management of herpes zoster (shingles) and postherpetic neuralgia

Review

2004 © Ashley Publications Ltd ISSN 1465-6566 551

Ashley Publicationswww.ashley-pub.com

1. Introduction

2. Herpes zoster

3. Expert opinion

Management of herpes zoster (shingles) and postherpetic neuralgiaRobert W Johnson† & Tessa L WhittonPain Management Clinic, Level 4, Bristol Royal Infirmary, Bristol BS2 8HW, UK

Herpes zoster (HZ) results from recrudescence of varicella zoster virus latentsince primary infection (varicella). The overall incidence of HZ is ∼ 3/1000 of thepopulation per year rising to 10/1000 per year by 80 years of age. Approxi-mately 50% of individuals reaching 90 years of age will have had HZ. In ∼ 6%,a second attack may occur (usually several decades after the first). Patientswith HZ can transmit the virus to a non-immune individual causing varicella.HZ is not contracted from individuals with varicella or HZ. Reduced cell-medi-ated immunity to HZ occurs with ageing, explaining the increased incidence inthe elderly and from other causes such as tumours, HIV and immunosuppres-sant drugs. Diagnosis is usually clinical from typical unilateral dermatomal painand rash. Prodromal symptoms, pain, itching and malaise, are common. Themost common complication of HZ is postherpetic neuralgia (PHN), defined assignificant pain or dysaesthesia present ≥ 3 months after HZ. PHN results fromdamage and secondary changes within components of the nervous system sub-serving pain. Some motor deficit is common; severe and long-lasting paresismay rarely accompany HZ. More than 5% of elderly patients have PHN at1 year after acute HZ. Predictors of PHN are, greater age, acute pain and rashseverity, prodromal pain, the presence of virus in peripheral blood as well asadverse psychosocial factors. Therapy for acute HZ is intended to reduce acutepain, hasten rash healing and reduce the risk of PHN and other complications.Antiviral drugs are close to achieving these aims but do not entirely removerisk of PHN. Oral steroids show no protective effect against PHN. Adequateanalgesia during the acute phase may require strong opioid drugs. Nerveblocks and tricyclic antidepressants (TCAs) may reduce the risk of PHNalthough firm evidence is lacking. PHN requires thorough evaluation anddevelopment of a management strategy for each individual patient. Initialtherapy is with TCAs (e.g., nortriptyline) or the anticonvulsant gabapentin.Topical lidocaine patches frequently reduce allodynia. Strong opioids aresometimes required. Topical capsaicin cream is beneficial for a small propor-tion of patients but is poorly tolerated. NMDA antagonists have not provedbeneficial with the exception of ketamine. Transcutaneous Electrical NerveStimulation (TENS) may be effective in some cases. HZ is a common condition.Severe complications such as stroke, encephalitis and myelitis are relativelyrare whereas sight threatening complications of ophthalmic HZ are more com-mon. PHN is common, distressing and often intractable. Good managementimproves outcome.

Keywords: herpes zoster, management, postherpetic neuralgia, shingles

Expert Opin. Pharmacother. (2004) 5(3):551-559

1. Introduction

Herpes zoster (HZ) or shingles, is the clinical manifestation of recrudescence oflatent varicella zoster virus (VZV), which can remain latent in the dorsal root and

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Management of herpes zoster (shingles) and postherpetic neuralgia

552 Expert Opin. Pharmacother. (2004) 5(3)

some cranial ganglia for several decades following primaryinfection with varicella. Its incidence increases with age; clini-cal features are frequently more severe and complications,especially postherpetic neuralgia (PHN), are also more com-mon in the elderly. Pain associated with HZ infection maynecessitate hospital admission; more rare complications of theacute illness may be sight- or life-threatening. PHN, althoughnot dangerous in itself, is associated with significant loss offunction, reduction in quality of life and significant cost topatient, carers and healthcare providers. Depression and socialisolation in the face of uncontrolled PHN may lead to despairand consideration of suicide. Even though no treatment relia-bly cures PHN, available modalities, alone or in combination,together with education and psychological support, mayrelieve the condition in some or make it more bearable in oth-ers. Most cases of HZ and PHN can be managed in a primarycare setting [1].

2. Herpes zoster

2.1 EpidemiologyA strong correlation between incidence of HZ infection andincreasing age has consistently been shown. Hope-Simpsondemonstrated an incidence of 3.4/1000 population per yearoverall, with a direct relationship to age such that the inci-dence in those in their 80s was 10/1000 per year [2]. A retro-spective study of records in Minneapolis confirmed Hope-Simpson’s findings but with a lower incidence, probably dueto under-reporting [3]. Both studies confirmed ongoing painas the most common complication. More recently, the inci-dence of HZ was shown to rise with increasing age to11.8/1000 person-years in persons > 65 years of age [4]. In∼ 6% of individuals, a second attack occurs, often after aninterval of several decades. Even though the effect on inci-dence of HZ of childhood vaccination against varicellaremains uncertain at this time, it is probable that it willincrease in the short-term [4].

The incidence of PHN also rises with increasing age with aprevalence rate recently demonstrated as 27.4 times higher inindividuals > 50 than in those < 50 years of age [5]. In theUK, ∼ 200,000 individuals develop HZ annually and, ofthese, 10,000 may proceed to PHN lasting > 12-months.Bowsher estimates that, at any one time 200,000 individualsin the UK have PHN. A lesser incidence of PHN comparedwith other published data has been reported in Iceland [6],with pain still present at 3 months in only 1.8% of those< 60 years of age and in 6.95% of patients > 60 years of age.There are currently 2.4 million people > 80 years of age inthe UK. By 2040 this number is expected to increase to4.4 million.

