Journal of Clinical Virology 48 (2010) S1, S20–S28

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Journal of Clinical Virology

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Management of herpes zoster and post-herpetic now and in the future

Richard J. Whitleya, *, Antonio Volpib, Mike McKendrickc, Albert van Wijckd, Anne Louise Oaklandere aUniversity of Alabama at Birmingham, CHB 303, 1600-Seventh Avenue South, Birmingham, AL 35233, USA bDepartment of Public Health, University of Rome Tor Vergata, Via Montpellier 1, 00133 Roma, Italy c South Yorkshire Regional Department of and Tropical Medicine, Royal Hallamshire Hospital, Sheffield S10 2JF, UK dPain Clinic, Department of Anaesthesiology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands eHarvard Medical School, Nerve Injury Unit, Massachusetts General Hospital, 275 Charles Street, Boston, MA 02214, USA article info summary

Keywords: Herpes zoster (HZ; ) – a reactivation of the latent (VZV) – can cause Zoster significant morbidity. Its major complication is , particularly post-herpetic neuralgia (PHN). VZV We will review the current management strategies available for the treatment of both acute HZ Antivirals and PHN, including antiviral drugs, analgesic agents, , tricyclic antidepressants and Management topical therapies. New molecules in development that show improved activity against VZV are also covered, and new drug targets are outlined. The role of translational neuroscience in moving towards a goal of finding disease-modifying treatments will be examined. © 2010 Elsevier B.V. All rights reserved.

Abbreviations 1. Introduction

HZ: herpes zoster The objectives of treating herpes zoster (HZ) are to control PHN: post-herpetic neuralgia acute pain, accelerate rash healing, minimize complications and VZV: varicella zoster virus reduce the risk of post-herpetic neuralgia (PHN) and other late- GP: general practitioner appearing sequelae. An additional objective, particularly important 5-FU: 5-fluorouracil for immunosuppressed patients, is to reduce the risk of cutaneous TTP: thrombotic thrombocytopoenic purpura and visceral dissemination of the varicella zoster virus (VZV).1 HUS: haemolytic-uraemic syndrome FDA: Food and Drug Administration ZAP: zoster-associated pain 2. Current management of acute HZ RR: risk ratio The diagnosis of HZ is generally evident at clinical presentation. DPD: dihydropyrimidine dehydrogenase However, there are situations where diagnosis is difficult, or the BVaraU: bromovinyl arabinosyl uracil patient or physician had not recognized the symptoms and signs BCNA: bicyclic nucleoside analogue early enough. Several studies indicate potential hurdles in diagnosis. SVV: simian varicella virus One seminal study tested the hypothesis that against BVDU: bromovinyldeoxyuridine VZV would decrease the incidence and/or severity of HZ and PHN HPMPA: 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine among adults aged >60 years, including the burden of illness. This PMEA: phosphonomethoxy-ethyl-adenine study involved >38,000 volunteers and demonstrated that 5–6% of TK: thymidine kinase the clinical diagnoses by academic physicians were not laboratory TCA: confirmed,2 suggesting that even knowledgeable infectious diseases ECG: electrocardiogram clinicians are occasionally wrong in their diagnosis. Similarly, a DRG: prospective study of HZ diagnoses by general practitioners (GPs) PRF: pulsed radio frequency found 17% of diagnoses to be incorrect.3 Furthermore, in a recent NE: norepinephrine study of psychosocial correlates of HZ,4 which used pain as an APN: aminopeptidase N indicator of disease onset, 92% of 533 individuals with HZ had NEP: neutral endopeptidase pain at presentation. However, only 46% sought medical attention CNS: central nervous system within 72 hours of pain onset and 54% within 72 hours of rash * Corresponding author. University of Alabama at Birmingham, appearance. Initial assessment was late, at a median time of CHB 303, 1600-Seventh Avenue South, Birmingham, AL 35233, USA. 72 hours after the onset of rash. Importantly, >80% of the subjects Tel.: +1 205 934 5316; fax: +1 205 934 8559. reported prodromal pain, which in the majority of cases lasted E-mail address: [email protected] (R.J. Whitley). 2or3days.

1590-8658 /$ – see front matter © 2010 Elsevier B.V. All rights reserved. R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28 S21

Table 1 Antivirals currently available for the treatment of HZ.

