Pcu Vol23 No4 May2015

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PAIN: CLINICAL UPDATES MAY 2015 1

VOL XXIII NO 4 MAY 2015

Treating Herpes Zoster and Postherpetic Neuralgia

Maija Haanp, MD, PhDDepartment of Neurosurgery,Helsinki University HospitalMutual Insurance Company Etera,Helsinki, FinlandEmail: maija.haanpaa@etera.

Andrew S.C. Rice, MB BS, MD,FRCA, FFPMRCAPain Research, Department of Surgery

and Cancer,Faculty of MedicineImperial College LondonChelsea and Westminster Hospital CampusLondon, United KingdomEmail: [email protected]

Michael C. Rowbotham, MDCalifornia Pacic Medical Center

Research InstituteDepartment of Anesthesia,UCSF School of MedicineSan Francisco, Calif., USAEmail: [email protected]

P ostherpetic neuralgia (PHN)is the most frequent chroniccomplication of herpes zoster(shingles). 1 Herpes zoster (HZ)represents a reactivation of the vari-cella zoster virus (VZV), a ubiquitous,highly neurotropic, exclusively human

-herpesvirus. Primary infection causesvaricella (chickenpox), after which VZVbecomes latent in sensory ganglia alongthe entire neuraxis. With the decline inVZV-specic cell-mediated immunityin elderly and immunocompromisedindividuals, VZV reactivates to causeHZ, characterized by a painful maculo-papular or vesicular rash in all or part ofthe skin territory innervated by a singledorsal root ganglion. 2 The most commonsite of HZ is thoracic, comprising abouthalf of all cases, followed by trigemi-nal (usually the ophthalmic branch),cervical, and lumbar distributions. HZgenerally resolves within a few weeks,

but a minority of patients experiencepain (PHN) persisting for months, years,or even a lifetime.

Epidemiology of HZ and PHN

According to a recent systematicreview, the incidence of HZ is 35cases per 1000 person-years. 3 Theage-specic incidence rates of HZ weresimilar across countries, with a steeprise after 50 years of age. The incidencewas 68 cases/1000 person-years at60 years of age and 812 cases/1000person-years at 80 years ofage. The incidence of HZ hasincreased in the past severaldecades across seven coun-tries. 3 A study in the UnitedStates could not explain theincrease by changes in ageor by the prevalence of im-munocompromised people. 4

Two-thirds of HZ cases occurin those 50 years or older, andthe lifetime risk is 30%. 2

Estimates of the inci-dence of PHN vary widelydepending on the popula-tion and the denition of PHN used.Denitions include the duration ofpersistent pain (30, 90, or 180 days) and

the severity of pain, either clinicallymeaningful pain (i.e., pain intensity ofat least 3/10) or any pain. 3 In a popula-tion-based study using medical recordsin the United States, 18% of patientsreported pain for at least 30 days and10% for at least 90 days. 4 Similarly,20% of patients had pain for at least 30days and 14% for at least 90 days in astudy from the United Kingdom, 5 and20% of zoster patients had pain at 3

months and 15% had pain at 2 years ina Dutch study. 6 In the landmark zostervaccine study, which included almost40,000 people aged 60 years or older(of whom fewer than 1000 developedHZ) and where PHN was dened aspain intensity of 3/10 or more, 30% of

patients who developed HZ had PHNat 1 month, 12% at 3 months, and 5%at 6 months in the placebo group. 7 Ac-cording to a meta-analysis, incidencerates of PHN varied from 3.9 cases per100,000 person-years to 42.0 cases per100,000 person-years across all ages. 8

PHN risk increases with age. Ina study from the United States, theincidence of PHN (dened as pain at 3

months) in zoster patients was 18% inpersons older than 50 years and 33%in those older than 80 years. Overall,80% of all PHN occurs among personsaged 50 years and older. 2 Analysis ofdata from the United Kingdom GeneralPractice Research Database showedthat the incidence of PHN (as denedby pain at 3 months) rose from 8% at5054 years of age to 21% at 8084years of age. 5
mailto:maija.haanpaa%40etera.fi?subject=mailto:a.rice%40imperial.ac.uk?subject=mailto:rowbotm%40cpmcri.org?subject=mailto:rowbotm%40cpmcri.org?subject=mailto:a.rice%40imperial.ac.uk?subject=mailto:maija.haanpaa%40etera.fi?subject=

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PAIN: CLINICAL UPDATES MAY 20152