It may be expected that both frequency, age-distributionand disease characteristics of HZ have changed over recentdecades and will change further as longevity increases and thelive attenuated vaccine against varicella (OKA strain) becomeswidely used in infants. The vaccine is in general use in some

populations (e.g., US) for childhood administration to pre-vent varicella and is being investigated for administration toadults with the expectation that the incidence and/or severityof HZ may be reduced [7]. In addition, immunosuppressivetherapy is used in a wide range of diseases and after organtransplantation. HZ is common in HIV-infected patients andits epidemiology will also be relevant. Close surveillance ofboth varicella and HZ will be crucial.

2.2 Transmission and recrudescenceA patient with HZ may transmit the virus to a non-immuneindividual causing varicella. No mechanism has been shownby which HZ may be contracted either from a patient withvaricella or with HZ.

During the period between primary infection with varicellaand the development of HZ due to recrudescence of the latentvirus, cell-mediated immunity may be enhanced by subclini-cal virus replication and contact with individuals infectedwith varicella. Only when cell-mediated immunity to VZVdecreases does reactivation and spread occur. A decrease incell-mediated immunity is a normal feature of ageing (immu-nosenescence) and explains the increased incidence of HZ inthe elderly [8]. Several investigators have shown an age-relatedreduction in the number of T cell responders to VZV antigen,with consistently reduced lymphocyte stimulation indices inolder subjects [9,10]. Malignancies (particularly lymphomas),HIV, use of immunosuppressant medications and chemother-apeutic agents also increase the risk of developing HZ.

2.3 PathophysiologyAcute HZ involves VZV replication and spread in the dorsalroot or cranial ganglion and peripheral sensory nerve. Localspread may extend to the corresponding or adjacent dorsalroots and spinal cord and the virus may disseminate via theblood. An associated response leads to anatomical and func-tional damage to neural tissue in peripheral nerve, dorsal rootganglion and spinal cord, resulting in the onset of neuropathicpain and sensory abnormalities in the affected dermatome,although at this stage, no rash may be evident. As the virusreaches the dermis and epidermis of the affected dermatome,inflammation and blistering of the skin occur, associated withperipheral sensitisation of cutaneous nociceptors.

The precise mechanisms which account for the pain andsomatosensory changes seen in acute HZ and PHN are uncer-tain. Heat hyperalgesia is more common in subjects withacute HZ, whereas mechanical allodynia and hypoalgesia arereported more in subjects with PHN. Ectopic impulse genera-tion by damaged peripheral afferent neurons may contributeto central sensitisation, as may reduction in presynaptic inhib-itory neurons and a preponderance of excitatory neurons [11].

Motor deficiency may occur as a result of inflammationaffecting the anterior horn of the spinal cord or anteriormotor roots or may result from peripheral ‘bystander’ fibredamage [12]. It is not known whether antiviral agents or ster-oids influence outcome.

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Expert Opin. Pharmacother. (2004) 5(3) 553

It is unclear why the incidence and severity of postherpeticneuralgia increases with age. Immunosenescence plays a rolein increased susceptibility to acute HZ, although it is conjec-tural that age-related changes of the nervous system render theelderly more susceptible to damage and less amenable torepair following the insult of acute HZ [13,14].

Some authorities consider that clinical virological studiesindicate that PHN may be related to viral persistence leadingto chronic viral ganglionitis [15].

2.4 DiagnosisDiagnosis is usually clinical and is made on the basis of unilat-eral pain in a defined area accompanied by a typical rash inthe dermatomal distribution of a segmental nerve. The rash issimilar to that of chicken pox and, unless attenuated by theuse of antiviral drugs, often progresses from vesicles to scabsbefore healing with variable scarring. Prodromal pain, dysaes-thesia and malaise are common. Diagnosis of HZ in the pro-dromal period can be extremely difficult, as the rash is a majordiagnostic feature [16]. Differential diagnoses at this stage mayinclude trauma, myocardial ischaemia, renal colic, gallbladderdisease, dental pain or pleurisy. The early use of antiviraldrugs is associated with attenuation of the acute illness andwith a lower incidence of PHN (vide infra) and scarring.Avoidance of the healthcare system, fear of an adverse diagno-sis, social isolation and cognitive impairment, may all result inlate presentation of older patients with consequent delay intreatment beyond the questionable 72 h window for use ofantiviral drugs which is commonly advised.

Occasionally, a painless rash or one where pain is delayeduntil the rash has healed, may occur. Also, pain without rash(zoster sine herpete) is described. Frequent recurrences shouldarouse suspicion that the diagnosis is incorrect – zosteriformherpes simplex is likely [17].

2.5 Clinical features2.5.1 Acute herpes zosterIn many individuals, HZ is a self-limiting disease causing nomore than 2 or 3 weeks of rash, pain and malaise. A prodromeof malaise, dysaesthesia and pain in the affected dermatome iscommon. The rash is almost invariably unilateral and coverspart or all of the distribution of a segmental nerve. The erup-tion is initially maculopapular and is followed by the develop-ment of vesicles which typically crust within 7 – 10 days toform scabs. Once these fall off, scarring, hyper- or hypopig-mentation may remain and can be extensive and disfiguring.

Pain may be burning or aching in nature, with superim-posed shooting or stabbing pains plus associated itching andother sensory disturbances. Allodynia and hyperalgesia maybe present, making the wearing of clothes over the affectedarea impossible. Hospital admission may be necessary due tothe severity of symptoms, complications or inadequate homecare facilities. One study of 105 patients with acute HZadmitted as in-patients found a mean age of 79 years and apreponderance of trigeminal HZ. Length of stay varied from

1 to 70 days (median: 11 days) and rose exponentially withthe patients’ age [18].