Drug Dosage a Comments, adverse events and contraindications Reference

Oral acyclovir 800 mg five times daily for • Adverse events similar to Prescribing information5 7–10 days Intravenous acyclovir 10 mg/kg three times daily • Indicated in immunocompromised patients Prescribing information5 Adults and children over 40 kg: • Adverse events include crystalluria associated with rapid infusion in patients 800 mg four times daily for with renal impairment 5days • Rarely, CNS disturbances in elderly with renal dysfunction Valacyclovir 1000 mg three times daily for • Acute hypersensitivity reactions including anaphylaxis, angioedema, Prescribing information6 7days dyspnoea, pruritus, rash and urticaria • Contraindications: Hypersensitivity to valacyclovir (e.g., anaphylaxis), acyclovir or any component of the formulation • Pregnancy category B: Should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus • In two clinical studies, adverse events included nausea, , vomiting, dizziness and abdominal pain • TTP/HUS reported in AIDS and transplant patients during clinical trials 500 mg every 8 hours for 7 days • Contraindicated in patients with known hypersensitivity to famciclovir, its Prescribing information7 components and penciclovir cream • Pregnancy category B: Should be used during pregnancy only if the benefit to the patient clearly exceeds the potential risk to the foetus • In clinical studies, adverse events included headache, , nausea and vomiting Brivudin 125 mg once daily for 7 days • Adverse events included nausea (incidence and type of potential adverse Product characteristics8 drug experiences were consistent with those known to occur with other nucleoside antiviral agents belonging to the same class) • Contraindicated in: – Patients undergoing cancer chemotherapy, especially if treated with 5-FU, including its topical preparations, its prodrugs (e.g., capecitabine, floxuridine, tegafur) and combination products containing these active substances or other 5-fluoropyrimidines – Immunocompromised patients such as those undergoing cancer chemotherapy, immunosuppressive therapy or therapy with flucytosine in severe systemic mycosis – Pregnant women or nursing mothers

Abbreviations: 5-FU, 5-fluorouracil; HUS, haemolytic-uraemic syndrome; TTP, thrombotic thrombocytopoenic purpura. a Dosage of antivirals may differ between countries. Please refer to local prescribing information.