Advancing age and the severityof acute HZ pain are the strongest riskfactors for PHN. Other predictors ofPHN are the severity of the rash, thepresence of prodromal pain, and theoccurrence of sensory abnormalitiessuch as hypoesthesia or allodynia. 9,10 Ophthalmic location of rash, psycho-

social distress in the acute phase, andproblems with usual activities beforedeveloping HZ (the last reectingpoorer health) are also reported as riskfactors. 11

Course of the Disease

HZ viral replication rst manifests asganglionitis and then spreads along thecorresponding peripheral nerve andthe skin. Hemorrhage and inam-

mation in the affected dorsal rootganglion and associated nerve maybe seen, and in patients with PHN,brosis and cell loss have been docu-mented post mortem in the dorsal rootganglion. 12 Pain and unilateral rashare typical symptoms, often accompa-nied by paresthesias and itching. Mostpatients experience pain during HZ.Pain precedes rash in three-quartersof cases, lasting usually for some daysbefore the eruption of the rash. Asdescribed above, only a minority ofpatients continue to have pain longafter the healing of the rash.

HZ can also give rise to non-paincomplications, which can be ophthal-mic (e.g., keratitis or uveitis), neuro-logical (e.g., cranial and peripheralnerve palsies), circulatory (vasculitisand stroke), dermatological (e.g., bacte-rial superinfection), or visceral (e.g.,pneumonia). 13

Those who continue to suffer fromprolonged pain after HZ may describeone or more of three broad types ofpain: (1) a constant deep aching orburning pain; (2) an intermittent parox-ysmal pain with a lancinating quality;and (3) an intermittent pain evoked bynormally innocuous sensory stimuli(allodynia), typically mechanical but insome patients thermal as well. Allodyn-ia is present in at least 70% of patientsand is usually considered to be themost distressing and debilitating PHN

component. 13 Itching and dysesthesiasmay accompany the pain, and in somepatients these symptoms can be evenmore annoying than the pain itself.

A longitudinal study of zosterpatients using quantitative sensory test-ing (QST) and skin biopsies showed thatthose who developed PHN (dened as

pain at 6 months) had signicantly moreimpaired sensory function and moresevere allodynia in the acute phase com-pared to those who experienced painresolution. 14 Sensory recovery pro-ceeded at the same rate in both groupsduring the rst 6 months. Epidermalnerve ber density was decreased byabout 40% in the affected skin but notin contralateral mirror image skin,with no improvement during the rst6 months. 15 In a long-term follow-up of

7 years, epidermal nerve ber densityremained low in spite of good clinicalrecovery, which strongly supports theconcept that recovery of sensory func-tion and anatomical reinnervation ofthe skin are not prerequisites for painresolution. 16

Burden of the Disease

Pain is the most important outcome ofHZ. It interferes with general activity,sleep, and mood, and patients withmore severe pain are more likely to re-port symptoms of anxiety and depres-sion. 17, 18 Health-related quality of lifeinstruments measure four key healthdomains: physical, psychological, so-cial, and functional. Both HZ and PHNhave effects on patients lives acrossall four health domains. Reduced qual-ity of life is a particular problem inpatients whose pain persists as PHN,and there is a correlation between in-creasing pain severity and the extent

of PHNs negative impact on quality oflife. 13 A study comparing patients withPHN to patients with chronic low backpain showed similar pain intensity,physical function, cognitive function,and mood in both groups, but painseverity depended on different things(PHN typically increased with touch,air movement, and stress, whereaslow back pain increased with activityand exercise). 19

HZ and PHN also cause a substan-tial economic burden to society in theform of increased health care use andneed for medication, lost working daysin those at working age, and the needfor assistance or even loss of indepen-dence in frail, elderly, people with mul-tiple comorbidities. In a study from the

United Kingdom, the average total costof a PHN case was estimated to be 340in 2006. The cost included outpatientvisits and prescribed medication, butat that time pregabalin and lidocainepatches were not available there, whichwould increase the current cost. 20

Pharmacotherapy of AcuteHerpes Zoster

The treatment of HZ aims to limit theduration and severity of the attack,relieve symptoms, and prevent com-plications. All patients should receivea medical and psychosocial historyevaluation and targeted physicalexamination to conrm the diagnosis,document comorbid illnesses, andprovide a basis for treatment.