In a small number of patients, severe complications occur.Ocular damage (and subsequent impaired vision) may com-plicate HZ ophthalmicus. Prompt referral of patients withophthalmic division HZ that affects the eye to an ophthal-mologist is recommended. Granulomatous arteritis of the cer-ebral vessels can result in stroke, sometimes weeks or monthsafter the acute illness [19]. The triad of hearing loss, vertigoand facial paresis is seen in Ramsay-Hunt syndrome. HZencephalitis may present in the elderly as cognitive impair-ment or confusion with or without evidence of recent HZinfection [20]. HZ myelitis has also been reported.

Secondary bacterial infection may be superimposed on therash and require antibiotic treatment and careful dressing.

A degree of motor deficit is common but often goes unde-tected clinically, especially where intercostal muscles areaffected. Severe and long-lasting motor deficit may accom-pany HZ affecting cervical and lumbosacral dermatomes(limb innervation) leading to significant disability. Clinicallydiscernible motor deficit has been recorded as occurring in1 – 5% of HZ patients [12]. In a much greater subset, signifi-cant pain persists for months or years (PHN).

2.5.2 Postherpetic neuralgiaPHN lacks a universally accepted definition. The definitionproposed by Dworkin & Portenoy is acceptable to many andsuggests that PHN exists when significant pain or dysaesthesiapersists or recurs for ≥ 3 months after rash healing [21]. Defini-tions used in studies of PHN have been arbitrary but recentresearch supports the distinction between three phases of pain:acute pain occurring within 30 days after rash onset; pain thatpersists ≥ 120 days after rash onset (PHN); and subacute her-petic neuralgia (pain that persists beyond the acute phase butresolves before the diagnosis of PHN can be made) [22,23].PHN includes some or all of the following characteristics [24]:

• spontaneous aching or burning• paroxysmal shooting pains• allodynia (pain evoked by application of a mild normally

non-noxious stimulus – this may be static or dynamic,heat, cold or tactile)

• hyperalgesia (severe pain evoked by application of a normally mildly painful stimulus)

• intense itching

In addition to being severe, PHN is often prolonged. Approx-imately 22% of patients with HZ still have spontaneousand/or evoked pain 3 months after rash appearance. At 1 year,∼ 5 – 10% still have PHN and by this stage further spontane-ous resolution is limited.

2.5.3 Prediction of riskIt is now well demonstrated that certain features present dur-ing acute HZ predict risk of ongoing pain. Older age, acutepain severity, rash severity, prodromal pain and presence of



virus in peripheral blood as well as adverse psychosocial fac-tors all indicate increased risk of developing PHN. It has beenshown that they are independent predictors and not all arefunctions of greater age [25]. Others are investigating the phys-iological ageing status of the nervous system at the time ofinfection as a possible factor in development of PHN [13,14].

2.6 CostComparison of the cost of active management aimed at pre-vention of PHN with the cost of no treatment or sympto-matic management of the acute disease and its long-termsequelae is appropriate. In human terms, the cost can only besurmised with patients and clinicians being in no doubtregarding the sometimes devastating consequences.

In financial terms, estimates of disease prevalence and eval-uation of disease management from specialist centres permitestimates of lifetime and episode costs. Davies et al. [26] in1994 estimated the lifetime cost of managing PHN to beUK£770 for a single patient and that an annual nationalspending on PHN (in the UK) might be between UK£4.8and 17.9 million. Another model estimated the cost-effective-ness of antiviral treatment compared to no treatment and con-cluded that antiviral therapy of HZ is cost-effective in patients≥ 50 years of age and for severe-acute HZ in all adults [27].

2.7 Management2.7.1 Acute herpes zosterTherapy at this stage is intended to reduce acute symptoms ofpain and malaise, to prevent rash progression and hasten rashhealing, thus limiting scarring and to reduce the risk of PHN.In the case of ophthalmic HZ and disease in immunocompro-mised patients, it should also reduce risk of complicationsother than PHN. In patients with pain but no rash (i.e., possi-ble prodrome) empirical antiviral treatment should not beoffered but patients should be asked to return promptly if arash develops [16].2.7.1.1 Antiviral drugsThe antiviral drugs acyclovir, valaciclovir, famciclovir and briv-udine, significantly reduce the risk of prolonged pain as well asreducing acute pain, hastening rash healing and shortening theperiod of viral shedding [26]. They also reduce the risk of severeeye disease in ophthalmic HZ. The more bioavailable

prodrugs, valaciclovir and famciclovir are more effective thanacyclovir [28] and more convenient to take (three versus fivetimes daily administration). Brivudine has the potential disad-vantage of risk associated with concomitant administration of5-fluorouracil but appears to be effective [29].