2.1. Current antiviral therapies follows disappearance of the rash of herpes zoster’, whereas other studies used the definition of ‘pain present for more than 1 or Three oral nucleoside analogues – acyclovir, valacyclovir (prodrug 2 months after rash onset’.10 However, recent models of pain of acyclovir) and famciclovir (prodrug of penciclovir) – are resolution and statistical analysis suggest that the most appropriate approved worldwide for the treatment of HZ, including in definition of PHN is pain that persists 90 days or more after the immunocompromised patients. An additional antiviral drug, onset of HZ rash.11 brivudin, is widely available in some countries but is limited to an indication for immunocompetent patients because of a potentially In early acyclovir studies, PHN was defined as ‘persistence 30 days fatal interaction with 5-fluorouracil (5-FU) (see Table 1). after disease onset or the healing of skin’. Thus, the early acyclovir All of the antiviral drugs significantly decrease the incidence of trials and a large meta-analysis involving 691 patients suggested new lesion formation and accelerate healing and the resolution of that acyclovir (800 mg five times daily for 7–10 days) was more 12 acute pain. In addition, antiviral therapy shortens the duration of effective than placebo in reducing pain. Benefits were particularly viral shedding,1 which hypothetically may limit damage, noticeable for patients aged >50 years. Overall, the incidence and thereby reducing the incidence, severity and duration of pain. duration of PHN among patients receiving acyclovir were half those An essential component of antiviral treatment is its effects on reported by placebo recipients, and fewer acyclovir-treated patients 12 the resolution of pain. There are three forms of pain defined as had PHN at 3 and 6 months. However, this has not been proven follows. First, pain at presentation is acute pain and the extent of in a sufficiently powered prospective study. its resolution can be quantified over the first 30 days. Second, and According to ZAP analyses from various clinical studies, valacy- the most debilitating form of pain, is PHN. Several definitions of clovir (a prodrug of acyclovir) is more efficacious than acyclovir. One PHN have been used over the past 30 years, and all have different study comparing two different regimens of valacyclovir (1000 mg implications for clinical studies. PHN is defined by the US Food and three times daily for 7 days, or 1000 mg three times daily for Drug Administration (FDA) as ‘Pain that has not resolved 30 days 14 days) with acyclovir (800 mg five times daily for 7 days) after disease onset’.9 An alternative definition is pain that persists showed that the time to ZAP resolution was significantly longer after skin healing. The third form of pain is that of zoster-associated with acyclovir therapy (median time to ZAP resolution: acyclovir, pain (ZAP), whereby pain is viewed as a continuum from the time 51 days; 7-day valacyclovir, 38 days [p = 0.002]; 14-day valacyclovir, of acute zoster until its complete resolution, if it occurs. 44 days [p = 0.03]).13 Valacyclovir therapy also had a faster time To date, there is no consensus on the definition of PHN. Early to ZAP resolution that had persisted for >30 days compared with studies used a wide range of definitions, including ‘any pain that acyclovir (HR 1.24; CI 1.04–1.48; p = 0.01 for the 7-day valacyclovir S22 R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28 group; HR 1.17; CI 0.98–1.39; p = 0.09 for the 14-day valacyclovir resulted in several deaths in Japan.24 Consequently, brivudin should group). In this study, pain was recorded in 85% of the patients in not be administered concomitantly with 5-FU or its derivatives, the acyclovir group, and in 79% and 80% of the patients receiving capecitabine, floxuridine or flucytosine. As a further precaution, valacyclovir for 7 and 14 days, respectively.13 DPD activity should be monitored before starting any treatment Famciclovir is also an effective and well-tolerated therapy of with 5-fluoropyrimidine drugs in patients who have recently HZ. A study of 419 patients with HZ given either famciclovir received brivudin.25 500 mg/day or 750 mg/day for 7 days, or placebo, showed that famciclovir treatment accelerated lesion healing and decreased 2.2. The rationale for existing antiviral treatment schedules the median duration of PHN resolution.14 The efficacy-evaluable analyses revealed that time to full crusting was 1.3- to 1.5-fold Current evidence from clinical trials is based on the initiation of faster in the 500 mg famciclovir (p = 0.02) and 750 mg famciclovir therapy within 72 hours of rash outbreak.26 There are no well- (p = 0.02) groups compared with the placebo group. PHN was also controlled clinical trials that have compared early-onset therapy significantly reduced in the famciclovir groups (500 mg famciclovir: with later therapy (>72 hours). Bean et al.27 found that the time HR 1.7 and 95% CI 1.1–2.7; 750 mg famciclovir: HR 1.9 and CI 1.2–2.9; to viral shedding was reduced by acyclovir therapy compared with p = 0.02 and 0.01, respectively). placebo in patients who had a zoster rash for <72 hours (Figure 