Antiviral Agents

Although HZ is a self-limiting andbenign disease in most patients, thosewho have a high risk of develop-ing complications should be treatedactively. Systemic antiviral therapyis strongly recommended as rst-linetreatment for all immunocompetentpatients with HZ who fulll any of thefollowing criteria (ideally within 72hours of the onset of rash): (1) are atleast 50 years of age; (2) have moder-ate or severe pain; (3) have a moderateor severe rash; or (4) have non-truncalinvolvement. 21

Acyclovir, famciclovir, and valacy-

clovir have been approved by the U.S.Food and Drug Administration for thetreatment of HZ. All of them inhibitviral replication in the infected cells,resulting in accelerated healing of rashand decreased severity and duration ofacute pain. Oral acyclovir does not re-duce the incidence of PHN signicant-ly, but there is insufcient evidence todetermine the effect of other antiviraltreatments preventing PHN. 22

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Treatment of Acute Zoster-Associated Pain

Active treatment of acute HZ pain isrecommended. In the absence of anextensive dataset of direct evidencefrom high-quality randomized con-trolled trials, it is reasonable to adhereto generic principles of acute pain

management; patients with mild tomoderate pain should take acetamino-phen (paracetamol) or NSAIDs, aloneor in combination with codeine ortramadol. Those with severe pain mayneed a strong opioid. In a randomizedcontrolled study, the number-needed-to-treat for clinically meaningful painrelief (>30% pain reduction) was 2.9for controlled-release oxycodone and9.6 for gabapentin during the 4-weekstudy. 23 In another study, a single dose(900 mg) of gabapentin decreased painseverity and both severity and area ofallodynia in patients with acute zoster. 24 For opioids, individual titration, routinelaxative use, and close follow-up areneeded to ensure the best compromisebetween efcacy and side effects.

Low-dose amitriptyline (25 mgonce daily for 3 months) has beenrecommended because it signicantlyreduced the prevalence of PHN at 6months in a placebo-controlled trial. 25 However, this small study requiresrepetition on a larger scale.

Corticosteroids in combination withacyclovir reduced pain and improvedshort-term quality of life comparedwith placebo in patients with HZ, butthey had no appreciable effect on theincidence or duration of PHN. 26 Corti-costeroids are associated with a consid-erable number of adverse effects andhence should be used only in patientswith severe symptoms at presentationor in whom no major contraindicationsto corticosteroids exist, and only in com-bination with antiviral treatment.

Although epidural local anestheticinjection, with or without a steroid,has been common practice for manydecades in patients with severe acute orsubacute zoster pain, there are few pro-spective controlled trials. A large studythat examined the effect of a singleepidural injection of local anestheticand a steroid demonstrated reduced

zoster-associated pain at 1 month but nosignicant reduction in the likelihoodof PHN. 6 A randomized nonblindedstudy reported effective pain relief andprevention of PHN (dened as presenceof any pain) at 1, 6, and 12 months withrepeated paravertebral blockades of a lo-cal anesthetic and steroid. 27 All patients

(aged 50 years or over) were treatedwith oral acyclovir, and the paraver-tebral blockade group received fourrepeated treatments within one week,whereas the standard group receivedsimple analgesics for their pain. Accord-ing to this study, repeated paravertebralblockades are effective for acute painand prevention of PHN. However, thisprocedure is obviously not suitable forpatients suffering from cranial zoster.

Treatment of PostherpeticNeuralgia

The efcacy of current treatments isstill far from satisfactory. PHN is a clas-sical model to test the efcacy of poten-tial new drugs for neuropathic pain. Aglobal database of all registered PHNtrials and results (if any are available)has been reported 28 and was updated inmid-2014. 29,30 The database is availableas part the Repository of RegisteredAnalgesic Clinical Trials (RReACT)through the ACTTION website (http://www.acttion.org/). Of 112 unique reg-istered trials, 66 were reported as com-pleted. Only 20 completed trials hadresults available in the peer-reviewedliterature, and another 17 had resultsavailable via the gray literature orposted on a trials registry. In addition tothe lack of results from a large propor-tion of completed trials, some importantclinical issues have not been tested in aclinical trial. For example, none of theavailable serotonin and norepinephrinereuptake inhibitors (SNRIs) have beenstudied for PHN.