Considering the good safety profile, beneficial effect onacute symptoms and partial but significant protective effectagainst PHN (risk of PHN is approximately halved) it is disap-pointing that more patients are not offered this therapy. Thedrugs are well-tolerated in most elderly patients, althoughheadache and nausea are frequently noted, albeit with similarfrequency to placebo groups of some studies (Table 1).2.7.1.2 SteroidsThe addition of oral steroids to acyclovir showed no protec-tive effect against PHN in two large studies [30,31]. There weresome acute benefits in both studies and an increased incidenceof adverse events in one. There may be other indications forthe use of steroids in some patients.2.7.1.3 AnalgesiaA paracetamol and weak opioid compound is effective inmany; stronger opioids (e.g., dihydrocodeine, tramadol, oxyco-done, morphine) are required by some and should not be with-held, but doses should reflect the age and frailty of the patient.2.7.1.4 SupportAn explanation of the disease and reassurance should accom-pany analgesia, as should encouragement to socialise and returnto premorbid activities as soon as acute symptoms subside.2.7.1.5 Nerve blocksA number of case series and anecdotal reports have proposedthe use of sympathetic and somatic nerve blocks to controlacute pain and prevent PHN. Some recent large studies havebeen reported and would suggest that epidural local anaes-thetic [32] or local anaesthetic with steroid [33] administeredover a period of days or weeks reduces duration of pain. Possi-bly, when predictive scores for PHN are refined and able toaccurately define a small group of very high-risk patients, thistherapy may be more widely offered. An excellent review of theuse of nerve blocks in HZ has been written by Wu et al. [34].2.7.1.6 Tricyclic antidepressantsThe use of tricyclic antidepressants (TCAs) during the acutedisease, with or without antiviral drug, may reduce the inci-dence of PHN [35]. Anticonvulsant drugs such as gabapentin

Table 1. Proportions of patients (≥ 50 years of age) with persisting pain in controlled trials of antiviral therapies for herpes zoster.

Acyclovir versus placebo (%)

Valaciclovir versus acyclovir (%)

Valaciclovir versus famciclovir (%)

Famciclovir versus placebo (%)

Dosage (800 mg five times daily for 7 – 10 days)

(1000 mg t.i.d. for 7 days) 1000 mg t.i.d. for 7 days versus(500 mg t.i.d. for 7 days)

(500 mg t.i.d. for 7 days)

Pain (PHN) at 3 months (%) 25 versus 54* 31 versus 38‡ 32 versus 34¶ 34.9 versus 49.2*

Pain (PHN) at 6 months (%) 15 versus 35* 19.9 versus 25.7§ 19 versus 19¶ 19.5 versus 40.3*

*p < 0.05 from 95% confidence interval for the relative risk for the difference between treatments. ‡Glaxo Wellcome (RJ Crooks), personal communication. §p = 0.08. ¶p = 0.84 from 95% confidence interval for the relative risk for the difference between treatments.PHN: Postherpetic neuralgia.

Johnson & Whitton


may offer a similar protective effect but so far no reports havebeen published.

2.7.2 Postherpetic neuralgia2.7.2.1 EvaluationBefore any appropriate management strategy can be devel-oped for an individual patient, it is essential to assess allaspects of the condition including psychosocial status, neuro-logical changes and concomitant disease.2.7.2.2 First-line therapyFollowing thorough evaluation and explanation of PHN to thepatient and general advice regarding activity levels, social inter-action, use of natural fibre clothing and ice packs, initial ther-apy will normally be with a TCA drug or gabapentin [36]. It isreasonable to extrapolate from existing high quality studies thatboth drugs are similarly efficacious with NNTs (numberneeded to treat) of ∼ 2.6 and 4.4, respectively. Tricyclics havemore adverse side effects and are more likely to interact withother drugs and diseases processes. The NNH (number neededto harm) is ∼ 5.7 for tricyclics and 4.1 for gabapentin. Gabap-entin is more expensive but better tolerated with a higher safetyprofile [37]. A given patient may respond favourably to either,neither or both. There is no published evidence regarding possi-ble benefits of prescribing both drugs concurrently althoughanecdote suggests that this may be useful.2.7.2.3 Tricyclic antidepressantsAmitriptyline, nortriptyline, desipramine and maprotilinehave all been used with some benefit in PHN [38-40]. All affectneuropathic pain independent of the presence of depression.Drugs affecting noradrenaline re-uptake are more effectivethan those affecting serotonin re-uptake. Nortriptyline seemsslightly more acceptable to patients than amitriptyline anddesipramine (no longer available in the UK) is less sedative[41,42]. Analgesia probably results from both central andperipheral actions. Patients need to be told that the drug isbeing used as a pain relief treatment not for depression or enu-resis. They need to be aware of the side effects of drowsiness,dry mouth, constipation and increased appetite and be taughtmeans of coping with these (e.g., high fibre diet, artificial salivaspray or lozenges). Blurred vision, urinary retention and exac-erbated glaucoma may rarely occur. It is preferable to prescribethese drugs for once-daily use ∼ 1.5 h before bedtime. Thenormal starting dose of 25 mg (reduced to 10 or even 5 mg inthe elderly and frail), increased by weekly increments of25(10)mg to a dose dictated by optimum balance of benefitversus side effects, should minimise adverse effects [43].

If one tricyclic drug does not produce benefit, it is appro-priate to try an alternative. Amitriptyline is the least expensivedrug of the group. Clinical experience suggests that the earlierthe treatment is commenced, the better the effect.2.7.2.4 Anticonvulsants2.7.2.4.1 GabapentinEvidence for the benefit of anticonvulsants in PHN was lack-ing until the publication of a report by Rowbotham et al. [44]

of a randomised, double-blind, large-scale clinical trial

evaluating the use of gabapentin for this indication [44].Patients receiving up to gabapentin 3600 mg/day exhibited asignificant reduction in average daily pain score compared withthe placebo group (p < 0.001). Gabapentin was effective notonly in pain control but also in the treatment of sleep interfer-ence associated with PHN, which in turn, improved mood andquality of life. Reported adverse effects included somnolence,dizziness, ataxia, peripheral oedema and infection. However,the number of withdrawals due to side effects was similar tothat seen with placebo. Confirmation of the beneficial effectsof gabapentin has been provided by Rice et al. [45].

