadone for, 83 maprotiline for, 4 49 management of, lidocaine plaster for, 84 tricyclic antidepressants treatment 88 of, placebo-controlled in hemodialysis and duloxetine, treatment algorithm placebo-controlled evidence-based adjuvant analgesics for, for, 8 74–75, 82 74–76 improving, 90 for, 4 3 trials of, 80–84, 8 36–37 and, 90 patients, 23 therapy with,22,89 combination 82 22–23, 74–75, for, 87 90 of, heterogeneity 85 3 trials of, 8 for, 59 (antagonists) for, 8 recommendations 8 t t t , 84, 86, 88 , 88 –83 t t f t –83 (Cont.) t t , 84 t t t t , 85 t t , 84 , 85 t t , 85 , Nonsteroidal Nonopioid(s), 9 Nociceptor(s), 48 Nociceptive pain, 8, 8 Nociception, 48 Nitrous oxide, 9 Neuropathic Pain adverse effects and side effects adverse on WHO analgesic/pain indications for, 3 as NMDA receptor effect anti-hyperalgesic for,venlafaxine 4, 7, tricyclic antidepressants treatment 7,7 of, topical, 7–74, 73 pain, postoperative for oral bisphosphonates in multimodal analgesia, and morphine, indications for, 3, 6, 6 contraindications to, 22 cancer pain, for 97 placebo-controlled placebo-controlled in,placebo 90 effect placebo-controlled clinical trials, factors mechanism of action mechanism of cancer pain, for 96 dosage and effects of, 3, of, effects drug 9 drugs (NSAIDs), anti-inflammatory ladder, 2, 2 47–48 blocker, 64 64 of, Questionnaire, 79 3 trials of, 80–84, 8 3 trials of, 8 for, 4–5, 7, 80, 3 trials of, 90 affecting, 7, 2, 27 of, 2 of, topical also 27 administration of, 2–22 43 interactions, 37 and, drug-drug 2–22 2–22 therapy with, combination 2–22 t . t See also , 88–89 Diclofenac, Diclofenac, t t t t t t , 4–5, , 88

f . t t t t specific , 6, 6 t See , t t , 8 t t t , Opioid(s), 9 Ofirmev, 2 Octreotide, 7 O  Nortriptyline, Norfluoxetine, and serotonin for cancer-relatedfor bowel cancer pain, for 97 precautions with, 8 neurotransmitter profile neuropathicfor pain, 4, 8 action of, mechanism of lowfor back pain, 6 2 of, half-life fibromyalgia,for 0 of, 4 efficacy dosage and administration cancer pain, for 96 and side effects adverse and NMDA receptor neuropathicfor pain, 5 administration, long-term 60–6 intraoperative, indications for, 3–4, 8 dosage and administration 4 diversion, dependence, 85 combinations efficacy of, chronicfor noncancer and cannabinoids and side effects adverse abuse, 4 dosage and placebo-controlled rheumatic pain, for interactions of, 40 interactions of, combination therapy 8 2 of, effects 40–4 syndrome, 09 activation, 60 activation, by, 85 problems caused 3 of, 3 of, pain, 7 with, 40 22 of, effects specific drug opioid-induced; Hyperalgesia, 03–04 obstruction, 99 of, administration 2 of, 3 trials of, 7, 8 2 of, t t . t t See also , 2 t t t t t , 8, 8 , 88 t t t

t t t t , t Osteoarthritis hypotension, Orthostatic µ-Opioid receptor(s) µ-Opioid agonists, 9 Opioid agonist(s) for phantom limb pain, for pain of in knee, intra-articular and NMDA receptors, as drug targets, 9 precautions with, 83 neuropathicfor pain, action mechanism of dosage and administration and side effects adverse weak, on WHO strong, on WHO spinal and serotonergic activity, serotonergic rotation 4 of, response to, factors pain, postoperative for treatment 6, 07 of, for,topical diclofenac topical capsaicin for, 75 topical analgesics for, of, pathophysiology neurogenic mechanisms 07 mechanisms of, herbal therapy for, 3 pain, postoperative for and side effects adverse and serotonin and other serotonergic 72–74, 73 2 07–08 in, 08 for, 2–3 acid hyaluronic drugs causing, 2 6, 6 link between, 83 83 of, 83 of, 83 of, effects 6, 6 ladder, 2–3, 2 analgesic/pain 6, 6 ladder, 2–3, 2 analgesic/pain 24 24 of, effects 39 syndrome, 40 interactions, 43 agents, drug-drug 3–4 affecting, 22 88 t , 85 t t t t t f t t t t t , 85 f f , 85 , , t Oxycodone Oxcarbazepine, 23, 86 Osteoclast inhibitor(s). Pain P precautions with, 83 neuropathicfor pain, 5, 83 action of, mechanism of low-dose, indications for, high-dose, indications for, dosage and administration chronicfor noncancer and side effects adverse precautions with, 25 action of, mechanism of dosage and administration contraindications to, 25 cancer-relatedfor cancer pain, for 96 and side effects adverse cancer-relatedfor bone cancer pain, for 97 chronic,  central poststroke, 4, cancer. bone. arthritis. acute dosage and postoperative, 26 postoperative, NMDA receptor 3, 34 management of, cannabinoids for, 34 acute crises, tricyclic antidepressants for,topical diclofenac 72 2–3, management of, See 83 6, 6 6, 6 83 of, pain, 7 83 of, effects 0 25 of, 0 neuropathic pain, 23, 25 of, effects pain, 02–03 99 of, administration Bisphosphonates See also 64–65 modulators for, 36–40, 64–65 36–39 3 management of, for, 8 27, 79 See 36 See Bone pain t t , 85 , 25 Cancer pain t t Arthritis pain Arthritis t t t t , 85 t

t t t t t t , t t t , t Pamidronate Pain management Pain emergencies, 99 PainDetect, 79 severe, treatment 2, of, rheumatic. postthoracotomy, postsurgical, 79. postmastectomy postamputation, nonmalignant, neuropathic. musculoskeletal. moderate, treatment of, mild, treatment 2, 2 of,  definition of, for cancer-relatedfor bone cancer pain, for 97  goals of, chronicfor pain, 3. approaches to treatment 23 of, chronic, 26 treatment 88, 98, of, gabapentin and without control, dosage and dosage and step-up approach, 3 step-down approach, 3 step up, 3 step down, 3 2 specific, psychological,   physical, pharmacological, 2–3 nonpharmacological,  2–3 invasive, –2 interventional, 2 (RA) arthritis Rheumatoid Rheumatic pain; Osteoarthritis; 00 treatment 22, of, Postoperative pain 00 therapy for, 0 combination EMLA cream treatment 00 of, 2–3 management of, Neuropathic pain pain Musculoskeletal 2, 2 3, 6, 6 3 management of, pain, 02–03 99 of, administration also f , 3–4, 6, 6 f Pain, chronic See , 3–4, 6, 6 t See t