Numerous meta-analyses andtreatment guidelines have been pub-lished. A PHN-specic meta-analysiswas published in 2005, 31 but recommen-dations provided here are largely basedon analyses from 2014 and 2015. 1,32

Tricyclic antidepressants (TCAs),gabapentinoids, opioids, and topi-cal capsaicin have strong evidence

Editorial Board

Editor-in-Chief

Jane C. Ballantyne, MD, FRCAAnesthesiology, Pain Medicine

USA

Advisory Board

Michael J. Cousins, MD, DSCPain Medicine, Palliative Medicine

Australia

Maria Adele Giamberardino, MDInternal Medicine, Physiology

Italy

Robert N. Jamison, PhDPsychology, Pain Assessment

USA

Patricia A. McGrath, PhDPsychology, Pediatric Pain

Canada

M.R. Rajagopal, MDPain Medicine, Palliative Medicine

India

Maree T. Smith, PhDPharmacology

Australia

Claudia Sommer, MDNeurologyGermany

Harrit M. Wittink, PhD, PTPhysical TherapyThe Netherlands

Publishing

Daniel J. Levin, Publications DirectorElizabeth Endres, Consulting Editor

Timely topics in pain research and treatmenthave been selected for publication, but theinformation provided and opinions expressedhave not involved any verication of the nd-ings, conclusions, and op inions by IASP. Thus,opinions expressed in Pain: Clinical Updates donot necessarily reect those of IASP or of theOfcers or Councilors. No responsibility is as-sumed by IASP for any injury and/or damageto persons or property as a matter of productliability, negligence, or from any use of anymethods, products, instruction, or ideas con-tained in the material herein.

Because of the rapid advances in themedical sciences, the publisher recommendsindependent verication of diagnoses and

drug dosages. Copyright 2014 International Associationfor the Study of Pain. All rights reserved.

For permission to reprint or translatethis article, contact:

International Associationfor the Study of Pain

1510 H Street NW, Suite 600,Washington, D.C. 20005-1020, USA

Tel: +1-202-524-5300Fax: +1-202-524-5301

Email: [email protected]
mailto:iaspdesk%40iasp-pain.org?subject=http://www.iasp-pain.org/http://www.iasp-pain.org/mailto:iaspdesk%40iasp-pain.org?subject=

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for efcacy in PHN (Table 1). Topicallidocaine gel (5% in a nonstandardformulation) for PHN showed efcacyin a double-blind, three-session study, 33 as did topical lidocaine patch (5%) in a

double-blind, four-session study. 34 Inan open-label, non-inferiority study, 5%lidocaine patch showed better efcacycompared with pregabalin in patientswith PHN. 35

First-Line Agents Accordingto the NeuPSIG Guidelines

The lack of evidence for differentefcacies for most drugs in distinct neu-ropathic pain disorders caused NeuPSIG

Table IStudies on evidence of TCAs, gabapentinoids, opioids, and topical capsaicin for postherpetic neuralgia

showing positive (P) or negative (N) outcomes

Study Drug, Maximal Daily Dose OutcomeNumberRandomized Duration

TCAsWatson et al. 1982 Amitriptyline, average 73 mg P 24 3 weeks

Max et al. 1988 Amitriptyline, average 65 mg P 62 6 weeksGraff-Radford et al. 2000 Amitriptyline, 200 mg NA 24/49 8 weeks

Kishore-Kumar et al. 1990 Desipramine, 250 mg P 26 6 weeks

Raja et al. 2002 Nortriptyline or desipramine, 160 mg P 76 8 weeks

PREGABALINDworkin et al. 2003 Pregabalin, 600 mg P 173 8 weeks

Sabatowski et al. 2004 Pregabalin, (150), 300 mg P 157/238 8 weeks

van Seventer et al. 2006 Pregabalin, (150), 300, 600 mg P 281/370 13 weeks

Stacey et al. 2008 Pregabalin, 300, 600 mg P 270 4 weeks

GABAPENTIN

Rowbotham et al. 1998 Gabapentin, 3600 mg P 229 8 weeksRice and Maton 2001 Gabapentin, 1800, 2400 mg P 334 7 weeks

GABAPENTIN ER or ENACARBILWallace et al. 2010 Gabapentin ER, 1800 mg N 407 10 weeks

Sang et al. 2012 Gabapentin ER, 1800 mg P 452 10 weeks

Irving et al. 2009 Gabapentine ER, 1800 mg P twice daily;N once daily

158 4 weeks

NCT00619476ClinTrials.gov

Gabapentin enacarbil, 1200, 2400,3600 mg

P 376 13 weeks

TRAMADOLBoureau et al. 2003 Tramadol, 400 mg P 127 6 weeks

OPIOIDSWatson and Babul 1998 Oxycodone, 60 mg P 50 4 weeks

Raja et al. 2002 Morphine, 240 mg, or methadone P 76 8 weeks

CAPSAICIN 8%Backonja et al. 2008 Capsaicin, 8%, single application P 402 12 weeks