Achieving compliance requires careful discussion with thepatient of expected benefits and side effects, the rate of doseelevation and the target dose. In our experience the rate ofdose elevation advised by the manufacturer’s data sheet is toorapid for many elderly patients and may need modification onan individual basis. In the UK the recommended maximumdose for neuropathic pain is 1800 mg/24-h. Once good anal-gesia has been attained the patient may remain on a stabledose for ∼ 2 months before careful titration downwards toestablish the minimum effective dose.

Few, if any, studies of the older drugs, phenytoin, car-bamazepine and sodium valproate that would justify inclusionin contemporary meta-analyses, have been undertaken.Lamotrigine, vigabactrin and topiramate may all have someeffect. Side effects of lamotrigine are similar to those of otheranticonvulsants but dermatological complications may bemore common and more severe. The benefit to side effectratio is an important factor in planning therapy and this prob-ably explains the current popularity of gabapentin [36,46].

Pregabalin, a new anticonvulsant drug and analogue ofgabapentin undergoing trials for neuropathic pain, has beenshown to significantly decrease pain and improve sleep in arecent double-blind, placebo-controlled, randomised trial ofPHN patients. Side effects were reported as mild-to-moderateand the drug was generally well-tolerated (Table 2) [47].2.7.2.5 Topical drugs2.7.2.5.1 5% Lidocaine patchWhere allodynia (pain in response to application of a normallynon-noxious stimulus such as light brushing or a cool breeze)is a significant component of PHN, topical application of

Table 2. Approximate costs for 30 days treatment.

Drug Dosage (mg/24-h)

Monthly cost (UK£)

Amitriptyline 50 1.29

Nortriptyline 50 15.12

Gabapentin 1800 95.40

Oxycodone 40 45.92

Methadone 15 5.35

Morphine (delayed release) 30 10.68

From The British National Formulary, September (2003).



local anaesthetic may be valuable. A preparation of 5% lido-caine absorbed into a self-adhesive patch (Lidoderm®) whichmay be cut to the size and shape of the affected area, is availa-ble. Published trials and personal experience suggest a highlevel of satisfaction. Local irritation may be minimised by agradual increase in the time for which the patch is worn in thefirst few days or weeks [48,49].2.7.2.5.1 CapsaicinCapsaicin (N-Vanillyl-8-methyl-6-(E)-noneamide) is a pun-gent derivative of hot chilli peppers, which when applied tosensory nerve tissue first stimulates then inhibits (by causingdepletion of the neurotransmitter substance P) activity innociceptive C-fibres. Topical applications of concentrationsvarying from 0.025 to 0.075% have been studied in a numberof painful conditions including osteoarthritis of the knee andPHN. A 0.075% preparation of capsaicin has been reportedto provide a significant benefit in the treatment of PHN [50].However, many patients reject this treatment because of per-sistent unpleasant burning sensation.2.7.2.6 OpioidsIt is well-established that contrary to older beliefs, opioidsmay be effective in controlling neuropathic pain. It is essentialwhen administering any opioid to consider the age and frailtyof the patient and to anticipate the need to treat nausea andconstipation. Weaker opioids such as dihydrocodeine and tra-madol may be useful [52,53]. Morphine and methadone haverecently been compared to TCAs and placebo in a double-blind, crossover trial. Both opioids and TCAs were effective inreducing pain when compared to placebo, although morepatients preferred opioids to TCAs (p = 0.02) [54].

Levorphanol, a potent mu-agonist, has been found to sig-nificantly reduce pain in patients with neuropathic pain,including those with PHN. Pain relief was dose-dependent, aswere side effects, with no improvement in other outcomemeasures at higher doses [55].

Controlled-release oxycodone has been studied, with acrossover trial demonstrating significantly greater pain relief(p < 0.0001) and reduction of allodynia (p = 0.0004) thanwith placebo in 50 patients with PHN. The average dose inthe last week was 45 mg/day [56].2.7.2.7 NMDA antagonistsThere has been a single controlled trial of ketamine for thetreatment of PHN, which suggested efficacy versus opiate andplacebo in a small number of patients [57]. Another NMDAantagonist, dextromethorphan, did not reduce pain in13 patients with established PHN when compared with pla-cebo, although the drug was found to be effective in diabeticneuropathy in the same trial [58]. A crossover trial of dex-tromethorphan and memantine versus active placebo did notdemonstrate any advantage of either drug over placebo [59].2.7.2.7.1 Nerve blocks and surgeryIn extreme cases of PHN refractory to other measures, patientsand physicians have resorted to surgery and there is anecdotalevidence for skin excision, sympathectomy, dorsal root entryzone lesions, cordotomy, thalamotomy, cingulumotomy and

spinal cord and deep brain stimulation. Undoubtedly somepatients have gained benefit but many more have not, in somecases developing severe deficits, particularly anaesthesia dolor-osa following peripheral nerve lesions or cordotomy.

In contrast, effectiveness of intrathecal methyl prednisolonein patients with long standing PHN which had been resistantto conventional therapy has been reported [60]. Serious adverseevents were not evident up to 2 years after treatment despiterepeat magnetic resonance imaging scanning of the spinal cord.Controversy exists because of the perceived risk of arachnoiditiswhich some believe may develop as a very delayed complicationand which has been reported in patients treated in this way forpain associated with multiple sclerosis in the past.