1). Famciclovir has the advantage of reduced frequency of dosing15,16 It is surprising that, in a HZ trial,2 only two thirds of the but it is important to note that the recommended dose of patients who developed HZ received appropriate antiviral treatment famciclovir varies between countries. A study of 545 patients with within 72 hours, despite being informed at study onset about HZ randomized to receive 7 days of either famciclovir 250, 500 the symptoms and signs of HZ. These drugs may afford greater or 750 mg three times daily or acyclovir 800 mg five times daily, benefit if they are used within the first 72 hours of rash onset. initiated within 72 hours of the onset of the zoster rash, showed Early diagnosis and treatment of HZ result in accelerated cutaneous that famciclovir was as effective as acyclovir at all doses for the healing and reduced median duration of pain according to the healing of cutaneous lesions.17 Time to resolution of acute pain was ZAP analyses. It seems likely that one of the major causes of similar in all arms, but time to ZAP resolution was significantly decreased efficacy of antiviral therapy is the delay between onset of shorter in those treated with famciclovir within 48 hours of symptoms and initiation of treatment. Treatment with more active rash onset compared with acyclovir (famciclovir 250, 500 and and lipophilic agents may be beneficial in reducing viral replication 750 mg vs. acyclovir, p = 0.006, 0.003 and 0.042, respectively).17 and consequent neural damage as quickly as possible, and hence Median time to ZAP resolution after skin healing was faster in may reduce both acute and chronic manifestations of HZ. The need the famciclovir arms than in the acyclovir arm (resolution was for more education of the public and healthcare providers on HZ is 1.4 [p = 0.086], 1.8 [p = 0.003] and 1.4 [p = 0.05] times faster in also evident. the 250 mg, 500 mg and 750 mg famciclovir groups, respectively, 100 compared with acyclovir).17 A direct head-to-head comparison of famciclovir and valacyclovir 90 in immunocompetent patients aged >50 years showed that the two 80 drugs were therapeutically equivalent, for both healing rate and 18 pain resolution. 70 Acyclovir The fourth commercially available anti-VZV drug used to treat Placebo HZ is the synthetic pyrimidine analogue, brivudin. Brivudin is 60 licensed in some European countries, South Africa and Israel for 50 the early treatment of HZ in immunocompetent adults.19 Brivudin is 200–1,000 times more effective in inhibiting viral replication 40 in vitro than acyclovir or penciclovir,20 and it accumulates rapidly 21 30 inside virus-infected cells. % with positive cultures Brivudin (125 mg once daily for 7 days) was more effective 20 than acyclovir (800 mg five times daily for 7 days) in a study of 1,227 immunocompetent patients with HZ.22 The time to ZAP 10 resolution was similar between the two groups (risk ratio [RR] 0 0.996; p = 0.001), but the brivudin group had a faster time to 0 12345678 last formation of new vesicles compared with acyclovir (RR 1.13; Study days p = 0.014). However, the intent-to-treat analysis of lesion healing Fig. 1. Time to cessation of viral shedding.27 Reprinted from Bean B, et al., Acyclovir indicated that brivudin is as effective as acyclovir according to therapy for acute herpes zoster. Lancet 1982;320(8290):118–21. © 1982, with time to first crust (brivudin RR 0.93; 95% CI 0.83–1.05; acyclovir permission from Elsevier. RR 0.93, CI 0.83–1.05), time to full crusting (brivudin RR 1.03; 95% CI 0.92–1.16; acyclovir RR 1.03, CI 0.92–1.16) and time to loss of Longer courses of antiviral therapy administered either orally crusting (brivudin RR 0.95; 95% CI 0.85–1.07; acyclovir RR 0.93, CI or intravenously do not confer additional benefit in reducing the 0.85–1.07). A large multicentre study of 2,027 patients with acute duration of PHN.10,28,29 HZ aged ≥50 years demonstrated that brivudin had a similar efficacy For individuals with zoster ophthalmicus, early antiviral treat- on pain and rash and a similar tolerability profile to famciclovir ment reduces the incidence of ocular complications. In placebo- (250 mg three times daily for 7 days).23 controlled studies, oral acyclovir, valacyclovir and famciclovir, Drug interactions have been reported between brivudin and 5-FU initiated within 72 hours of rash onset, reduced the incidence of and other 5-fluoropyrimidines. The main metabolite of brivudin, ocular complications in patients with ophthalmic zoster compared bromovinyl uracil, inhibits dihydropyrimidine dehydrogenase with placebo or historical untreated controls (reviewed in Johnson (DPD), which regulates the metabolism of pyrimidine derivatives; et al., 2001).30 A retrospective comparison of ocular outcomes hence, brivudin therapy can cause the accumulation and enhanced in 202 antiviral-treated and 121 non-treated ophthalmic zoster toxicity of these drugs. A congener analogue, bromovinyl arabinosyl patients in Minnesota, USA, showed that patients treated with uracil (BVaraU), when administered to patients receiving 5-FU, antivirals had a lower risk of severe visual loss or other adverse R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28 S23