Backonja et al. 2010 Capsaicin, 8%, single application P 38 4 weeks

Irving et al. 2011 Capsaicin, 8%, single application P 418 12 weeks

Webster et al. 2010 Capsaicin, 8%, single application P 299 12 weeks

Webster et al. 2010 Capsaicin, 8%, single application N 155 12 weeks

CAPSAICIN CREAMBernstein et al. 1989 Capsaicin, 0.075% P 32 6 weeks

Watson et al. 1993 Capsaicin, 0.075% P 143 6 weeks

Source: Data from supplementary material of Finnerup et al.32 Abbreviations: ER, extended release; NA, not applicable; TCAs, tricyclic antidepressants.

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to prepare recommendations for neu-ropathic pain in general instead of forvarious etiologies. 32 First-line agents forneuropathic pain are TCAs, SNRIs, andgabapentinoids on the basis of evidenceof their efcacy and safety. However,there are no published reports of ran-domized controlled clinical trials of any

of the SNRIs in PHN patients. Table 2presents the mechanisms of action anddosing for these drugs.

TCAs are inexpensive drugs. Thepresence of depression is not requiredfor their analgesic effect, and painrelief occurs with lower doses thanare required for an effect on mood. 36 The most common side effects ofTCAs include sedation, anticholinergiceffects (e.g., dry mouth, constipation,

and urinary retention), and ortho-static hypotension. In a head-to-headcomparison, amitriptyline and nortrip-tyline were equally effective, but nor-triptyline was better tolerated. 37 Thesedrugs are contraindicated in patientswith cardiac conduction problems orrecent myocardial infarction. Patients

may complain of excessive sedationor confusion as the most troublesomeside effect, and pre-existing cognitiveimpairment may become signicantlyworse, which may require a caution-ary approach to driving. Accidental orintentional overdose with a TCA maybe lethal, and is more dangerous com-pared to SSRI antidepressants.

Gabapentinoids (gabapentin andpregabalin) have been studied extensively

for PHN (Table 1). Their advantage islack of pharmacokinetic interactions,as they are not bound to plasma pro-teins and are secreted to urine withouthepatic metabolism. Gabapentin has asaturable transport mechanism in thegut, whereas absorption of pregabalinis more linear. The typical side effects

of gabapentinoids are somnolence,dizziness, and peripheral edema. Dosesmust be adjusted downward if renalfunction is impaired. Gabapentin isdosed differently depending on thepreparation. Neurontin and genericgabapentin differ from the gabapentinextended-release (Gralise) preparationand the gabapentin enacarbil prodrug(Horizant) (see each manufacturersrecommendations).

Table 2Mechanisms of action and dosing of systemic drugs for neuropathic pain

Medication Mechanism of Action Starting Dose TitrationMaximum RecommendedDose

TCAs

Nortriptyline, desipramine,(amitriptyline, imipramine)1

Serotonin and norepineph-rine reuptake inhibition,sodium channel block,NMDA-receptor antago-nism

1025 mg atbedtime

Increase by 1025mg every 37days as tolerated

Usual effective doses in75100 mg/day range.Upward titration from 75mg/day guided by bloodconcentration of the drugand its active metabolite.Pretreatment cardiac con-duction screening in olderpatients and re-screeningas the dose rises may beindicated. Do not exceed150 mg daily.

Gabapentinoids

Gabapentin Calcium-channel a2 bind-ing, which reduces releaseof presynaptic transmitters

100300 mg atbedtime

Increase by100300 mgthree times dailyevery 17 days

3600 mg daily (divided into3 doses)

Pregabalin Calcium-channel a2 bind-ing, which reduces releaseof presynaptic transmitters

75 mg twicedaily

Increase to 300mg daily after 37days, then by 150mg/d every 37days

600 mg daily (divided into23 doses)

Opioid Agonists

Tramadol -opioid receptor bind-ing and serotonin andnorepinephrine reuptakeinhibition

50 mg once ortwice daily

Increase by50100 mg dailyin divided dosesevery 37 days astolerated

400 mg daily; in patientsolder than 75, 300 mg daily

Oxycodone CR -opioid receptor binding 10 mg twicedaily

Increase by 20mg daily or moreslowly as tolerated

120 mg daily (divided into 2doses)2

Abbreviations: CR, controlled release; TCAs, tricyclic antidepressants.1 Secondary amine TCAs (nortriptyline, desipramine) are preferred owing to better tolerability.2 Highest dose used in randomized controlled studies for neuropathic pain.