Intrathecal administration of methylprednisolone wasfound to be effective for the treatment of PHN in a ran-domised study of 270 patients who had had treatment-resist-ant PHN for at least 1 year. Intrathecal methylprednisoloneand lidocaine was compared to intrathecal lidocaine and to notreatment. Pain was evaluated at the end of the 4-week studyperiod, then at 4 weeks, 1- and 2 years later and found to besignificantly reduced in the lidocaine with steroid group.

Until or unless a carefully designed study confirms thesefindings, it would seem unwise to adopt this therapy in viewof the serious concerns regarding safety [61,62].2.7.2.8 Other treatmentsHomoeopathy, acupuncture, TENS (transcutaneous electricalnerve stimulation), topical geranium or peppermint oil orbenzydamine, cryotherapy and many others have beenreported, but satisfactory evidence of efficacy is lacking. Vinc-ristine administered by iontophoresis is ineffective.

2.7.3 Pain management programmesMultidisciplinary pain management programmes exist forsufferers of pain not controlled by conventional or comple-mentary therapies. Their effectiveness in returning patientsto employment has been validated but little evidence is avail-able that they impact on independence, mobility and qualityof life in the elderly. A multidisciplinary approach includinginput from psychologists experienced in working withchronic pain patients, may be an effective way to managethose patients with overwhelming pain. Further research inthis area is underway.

2.7.4 Guidelines A number of Guidelines for HZ and PHN management existbut earlier ones do not conform with the contemporaryrequirements for such documents. The IHMF (InternationalHerpes Management Forum) has published peer-reviewedguidelines [63]. The guidelines, the evidence on which they arebased and a management algorithm may be accessed at theIHMF website [101].

2.7.5 SummaryIn summary, effective treatment of established PHN is likelyto be multimodal and may involve:

Johnson & Whitton


• prevention of PHN by active management of acute HZ• TCAs (initiated at 10 – 25 mg)• anticonvulsants (gabapentin 300 – 1800 mg/day or more)• opioids (tramadol, oxycodone, methadone or morphine)• topical agents (lidocaine or capsaicin)• education, counselling and support

3. Expert opinion

Widespread adoption of a varicella vaccine for childhood usemay be expected to eradicate wild type varicella in due

course. Approximately two generations later, HZ should sim-ilarly disappear. In the meantime, the influence of varicellavaccine on HZ is less certain and may increase the incidenceof HZ [4]. Results of a major study of the effects of adult vac-cination are awaited.

Although pharmacotherapy is likely to remain the mainstayof treatment, more trials are needed to elucidate the efficacyof regional blocks and to properly evaluate a number of thetreatment options in use today. New drugs acting on specificneural targets will be developed as our understanding of thepathophysiology of pain improves.

BibliographyPapers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

1. JOHNSON RW, DWORKIN RH: Treatment of herpes zoster and postherpetic neuralgia. Br. Med. J. (2003) 326:748-750.

2. HOPE-SIMPSON RE: The nature of herpes zoster: a long-term study and a new hypothesis. Proceedings of the Royal Society of Medicine (1965) 58:2-20.

•• A seminal paper describing epidemiology and relationship of varicella to HZ. Edgar Hope-Simpson died at the age of 95 in 2003.

3. RAGGOZINO MW, MELTON LJ, KURLAND LT: Population-based study of herpes zoster and its sequelae. Medicine (1982) 61:310-316.

4. BRISSON M, EDMUNDS WJ: Varicella vaccination: impact of vaccine efficacy on the epidemiology of VZV. J. Med. Virol. (2003) 70(Suppl. 1):S31-S37.

5. CHOO PW, GALIL K,DONAHUE, J G, WALKER AM, SPIEGELMAN D, PLATT R: Risk factors for postherpetic neuralgia. Arch Intern. Med. (1997) 157(11):1217-24.

6. HELGASON S, PETURSSON G, GUDMUNDSSON S, SIGURDSSON JA: Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long term follow up. Br. Med. J. (2000) 321:794-796.

7. OXMAN MN: Immunization to reduce the frequency and severity of herpes zoster and its complications. Neurology (1995) 45(Suppl.8): S41-45.

•• Discussion of the possible place of adult vaccination to enhance immunity to VZV

8. WEKSLER ME: Immune senescence. Ann. Neurol. (1994) 35(Suppl.):S35-S37.

9. BERGER R, FOREST G, JUST M: Decrease of the lymphoproliferative response to varicella-zoster antigen in the aged. Infection and Immunology (1981) 32:24-27.

10. BURKE BL, STEELE RW, BEARD OW, WOOD JS, CAIN TD, MARMER DJ: Immune responses to varicella zoster in the elderly. Arch. Intern. Med. (1982) 142:291-293.

11. BENNETT GJ: Hypotheses on the pathogenesis of herpes zoster-associated pain. Ann. Neurol. (1994) 35(Suppl.):S38-S41.

12. HAANPAA MD, HAKKINEN V, NURMIKKO T: Motor involvement in acute herpes zoster. Muscle Nerve (1997) 20:1433-1438.

•• Authoritative work on motor deficiency and HZ.

13. BARON R, HAENDLER G, SCHULTE H: Afferent large fibre polyneuropathy predicts the development of postherpetic neuralgia. Pain (1997) 73:231-238.

14. WHITTON T, HOWELL T, JOHNSON RW: Use of the Rydel-Seiffer graduated tuning fork in the assessment of vibration threshold in postherpetic neuralgia patients and healthy controls. Abstract 422.T, ‘Pain in Europe IV’, 4th congress of EFIC -the European Federation of the International Association for the Study of Pain, Prague, September 2 – 6 (2003).