Fig. 2. Molecular structures of Cf1743 (left) and FV100 (right).39,40 outcome at 5 or 10 years than non-treated patients (2.1% vs. 8.9%, added symptoms from the compression of enlarged, inflamed nerve respectively, p = 0.009).31 Furthermore, the development of serious roots, such as in VII nerve palsy. inflammatory complications among treated patients appeared to be associated with a delay in antiviral treatment, which emphasizes 2.4. New molecules in development the importance of early treatment. The concomitant treatment with corticosteroids under the supervision of an ophthalmologist Four new drugs are being considered for the treatment of HZ: is discussed here. CMX001; a nucleoside analogue valomaciclovir (H2G); a helicase- Current International Herpes Management Forum (IHMF®) primase inhibitor; and two bicyclic nucleoside analogues (BCNAs). guidelines30 recommend that all patients with zoster ophthalmicus CMX001 (hexadecyloxypropyl-cidofovir) is a lipid ester of presenting within 1 week of rash onset should be offered oral cidofovir with enhanced oral bioavailability conferred by the lipid antiviral therapy with one of the following to reduce the incidence moiety. The enhanced bioavailability of the ester also reduces of ocular complications: (a) acyclovir 800 mg five times daily for nephrotoxicity by reducing exposure to cidofovir.33 Once inside the 10 days; (b) valacyclovir 1000 mg three times daily for 7 days; or cell, the molecule is cleaved by phospholipase to liberate cidofovir. (c) famciclovir 500 mg three times daily for 7 days. In cell culture assays, CMX001 is significantly more active than cidofovir against all double-stranded DNA viruses, including VZV and other herpesviruses.34 Because it is a derivative of and is 2.3. The role of corticosteroids metabolized to cidofovir, there is a persistent concern for its toxicity, When administered systemically within 72 hours of rash onset, and in particular its carcinogenicity.35 Importantly, in Phase IB and corticosteroids have a clinically significant benefit on acute pain early Phase II studies, nephrotoxicity has not been a concern. It but no demonstrable effect on PHN.28,32 A double-blind study of is envisioned that CMX001 will have a primary role in the organ 400 acute zoster patients, comparing oral acyclovir (800 mg five transplant setting. times daily) with and without prednisolone, found that more of Valomaciclovir is the diester prodrug (valine and stearic the rash area had healed on Days 7 and 14 (p = 0.02) in those acid) of the acyclic guanosine derivative, H2G. It is a potent, receiving steroids.28 Pain reduction was greater during the acute broad-spectrum anti-herpes agent, especially active against VZV phase of the disease in those treated with steroids than in those infection, and is phosphorylated by virus-infected cells to H2G without steroids. However, there were no significant differences triphosphate to yield a potent inhibitor of viral DNA synthesis. between any of the groups in the time to first or complete The pre-clinical pharmacology and toxicology, initial human clinical cessation of pain. Notably, no placebo controls were included in pharmacology and pharmacokinetics, and Phase II proof-of-efficacy this study.28 of valomaciclovir have now been completed.36 There is evidence that the use of steroids in combination with Helicase-primase inhibitors prevent viral DNA replication by acyclovir can improve quality-of-life outcomes in healthy patients inhibiting VZV-specific enzymes. The helicase-primase inhibitor aged >50 years with localized HZ.32 More than 200 patients with ASP2151 is more potent against VZV than acyclovir in tests against acute HZ were stratified into four arms to receive acyclovir or several strains of the virus, including clinical isolates.37,38 placebo plus prednisone or placebo during the acute phase of The aryl BCNAs are extremely potent and selective against their illness. Times to total crusting and healing were accelerated VZV. The lead molecule, Cf1743 (Figure 2),39 shows activity at in patients receiving acyclovir plus prednisone compared with around 0.1 nM in vitro, making it 10,000 times more potent patients receiving two ; patients receiving acyclovir plus than acyclovir. The BCNAs are also highly selective: whereas prednisone had a shorter time to cessation of acute neuritis, time to other nucleoside analogues have activity against simian varicella return to uninterrupted sleep, time to return to usual daily activity virus (SVV), the BCNAs are inactive against SVV. Moreover, SVV and time to cessation of analgesic therapy. However, there was no has a genome sequence that is 75% homologous to VZV and difference in pain resolution during the 6 months after rash onset shares many common features, including latency, recurrence and between the combination therapy group and the other groups. varicella-like disease. All previous compounds that inhibit VZV also