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Second-Line Agents Accordingto the NeuPSIG Guidelines

Lidocaine patches (5%), capsaicinpatches (8%), and tramadol are recom-mended as a second line of treatment.The reason for their being second-lineis a low quality of evidence (lidocaine),a relatively small effect size (topi-

cal capsaicin), or lower tolerability orsafety (tramadol).Topical lidocaine blocks voltage-

dependent sodium channels in thearea of application. Lidocaine patches(a maximum of three patches) are ap-plied to the region of pain once a dayfor up to 12 hours. For old and frailpatients and for those with concernsabout the side effects or safety ofrst-line treatments, lidocaine patchesmight be a rst-line option. If lidocainepatch is not available, lidocaine gel orcream (5%) can be tried instead (dosingthree times daily), although alternatepreparations have not been tested forefcacy in a clinical trial.

Topical capsaicin is an agonistof the TRPV1 ion channel and bindsits receptors, which are expressed bynociceptive primary sensory neurons,causing excitation of neurons and a pe-riod of enhanced sensitivity perceivedas itching, pricking, or burning, withcutaneous vasodilatation. This phase isfollowed by persistent desensitization.A high-concentration capsaicin plaster(8%) has shown efcacy in clinical trialsas a single treatment applied to thepainful area for 60 minutes by a medi-cal professional. The treatment can berepeated in every 3 months, if needed.

Tramadol has good evidence of ef-cacy and a lower potential for misuse,abuse, and dependency compared tostrong opioids, but it is recommendedas a second-line drug owing to poten-

tial safety concerns. It exerts its analge-sic action by increasing noradrenergicand serotonergic neurotransmission inthe central nervous system. The parentcompound is demethylated to an activemetabolite, trans-O-desmethyltram-adol, by the CYP2D6 enzyme. Thisbiotransformation is a prerequisite forthe clinical opioid effect of tramadol.Poor metabolizers lack this bioactiva-tion, and they have a weaker analgesic

response to tramadol compared to ex-tensive metabolizers and ultra-rapidmetabolizers. The typical side effectsof tramadol are nausea, dizziness, seda-tion, and headache. Tramadol shouldbe used with caution with concomitantantidepressant medication owing to itsinteraction potential. 38

Third-Line Agents Accordingto the NeuPSIG Guidelines

Strong opioids (particularly oxycodoneand morphine) and botulinum toxin Aare recommended as third line mainly be-cause of safety concerns (opioids) or weakquality of evidence (botulinum toxin A). 32

Strong opioids (oxycodone, mor-phine and methadone) have shownefcacy in PHN. Typical side effectsare constipation, nausea, itching, andsweating. Opioids are recommended asa third-line option owing to their abusepotential and side effects, includingendocrine effects. Long-term opioidtreatment should be considered fornonmalignant pain only when otherrelevant treatment options have beentried. Psychosocial evaluation shouldprecede commencement of opioidtreatment. After a treatment trial, theachieved benecial effects (pain reliefand improved function) are weighedagainst adverse drug reactions. Slow-release formulations are preferred.

Botulinum toxin has been studiedfor PHN in two randomized controlledtrials with positive results. Currentlythis treatment is recommended onlyfor specialist use in refractory cases. 32

Combination Therapy

Few studies of drug combinations havebeen published, even though combi-nation therapy reects actual clinicalpractice. Randomized trials suggest

that the combination of pregabalin orgabapentin and duloxetine or tricy-clic antidepressants is an alternativeoption to increasing doses of one classof drugs for patients unresponsive tomoderate doses of monotherapy. 32 Asmultiple pain mechanisms coexist inPHN, combining drugs with differentmechanisms of action is rational andshould be studied further to betterunderstand its value in the clinic.

Combining a locally acting preparation(lidocaine or capsaicin) with a systemicdrug is reasonable and should be tried,especially for those with comorbiditiesand multiple medications, to reduce therisk of interactions of systemic drugs.