15. GILDEN DH, COHRS RJ, HAYWARD AR, WELLISH M, MAHALINGAM R: Chronic varicella zoster vitus ganglionitis – a possible cause for postherpetic neuralgia. J. Neuro. Virol. (2003) 9:404-407.

•• Discussion of possible persistence of VZV as a cause of PHN

16. McKENDRICK MW, CARE CC, KUDESIA G, BATES CJ, OXLEY MK,

ELEY A: Is VZV reactivation a common cause of unexplained unilateral pain? Results of a prospective study of 57 patients. J. Infect. (1999) 39(3):209-212.

17. KALMAN CM, LASKIN OL: Herpes zoster and zosteriform herpes simplex virus infections in immunocompetent adults. Am. J. Med. (1986) 81:775-778.

18. TORRENS J, NATHWANI D,MACDONALD T, DAVEY PG: Acute herpes zoster in Tayside: Demographic and treatment details in immunocompetent patients between 1989 – 1992. J. Infect. (1998) 36:209-214.

19. MARTIN JR, MITCHELL J, HENKEN DB: Neurotropic herpes viruses, neural mechanisms and arteritis. Brain Pathol. (1990) 1:6-10.

20. GILLANDERS I, MACKAY J, CAMPBELL F, MACLENNAN WJ: Herpes zoster encephalitis in the elderly. Postgrad. Med. J. (1994) 70(830):940 (Letter).

21. DWORKIN RH, PORTENOY RK: Proposed classification of herpes zoster pain. Lancet (1994) 343:1648.

22. ARANI RB, SOONG SJ, WEISS HL, WOOD MJ, FIDDIAN PA, GNANN JW, WHITLEY RJ et al.: Phase specific analysis of herpes zoster associated pain data: a new statistical approach. Stat. Med. (2001) 20:2429-2439.

•• Evidence for the three phase model of pain associated with HZ.

23. DESMOND RA, WEISS HL, ARANI RB et al.: Clinical application for change-point analysis of herpes zoster pain. J. Pain Symptom Manage. (2002) 23:510-516.

24. OAKLANDER AL, BOWSHER D, GALER B, HAANPAA M, JENSEN MP: Herpes zoster itch: preliminary epidemiologic data. Pain (2003) 4(6):338-43.



25. JUNG BF, JOHNSON RW, GRIFFIN DRJ, DWORKIN RH: Risk factors for postherpetic neuralgia in patients with herpes zoster. Accepted for publication in Neurology.

•• An analysis of a large cohort of HZ patients.

26. DAVIES L, COSSINS L,BOWSHER D, DRUMMOND M: The cost of treatment for postherpetic neuralgia in the United Kingdom. Pharmacoeconomics (1994) 6:142-148.

27. SMITH KJ, ROBERTS M.S: Cost effectiveness of newer antiviral agents for herpes zoster: is the evidence spotty? J. Infect. Dis. (1998) 178(Suppl.1):S85-S90.

28. WOOD MJ, KAY R, DWORKIN RH, SOONG SJ, WHITLEY RJ: Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin. Infect. Dis. (1996) 22:341-347.

29. BEUTNER KR, FRIEDMAN DJ, FORSZPANIAK C, ANDERSEN PL, WOOD MJ: Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob. Agents Chemother. (1995) 39:1546-1553.

30. WASSILEW SW, WUTZLER P, BRIVUDIN HERPES ZOSTER STUDY GROUP: Oral brivudin in comparison with acyclovir for herpes zoster: a survey study on postherpetic neuralgia. Antiviral Res. (2003) 59(1):57-60.

31. WOOD MJ, JOHNSON RW, MCKENDRICK MW, TAYLOR J, MANDAL BK, CROOKS JA: Randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N. Engl. J. Med. (1994) 330:896-900.

•• First evidence for lack of effectiveness of oral steroid in preventing PHN.

32. WHITLEY RJ, WEISS H, GNANN JW Jr et al.: Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann. Intern. Med. (1996) 125(5):376-383.

33. HIGA K, HORI K, HARASAWA I, HIRATA K, DAN K : High thoracic epidural block relieves acute herpetic pain involving the trigeminal and cervical regions: Comparison with effects of stellate

ganglion block. Reg. Anesth. Pain Med. (1998) 23:25-29.

34. PASQUALUCCI A, PASQUALUCCI V, GALLA F et al.: Prevention of post-herpetic neuralgia: acyclovir and prednisolone versus epidural local anesthetic and methyl prednisolone. Acta Anaesthesiol. Scand. (2000) 44:910-918.

35. WU CL, MARSH A, DWORKIN RH: The role of sympathetic nerve blocks in herpes zoster and postherpetic neuralgia. Pain (2000) 87:121-129.

36. BOWSHER DR: The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial. J. Pain Symptom Manage. (1997) 13:327-331.

37. COLLINS SL, MOORE RA, MCQUAY HJ: Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J. Pain Symptom Manage. (2000) 20(6):449-458.

38. DALLOCCHIO C, BUFFA C, MAZZARELLO P, CHIROLI S: Gabapentin versus amitriptyline in painful diabetic neuropathy: an open-label pilot study. J. Pain Symptom Manage. (2000) 4:280-285.

39. GRAFF-RADFORD SB, SHAW LR, NALIBOFF BN: Amitriptyline and fluphenazine in the treatment of postherpetic neuralgia. Clin. J. Pain (2000) 16:188-192.

40. WATSON CP, EVANS RJ, REED K, MORSKY H, GOLDSMITH L, WARSH J: Amitriptyline versus placebo in postherpetic neuralgia. Neurology (1982) 32:671-673.