Individuals at risk for complication of steroid therapy were excluded inhibited SVV, the ratio of EC50 values (SVV:VZV) being 0.2:7 among from this trial (e.g., those with hypertension, osteoporosis and/or the diverse families of antivirals, including bromovinyldeoxyuri- , among others).32 dine (BVDU), BVaraU, acyclovir, ganciclovir, penciclovir, 9-(S)- If there is any evidence of uveitis or corneal inflammation, [3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) and topical ophthalmic steroids are prescribed by ophthalmologists in phosphonomethoxy-ethyl-adenine (PMEA).41 Therefore, the BCNAs combination with an oral drug for zoster ophthalmicus. Systemic are the first compounds shown to inhibit VZV while being inert to steroids are routinely considered in patients with HZ who have SVV. This result cannot be explained by lack of phosphorylation S24 R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28

Table 2 Prevalence of PHN at 6 months in selected clinical trials.

Study Proportion of patients Reference with pain (%)

Acyclovir (800 mg five times daily) vs. placebo for 7 days 14 vs. 13 McKendrick et al., 198945 Acyclovir (800 mg five times daily for 7 days) vs. placebo 15 vs. ≥50 a Morton and Thomson, 198944 Valacyclovir (1000 mg three times daily for 7 or 14 days) vs. acyclovir (800 mg five times daily for 7 days) 19.3 vs. 25.7 a Beutner et al., 199513 Valacyclovir (1000 mg three times daily for 7 days) vs. valacyclovir (1000 mg three times daily for 14 days) 19.9 vs. 18.6 a Beutner et al., 199513 Famciclovir (500 or 750 mg three times daily) vs. placebo for 7 days Approximately 20 vs. 40 a Tyring et al., 199517 Valacyclovir (1000 mg three times daily) vs. famciclovir (500 mg three times daily) for 7 days 19 vs. 19 a Tyring et al., 200014 Brivudin (125 mg once daily) vs. famciclovir (250 mg three times daily) for 7 days 11.3 vs. 9.6 a,b Wassilew et al., 200523 Brivudin (125 mg once daily) vs. acyclovir (800 mg five times daily) for 7 days 32.7 vs. 43.5 a,b Wassilew et al., 200322 a p<0.05. b 3-month follow-up. because the BCNAs are competitive inhibitors; also, alternative and GPs in Italy showed that the most frequently occurring zoster- substrates for the SVV include thymidine kinase (TK), therefore related complications, excluding PHN, were ocular complications BCNA nucleotides must arise in SVV-infected cells. (5.7%) and facial palsy (0.6%), with the risk increasing with BCNAs are non-toxic in vitro and have no toxicity up to very high age.4,42 Individuals aged >65 years had almost four times the doses (2000 mg/kg) in vivo. They are highly lipophilic and rapidly risk of complications as those aged <35 years. Interestingly, permeate cells. Whereas the parent compounds have poor water much lower rates of zoster complications were observed in the solubility and low oral bioavailability, these problems are both recent Shingles Prevention Study.2 The most frequent zoster-related solved by esterification, resulting in the valyl prodrug FV100. FV100 complications, excluding pain, were neurological (1.4%) and ocular is currently under development, having successfully completed (0.7%) in non-vaccinated individuals, and cutaneous (0.7%) and Phase I clinical trials in the USA; Phase II studies in HZ are neurological (0.5%) in vaccine recipients.2 Ocular complications ongoing.40 were markedly lower in this North American population than in Italian clinical practice, which could be attributed to the prompt use of antiviral drugs for the majority of patients.48,49 3. PHN and other complications However, it could also reflect regional variations, differences in HZ is associated with significant neurological complications, the study selection criteria or some other unidentified cause, such most prevalent being pain (see Gershon et al., this supplement,42 as concurrent use of biological therapies (e.g., the monoclonal and Opstelten et al., this supplement43). infliximab and adalimumab or the fusion protein etanercept used to treat autoimmune diseases such as rheumatoid arthritis), which appear to have an effect on the incidence, severity 3.1. The limitations of antiviral therapies in PHN and type of HZ. A disproportionately high incidence of atypical While antiviral drugs are clinically effective in the treatment of and severe presentations occurs in patients receiving biological acute HZ, the data about their benefit in reducing the duration or therapies.50,51 incidence of PHN are conflicting. The incidence of PHN in selected clinical trials is summarized in Table 2. A meta-analysis of all 3.2. Other treatments for PHN placebo-controlled trials with acyclovir for HZ established that there is a significant reduction in ZAP in patients who received analgesics are frequently prescribed for the treatment of acyclovir.9,46 Similar results were obtained with valacyclovir (ZAP acute and persistent pain. Both short- or long-acting agents, such analysis), which is also more effective than acyclovir at reducing as controlled-release and , may be used.52 The the duration of PHN11 ; the average duration of pain was 38 days side effects of opioid analgesics include drowsiness and cognitive with valacyclovir and 51 days with acyclovir. Similar reductions slowing, nausea, and pruritus. General concerns about in pain were also noted at 6 months after healing of the rash; the potential for abuse are less relevant for geriatric populations, only 19% of patients taking valacyclovir reported pain compared particularly in older patients with no previous history of substance with 26% of patients taking acyclovir.11 However, a recent Cochrane abuse. In a blinded, within-patient, crossover trial comparing report47 concluded that acyclovir has no effect on PHN, although , tricyclics and placebo for established PHN, opioids had the the study design determined which studies were included in the highest patient preference.53 review – and many were excluded. The Cochrane report noted that Tricyclic antidepressants (TCAs) and the anticonvulsants gaba- pain severity, in addition to pain duration, should be used as an pentin and have been the most frequently studied drug efficacy measure in future randomized trials of antivirals for the classes for the management of , including PHN.54 prevention of PHN.47 TCAs provide moderate to excellent pain relief and have been used Famciclovir has also proven effective in acute HZ, promoting extensively for the treatment of PHN.55,56 They are widely available cutaneous healing and reducing the duration of acute pain. The in generic form and can have added benefits for mood and sleep. median duration of pain was half as many days in patients In a retrospective study to assess the effects of acyclovir treatment who received famciclovir compared with those receiving placebo, of acute HZ on subsequent PHN, the effect of amitriptyline was resulting in a 3.5-month reduction in the average duration of pain.17 also examined; early treatment was almost twice as likely to be When famciclovir and valacyclovir were compared in a head-to- successful as late treatment.57 Amitriptyline is the most widely head study, the drugs were equally effective at resolving ZAP.18 prescribed TCA for PHN, but others, such as and Complications of HZ other than PHN are poorly studied, and , can also be used effectively and may have fewer side reliable epidemiological information is scarce. An observational, effects.58 Side effects associated with amitriptyline are common and retrospective analysis of 1,401 HZ cases recorded by dermatologists include cardiovascular problems such as orthostatic hypotension, R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28 S25 Control (0.04% patch) 8% capsaicin patch 0