Drugs Not Recommended by NeuPSIG

The recommendations for tapentadol,other antiepileptics, capsaicin cream,topical clonidine, selective serotoninreuptake inhibitor antidepressants, andNMDA antagonists are inconclusive,mainly because of discrepant ndings.Cannabinoids and valproate have weakrecommendations against their use inneuropathic pain, and levetiracetamand mexiletine have strong recom-mendations against their use becauseof generally negative trials or safety

concerns, or both.32

Role of Invasive Treatments forPostherpetic Neuralgia

A recent comprehensive review oninterventional management of neuro-pathic pain concluded that owing to thelow quality of the available evidenceand the potential for adverse events,the role of spinal cord stimulation,deep brain stimulation, and intrathe-cal medication delivery is inconclusivein PHN. 39 The authors recommendedagainst sympathetic blocks for PHN be-cause nonrandomized studies have notshown benet and there are no well-controlled prospective clinical trials.

A randomized controlled studyappeared to demonstrate efcacy over12 years for four intrathecal injec-tions of methylprednisolone performedover 1 month compared with lidocainealone and with a no-treatment controlgroup. 40 Another group attempted toreplicate the ndings, but the trial was

terminated early after all six patientsrandomized to intrathecal methylpred-nisolone experienced an increase inpain at 8 weeks (compared to one offour participants in the control group). 41

Given the failure to replicate the strik-ing result of the rst study and thepotential risks of intrathecal methyl-prednisolone injections, the role of thistreatment remains inconclusive, 39 andwe strongly recommend against its use.

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Prevention of PostherpeticNeuralgia

The only well-documented means of pre-venting PHN is the prevention of HZ. Alive attenuated VZV vaccine is approvedfor immunocompetent persons of age 50years or older. The Shingles PreventionStudy, which included people 60 years or

older, showed that the vaccine reducedthe incidence of HZ by 51% and the inci-dence of PHN by 66%. 7 A much smallerstudy involving persons 50 to 59 years ofage showed that vaccination reduced theincidence of HZ by 70%. 42 A long-termpersistence substudy showed that vac-cine efcacy decreased from 51% to 21%for incidence of HZ and from 66% to 35%for incidence of PHN from 7 through11 years post-vaccination. Statisticallysignicant vaccine efcacy for incidence

of HZ persisted only through year 8.43

Cost-effectiveness analyses of the zostervaccine have estimated the cost of a qual-ity-adjusted life year from US$10,000 tomore than US$100,000 depending on as-sumptions regarding duration of vaccineprotection and the magnitude of the lossin quality of life associated with HZ andPHN. 3 In the United Kingdom, research-ers estimated that vaccination at either65 or 70 years is the most cost-effective, 20 whereas a German study concluded

that vaccinating individuals aged 60years seems to represent the most cost-effective vaccination strategy. 44 Futurecost-effectiveness analyses should alsoincorporate the employment-related pro-ductivity loss in addition to health carecosts and lost quality of life. 18,45

ConclusionHZ and PHN present challenges tohealth care systems, as they are preva-lent, cause suffering and impairedfunction, and are difcult to treat sat-isfactorily, especially in societies withaging populations. The optimal use ofthe current therapies by tailoring thetreatment individually, monitoring thepatients to assess efcacy, tolerability,and functional status, and provid-ing support in psychosocial aspectswhen needed may improve the results.Zoster vaccine is available to preventzoster, and new compounds to treatPHN are awaited.

Conflicts of Interest

Maija Haanp has been a member ofthe advisory boards of Abbvie, Aller-gan, Astellas, Eli Lilly, Janssen Cilag,Pzer, and Sano-Aventis. Interna-tional congress attendance (registration

fees, travel costs, accommodation) hasbeen nancially supported by Astellasand Pzer. Lecture fees related withlectures at seminars or symposia arepaid by Astellas, Eli Lilly, Janssen Cilag,MSD, Mundipharma, Orion, Pzer, andSano-Pasteur MSD.

Andrew Rice is a member of

varicella zoster the Joint Committeeon Vaccination and Immunisation(JCVI), which advises U.K. healthdepartments on immunization. He isa member of the scientic advisoryboard of Spinifex Pharmaceuticals andholds share options in the company.Through Imperial College Consul-tants, he has in the past 24 monthsprovide consultancy services fromSpinifex, Relamda, Neusentis, Astellas,Abide, Aquilas, Mitsubishi, Medivir,

and Asahi Kasei Pharma. His labora-tory has within the last 24 monthsreceived research funding from Pzerand Astellas.