41. WATSON CP, CHIPMAN M, REED K, EVANS RJ, BIRKETT N: Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial. Pain (1992) 48:29-36.

42. WATSON CP, VERNICH L, CHIPMAN M, REED K: Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology (1998) 51:1116-1171.

43. KISHORE-KUMAR R, MAX MB, SCHAFER SC et al.: Desipramine relieves postherpetic neuralgia. Clin. Pharmacol. Ther. (1990) 47(3):305-312.

44. MCCUE RE: Using tricyclic antidepressants in the elderly. Clin. Geriatr. Med. (1992) 8(2):323-334.

45. ROWBOTHAM M, HARDEN N, STACEY B, BERNSTEIN P, MAGNUS-MILLER L: Gabapentin for the treatment of postherpetic neuralgia. J. Am. Med. Assoc. (1998) 280(21):1837-1842.

•• First clear evidence for effectiveness of gabapentin in PHN.

46. RICE ASC, MATON S, POSTHERPETIC NEURALGIA STUDY GROUP: Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain (2001) 94:215-224.

47. GERSON GR, JONES RB, LUSCOMBE DK: Studies on the concomitant use of carbamazepine and clomipramine for the relief of post-herpetic neuralgia. Postgrad. Med. J. (1977) 53(Suppl.4):104-109.

48. DWORKIN RH, CORBIN AE, YOUNG JP Jr et al.: Pregabalin for the treatment of postherpetic neuralgia. A randomized, placebo-controlled trial. Neurology (2003) 60:1274-1283.

49. DEVERS A, GALER BS: Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clin. J. Pain (2000) 16:205-208.

50. ROWBOTHAM MC, DAVIES PS, VERKEMPINCK C, GALER B: Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain (1996) 65:39-44.

51. WATSON CPN, EVANS RJ, WATT VR et al.: A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin. Ther. (1993) 15(3):510-526.

52. GOBEL H, STADLER T: Traitement des douleurs post-zosteriennes par le tramadol. Clin. Drug Invest. (1995) 10(4):208-21.

53. BOUREAU F, LEGALLICIER P, KABIR-AHMADI M: Tramadol in postherpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain (2003) 104:323-331.

54. RAJA SN, HAYTHORNTHWAITE JA, PAPPAGALLO M et al.: Opioids versus antidepressants in postherpetic neuralgia. A randomized, placebo-controlled trial. Neurology (2002) 59:1015-1021.

55. ROWBOTHAM MC, TWILLING L, DAVIES PS REISNER L, TAYLOR K, MOHR D: Oral opioid therapy for chronic peripheral and central neuropathic pain. N. Engl. J. Med. (2003) 348(13):1223-1232.

Johnson & Whitton


56. WATSON CPN, BABUL N: Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology (1998) 50:1837-1841.

•• Evidence for effectiveness of opioid in neuropathic pain.

57. EIDE PK, JORUM E, STUBHAUG S, BREMNES J, BREIVIK H: Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain (1958) 58:347-354.

58. NELSON KA, PARK KM, ROBINOVITZ E, TSIGOS C, MAX MB: High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology (1997) 48:1212-1218.

59. SANG CN, BOOHER S, GILRON I, PARADA S, MAX MB: Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia. Anesthesiology (2002) 96:1053-1061.

60. KOTANI N, KUSHIKATA T, HASHIMOTO H et al.: Intrathecal methylprednisolone for intractable postherpetic neuralgia. N.Engl. J. Med. (2000) 23:1514-1519.

61. NELSON DA: Dangers from methylprednisolone acetate therapy by intraspinal injection. Arch. Neurol. (1988) 45:804-806.

62. NELSON DA, LANDAU WM: Intraspinal steroids: history, efficacy, accidentality and controversy with review of United States Food and Drug Administration reports. J. Neurol. Neurosurg. Psychiatry (2001) 70(4):433-443.

63. INTERNATIONAL HERPES MANAGEMENT FORUM WORKSHOP: Improving the management of varicella, herpes zoster and zoster-associated pain. Johnson RW, Patrick D (Eds), Parexel MMS ISBN 0 904052 745 (2001).

Websites101. http://www.IHMF.org

The International Herpes Management Forum website.

Recommended readingVaricella-Zoster Virus. Virology and Clinical Management. Arvin AM, Gershon AA (Eds), Cambridge University Press, Cambridge, UK (2000) ISBN:0 521 660246.

Neuropathic Pain: Pathophysiology and Treatment. In: Progress in Pain Research and Management (Vol. 21). Hansson P, Fields H, Hill R, Marchettini P (Eds), IASP Press, Seattle, USA (2001). ISBN:0-931092-38-8.

A Belt of roses from hell: pain in herpes zoster and postherpetic neuralgia. In: Handbook of Pain Syndromes. Block A, Kremer E, Fernadez E (Eds), Lawrence Erlbaum Associates, London & Mahwah, New Jersey, USA (1999)ISBN:0-8058-2680-7.

Herpes Zoster and Postherpetic Neuralgia. Pater C, Watson N (Eds), Elsevier, Amsterdam, The Netherlands (2001). ISBN:0 444 89271 0.

Herpes Virus Infections. Glaser R, Jones J (Eds), Dekker, New York, USA (1994). ISBN 0-8247-8867-2.

AffiliationRobert W Johnson MB, BS, FRCA† & Tessa L Whitton BM, FRCA†Author for correspondencePain Management Clinic, Level 4, Bristol Royal Infirmary, Bristol, BS2 8HW, UKFax: +44 1275 392778;E-mail: [email protected]

management of herpes zoster (shingles) and postherpetic neuralgia

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