–10

–20

–30

Change from baseline in aabbcc a ccc c c –40

numeric pain rating scale score (%) 10987654321 11 12 Time (weeks) Number at risk 8% capsaicin 206 203 202 202 202 199 198 197 196 190 187 187 185 Control 196 189 189 189 190 186 186 185 184 180 177 177 172 a bc 8% capsaicin patch vs. control: ppp< 0.05, < 0.01, < 0.001.

Fig. 3. Rapid and sustained pain relief with the 8% capsaicin patch.68 Reprinted from Backonja M, et al., NGX-4010, a high concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised double-blind study. Lancet Neurol 2008;7(12):1106–12. © 2008, with permission from Elsevier. arrhythmias and electrocardiogram (ECG) abnormalities. These side pregabalin, are approved by the FDA for the treatment of PHN and effects may be an issue when prescribing to elderly patients; hence, may be considered as first-line treatments. either nortriptyline or desipramine is the preferred treatment. Alternative therapies for the relief of PHN, and methods of less- , a second-generation , significantly certain efficacy, include: reduces the severity of PHN.59,60 Patients receiving gabapentin • Invasive techniques, such as nerve blocks, intrathecal administra- have lower daily pain scores and fewer disturbances in mood tion of local anaesthetics and excision of the affected skin and sleep compared with those receiving placebo.59,60 Although • Neuromodulation techniques there is no standard dosing regimen, recent studies indicate that • Toxins such as BOTOX-A® treatment can be initiated at 900 mg/day and, if pain relief is • Combinations of drugs not satisfactory, the dose may be titrated to 1800 mg/day as side • Pain management programmes. effects permit (often about 7–10 days).61 Higher doses (up to Nerve blocks are often used by anaesthesiologists in pain clinics 3600 mg/day) may be required in some patients. Gabapentin has for the treatment of HZ, but there are no controlled clinical a good safety profile, especially among older patients. Designed studies demonstrating their efficacy. The rationale for sympathetic as a more potent successor to gabapentin, the anticonvulsant blockade is particularly problematic as the sympathetic ganglia pregabalin, like gabapentin, is associated with analgesic, anxiolytic are spared from acute HZ involvement. Nerve-block interventions and antiepileptic activity.62 Analgesic effects are mediated through can target several sites, such as the dorsal root ganglion (DRG), the a2-d-l subunit. Oral bioavailability is ≥90%, and peak blood level peripheral nerves, sympathetic chain and epidural blocks. is achieved in 1.3 hours with no plasma protein binding. Pregabalin A recent study of epidural steroid injection failed to show is devoid of drug interactions. Because it is excreted unchanged that this approach provided any benefit in preventing long-term by the kidneys, it is contraindicated in severe renal impairment PHN. A single epidural injection of steroids and local anaesthetics 63 (CLCR ≤30). Four studies using 150–600 mg/day in divided doses during the acute phase of HZ modestly reduced pain for 1 month showed efficacy in reducing pain and sleep interference in PHN.64 (ZAP analysis),70 but the benefit was lost by 3 months post- It is generally well tolerated but may cause side effects similar to treatment. Treating PHN with a single injection near a single DRG those of gabapentin. Pregabalin offers a more rapid clinical effect is not always advisable as it can be difficult to tell precisely than gabapentin. which is affected. Prognostic nerve blocks may need Topical analgesics are commonly used for the relief of PHN, to be performed to identify the correct ganglion, and there are despite very limited evidence of efficacy. Topical agents for the no data to support the efficacy of this invasive treatment. The treatment of PHN include: acetylsalicylic acid 500 mg in 95% alcohol intrathecal administration of local anaesthetics, corticosteroids 5 mL; 5% patch or gel; geranium oil65; and capsaicin.66 and neuroactive peptides is another potential therapy. In a trial Capsaicin cream 0.025%, applied three or four times daily, is comparing lidocaine with lidocaine and methylprednisolone,71 the commonly prescribed (but rarely tolerated). It reduces pain by combination of lidocaine and methylprednisolone administered activating the TRPV1 receptor and depleting substance P,66 leading in weekly injections over 4 weeks decreased the intensity and to subsequent desensitization and dying back of nociceptive axon area of pain and reduced the use of the non-steroidal anti- endings. Side effects include intolerable burning pain, and one inflammatory drug diclofenac compared with either lidocaine alone meta-analysis showed the efficacy of this therapy to be limited.67 or no treatment. One year after treatment, 82% of patients in the An 8% formulation patch of capsaicin following topical local lidocaine and methylprednisolone group reported good or excellent anaesthesia was recently compared with the usual 0.04% capsaicin pain relief compared with only 5% in the lidocaine-only group. patch in a randomized controlled trial of 402 patients with PHN.68 Despite the promising results from this trial, intrathecal steroid One 60-minute application of the 8% capsaicin patch provided injections have not become widely used for the management rapid and sustained pain relief, with 42% of patients experiencing of PHN, mainly owing to concerns over safety and the lack of >30% pain relief compared with 32% of patients in the 0.04% confirmation or verification in clinical practice. capsaicin patch group (Figure 3). Actual benefit and tolerability of Neuromodulation refers to a group of techniques that stimulate the capsaicin patch in clinical practice remain to be determined, as various parts of the nervous system to relieve pain. Limited does the long-term effect on axonal damage. data support the use of implanted spinal cord stimulators for A topical 5% lidocaine patch can also provide PHN relief for PHN. A single study reports that pulsed radio frequency (PRF) approximately 12 hours after application, with no or mild side ablation of the DRG provided significant pain relief compared with effects.69 Both oral gabapentin and the lidocaine patch, as well as conventional pain treatments in patients with intractable PHN.72 S26 R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28

Density of epidermal nerve endings in HZ-affected skin 100 90 80 70 60 50 40 30 20 10 0

Number of epidermal fibres/mm No pain group PHN pain group

Fig. 4. Loss of neurites in skin previously affected by shingles as depicted in vertical sections from skin biopsies immunolabelled against PGP9.5, a standard pan-axonal marker.76 A patient with PHN (B) has far fewer remaining nerve endings than a demographically matched patient without PHN (A) after shingles. Because HZ kills the entire neuron, the loss of nerve endings in the skin is likely to predict a loss of sensory input into the CNS. Modified from Oaklander AL, Romans K, Horasek S, StocksA,HauerP, Meyer RA. Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage. Ann Neurol 1998 Nov;44(5):789–95. © 1998 Annals of .