Michael Rowbotham has servedas a consultant to Xenoport, Lilly,Chromocell, Signature Therapeutics,ViroBay, and Nektar. He holds stockor stock options in Xenoport, Afferent,Signature Therapeutics, VistaGen, andCentrexion.

References

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http://www.ncbi.nlm.nih.gov/pubmed/20921251http://www.ncbi.nlm.nih.gov/pubmed/18164225http://www.ncbi.nlm.nih.gov/pubmed/19135492http://www.ncbi.nlm.nih.gov/pubmed/17143845http://www.ncbi.nlm.nih.gov/pubmed/24500927http://www.ncbi.nlm.nih.gov/pubmed/24500927http://www.ncbi.nlm.nih.gov/pubmed/19195785http://www.ncbi.nlm.nih.gov/pubmed/16087911http://www.ncbi.nlm.nih.gov/pubmed/9204652http://www.ncbi.nlm.nih.gov/pubmed/23543541http://www.ncbi.nlm.nih.gov/pubmed/23543541http://www.ncbi.nlm.nih.gov/pubmed/19713253http://www.ncbi.nlm.nih.gov/pubmed/22795917http://www.ncbi.nlm.nih.gov/pubmed/24726925http://www.ncbi.nlm.nih.gov/pubmed/25599303http://www.ncbi.nlm.nih.gov/pubmed/25599303http://www.ncbi.nlm.nih.gov/pubmed/16013891http://www.ncbi.nlm.nih.gov/pubmed/25575710http://www.ncbi.nlm.nih.gov/pubmed/7847866http://www.ncbi.nlm.nih.gov/pubmed/8826488http://www.ncbi.nlm.nih.gov/pubmed/19485723http://www.ncbi.nlm.nih.gov/pubmed/3412591http://www.ncbi.nlm.nih.gov/pubmed/9781549http://www.ncbi.nlm.nih.gov/pubmed/20194144http://www.ncbi.nlm.nih.gov/pubmed/23748119http://www.ncbi.nlm.nih.gov/pubmed/11087880http://www.ncbi.nlm.nih.gov/pubmed/23059790http://www.ncbi.nlm.nih.gov/pubmed/22291101http://www.ncbi.nlm.nih.gov/pubmed/25416754http://www.ncbi.nlm.nih.gov/pubmed/25416754http://www.ncbi.nlm.nih.gov/pubmed/24070414http://www.ncbi.nlm.nih.gov/pubmed/22285632http://www.ncbi.nlm.nih.gov/pubmed/22285632mailto:iaspdesk%40iasp-pain.org?subject=mailto:iaspdesk%40iasp-pain.org?subject=http://www.ncbi.nlm.nih.gov/pubmed/22285632http://www.ncbi.nlm.nih.gov/pubmed/24070414http://www.ncbi.nlm.nih.gov/pubmed/25416754http://www.ncbi.nlm.nih.gov/pubmed/22291101http://www.ncbi.nlm.nih.gov/pubmed/23059790http://www.ncbi.nlm.nih.gov/pubmed/11087880http://www.ncbi.nlm.nih.gov/pubmed/23748119http://www.ncbi.nlm.nih.gov/pubmed/20194144http://www.ncbi.nlm.nih.gov/pubmed/9781549http://www.ncbi.nlm.nih.gov/pubmed/3412591http://www.ncbi.nlm.nih.gov/pubmed/19485723http://www.ncbi.nlm.nih.gov/pubmed/8826488http://www.ncbi.nlm.nih.gov/pubmed/7847866http://www.ncbi.nlm.nih.gov/pubmed/25575710http://www.ncbi.nlm.nih.gov/pubmed/16013891http://www.ncbi.nlm.nih.gov/pubmed/25599303http://www.ncbi.nlm.nih.gov/pubmed/24726925http://www.ncbi.nlm.nih.gov/pubmed/22795917http://www.ncbi.nlm.nih.gov/pubmed/19713253http://www.ncbi.nlm.nih.gov/pubmed/23543541http://www.ncbi.nlm.nih.gov/pubmed/9204652http://www.ncbi.nlm.nih.gov/pubmed/16087911http://www.ncbi.nlm.nih.gov/pubmed/19195785http://www.ncbi.nlm.nih.gov/pubmed/24500927http://www.ncbi.nlm.nih.gov/pubmed/17143845http://www.ncbi.nlm.nih.gov/pubmed/19135492http://www.ncbi.nlm.nih.gov/pubmed/18164225http://www.ncbi.nlm.nih.gov/pubmed/20921251

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