There is limited evidence concerning efficacy of stimulation.73 PHN pain, and a threshold of 650 neurites/mm2 dichotomizes HZ Medically unresponsive PHN affecting the face or hand is a patients with or without PHN.77 This implies that the absence of reasonable target for motor cortex stimulation, a minimally invasive pain after HZ may require the preservation of a minimum density option in which electrodes are placed outside the brain. A meta- of primary nociceptive . Because virtually all axons that analysis of 11 studies using non-invasive brain stimulation and end in the epidermis are nociceptors,78 the loss of nociceptive 22 studies using invasive brain stimulation74 showed that brain input from the skin into the central nervous system (CNS) may stimulation of the motor cortex can have a significant effect on contribute towards maintaining ongoing pain. Similar mechanisms chronic pain, with responder rates of 73% in the invasive stimulation contribute to phantom limb pain after amputation. The plasticity studies and 45% in the non-invasive stimulation studies. Such of the nervous system is becoming better understood, particularly treatments are rarely indicated. the way in which near-normal function can be maintained in some degenerative conditions (including Parkinson’s disease, optic nerve crush, spinal cord injury and stroke) despite the degeneration 3.3. New drug targets for PHN of many neurons.79 After injury, post-synaptic neurons adapt to Many targets for drugs in the pain pathway have been identified, enlarge capacity by increasing their gain–astrategythat can indicating the complexity of pain pathways and the inability to ultimately lead to unprovoked firing of central neurons when identify one key target. Among the candidates being assessed are: peripheral input is reduced to near zero. If this also applies in • TRPV1 receptor, which has been targeted by many drugs, PHN, the implication is that even small reductions in neuronal including capsaicin death might preserve the minimal necessary residual number of • NMDA receptor; drugs targeting this receptor have not been found neurons and thereby decrease the likelihood of PHN. A better to be effective in the treatment of PHN understanding of this pathophysiology will inform the development • Cannabinoids have been tested in studies, but they are unlikely of therapeutic and preventative strategies for PHN and other chronic to be used in the clinic because of their legal status in the USA pain syndromes. • Calcium channels are targeted by pregabalin and gabapentin, but Other observations of the CNS and nerve injury may provide there are other subunits of the channel that could represent insight into chronic pain syndromes. For example, unilateral nerve therapeutic targets injury from HZ can cause profound, long-lasting, nerve-branch- • Sodium channels are the targets for many antiepileptic drugs, specific loss of distal innervation on the unaffected opposite side some of which have been tested in PHN with only minimal of the body (contralaterally), as well as in the territory affected efficacy by the rash. This suggests that CNS changes may have important • The norepinephrine (NE) transporter is a new target, and effects on pain pathogenesis even in the absence of direct spinal drugs that interact with this molecule are still at Phase I of cord inflammation or injury.76 development Animal research shows that minor nerve injuries can have • Drugs that target the aminopeptidase N (APN) and neutral disproportionately large effects on dorsal-horn neurons and glia, endopeptidase (NEP) are still in early phases of research perhaps providing a biological correlate for the disproportionate • Neurotrophic factors and growth factors are potentially interest- pain of post-traumatic that follow seemingly minor ing targets because it is thought that the loss of nerve fibres plays nerve injuries.80 It is well documented that reduced nociceptive an important role in the pathogenesis of PHN. afferent input causes hyperactivity of central pain neurons,81–86 and limited autopsy data comparing patients with or without PHN after HZ identified degeneration in the spinal-cord dorsal horn as the 3.4. Managing PHN in the future: Translational neuroscience crucial difference between these outcomes.87 The goal for managing PHN in the future will be to move away from palliative care towards disease-modifying treatments. Identifying 4. Summary patients at highest risk of developing PHN might permit the development of new translational therapies to be used early in the The objectives of treating HZ are to control acute pain, accelerate disease. Surrogate markers obtained from skin biopsy data might rash healing, minimize systemic complications and reduce the risk enable early identification of HZ patients at high risk for PHN, e.g., of PHN and other complications. Existing therapies, particularly vibration threshold measurements using graduated tuning forks75 antiviral agents, shorten the duration of HZ and promote rash or laser Doppler measurements of skin blood flow. healing, but they are not completely effective at preventing PHN, An important advance in the understanding of the pathogenesis perhaps partly because of delays in diagnosis and administration. of PHN was the documentation of the loss of neurites in the skin New treatments with different mechanisms of action are under during HZ (Figure 4). It is known that there is a step-function development for the prevention and management of PHN. Existing relationship between axonal degeneration and the presence of therapies for established PHN are palliative and mainly include R.J. Whitley et al. / Journal of Clinical Virology 48 (2010) S20–S28 S27 opioids, TCAs and anticonvulsants. The goal for PHN management 20. De Clercq E. Discovery and development of BVDU (brivudin) as a therapeutic for in the future must be to move away from palliative care and the treatment of herpes zoster. Biochem Pharmacol 2004;68:2301–15. towards disease-modifying treatments. Recent developments in the 21. Keam SJ, Chapman TM, Figgitt DP. Brivudin (bromovinyl deoxyuridine). Drugs 2004;64:2091–7. understanding of the neuropathogenesis of pain in general, and of 22. Wassilew SW, Wutzler P; Brivudin Herpes Zoster Study Group. Oral PHN in particular, have identified potential points of intervention brivudin in comparison with acyclovir for improved therapy of herpes for the future management of chronic pain syndromes, including zoster in immunocompetent patients: results of a randomized, double-blind, PHN. multicentered study. Antiviral Res 2003;59:49–56. 23. Wassilew S; Collaborative Brivudin PHN Study Group. 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