Herpes zoster

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101

Herpes zoster

Rana Majd Mays, Erik T. Petersen, Rachel A. Gordon and Stephen K. Tyring

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Reactivation of latent varicella zoster virus (VZV) produces the clinical syndrome herpes zoster (shingles), which manifests as a unilateral eruption along a single dermatome and is usually preceded by prodromal pain and paresthesia. The eruption lasts around seven to 10 days, and progresses from erythematous macules and papules to vesicles, then pustules, and finally crusts over. One of the most common complications of herpes zoster is postherpetic neuralgia (PHN), which is dermatomal pain persisting longer than 3 months.

Management strategy

Early treatment – within the first 72 hours of vesicle formation – is important for antiviral efficacy, time to lesion healing, and minimizing zoster-associated pain (although initiating treatment after 72 hours may still be effective). Acyclovir, valacyclovir, and famciclovir are guanosine analogs that are phosphorylated by thymidine kinase to a triphosphate form that inhibits viral DNA polymerase. The oral bioavailability of the antivirals determines the number of daily administrations. Patient compliance tends to decrease as the number of daily administrations increases. The most common side effects seen are nausea, headache, and gastrointestinal upset, but these drugs are otherwise safe and well tolerated. Patients with renal insufficiency will need an adjusted dose, as these medications are excreted by the kidneys.

Acyclovir-resistant VZV infections have been reported in immunocompromised patients (i.e., AIDS, transplant patients) and in these cases foscarnet (given intravenously 40 mg/kg three times daily) can be used as an alternative.

Acutely, corticosteroids may reduce zoster-associated pain, but they are associated with a risk of serious adverse events and have shown no benefit in reducing time to complete cessation of pain.

Current therapeutic options for PHN include the anticonvulsants gabapentin and pregabalin, opioid analgesics, tricyclic antidepressants (Table 101.1), lidocaine patch 5%, and capsaicin cream. Choice of therapy should be guided by considering a patient’s comorbidities, drug adverse event profiles, and preference. Combination therapy is common in clinical practice, but there is no evidence base to support this practice.

Table 101.1

Treatment options for postherpetic neuralgia

Drug class	Examples	Initial daily dose (mg)	Titration to maximum dose
Anticonvulsants	Gabapentin	100–300	Start qhs and increase to tid dosing; increase by 100–300 mg every 3 days to total dose of 1800–2400 mg/day
Anticonvulsants	Pregabalin	150	Titrate up to 300 or 600 mg/day
Opioids	Hydrocodone	5–10	No titration
Opioids	Oxycodone (extended release)	20	Titrate up to 60 mg daily
Tricyclic antidepressants	Nortriptyline	10–25	Increase by 10–25 mg weekly, with a target dose of 75–150 mg daily; single dose or two divided doses
	Amitriptyline	10–25	Titrate up to 100 mg daily; single dose
	Desipramine	10–25	Increase every 3 days as needed up to 150 mg daily; single dose

Vaccination of patients aged 50 years and over with VZV is the most promising option for the prevention of herpes zoster. Administration of gabapentin in conjunction with antivirals (and analgesics) during the acute phase of zoster may offer further protection against PHN. Asymptomatic reactivation of the VZV and contact with patients with chickenpox may enhance cell-mediated immunity.

Specific investigations

Tzanck smear

Viral culture

Serology (acute plus chronic)

Electron microscopy

Polymerase chain reaction

In most cases no investigation is required to establish the diagnosis.

First-line therapies

Antiviral agents
Acyclovir	A
Famciclovir	A
Valacyclovir	A

Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults.

Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ. Antimicrob Agents Chemother 1995; 39: 1546–53.

Valacyclovir is comparable to acyclovir in the resolution of zoster eruption (Table 101.2), but it accelerates the resolution of pain compared to acyclovir and is more convenient.

Table 101.2

First-line therapy for acute herpes zoster

Medication	Dose (mg)	Number of daily doses	Duration (days)
Valacyclovir	1000	3	7
Famciclovir	500	3	7
Acyclovir	800	5	7

Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older.

Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ. Arch Fam Med 2000; 9: 863–9.

Valacyclovir is comparable to famciclovir in the resolution of zoster-associated pain and PHN.

Factors influencing pain outcome in herpes zoster: an observational study with valacyclovir.

Decroix J, Partsch H, Gonzalez R, Mobacken H, Goh CL, Walsh L, et al.; Valacyclovir Zoster Assessment Group (VIZA). J Eur Acad Dermatol Venereol 2000; 14: 23–33.

An open-label study using a 7-day course of valacyclovir to treat 1897 immunocompetent patients with acute herpes zoster. Valacyclovir was safe, effective (even when initiated more than 72 hours after the first vesicle), and associated with very few adverse events.

Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo controlled trial.

Tyring S, Barbarash RA, Nahlik JE, Cunningham A, Marley J, Heng M, et al. Ann Intern Med 1995; 123: 89–96.

Famciclovir recipients had faster resolution of pain following an acute episode than those receiving placebo.

Double-blind, randomized, acyclovir-controlled, parallel-group trial comparing the safety and efficacy of famciclovir and acyclovir in patients with uncomplicated herpes zoster.

Shen MC, Lin HH, Lee SS, Chen YS, Chiang PC, Liu YC. J Microbiol Immunol Infect 2004; 37: 75–81.

Famciclovir is comparable to acyclovir in the resolution of zoster cutaneous eruption but is more convenient.

Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials.

Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Clin Infect Dis 1996; 22: 341–7.

In four placebo-controlled studies acyclovir was clearly shown to accelerate pain resolution.

Antiviral treatment for preventing postherpetic neuralgia.

Li Q, Chen N, Yang J, Zhou M, Zhou D, Zhang Q, et al. Cochrane Database Syst Rev, 2009; Issue 2.

Systematic review of available literature concluded that acyclovir does not significantly reduce the incidence of PHN when initiated within 72 hours of herpes zoster onset. Additional well-designed studies are warranted to determine whether other antiviral agents may prevent PHN.

Second-line therapies

Agents to reduce postherpetic neuralgia
Anticonvulsants	A
Tricyclic antidepressants	A
Lidocaine patch	A
Oxycodone	A

Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.

Dworkin RH, Corbin AE, Young JP, Sharma U, LaMoreaux L, Bockbrader H, et al. Neurology 2003; 60: 1274–83.

Pregabalin is effective in the treatment of pain and sleep interference associated with PHN. It was associated with greater global improvement than treatment with placebo.

Pregabalin and transcutaneous electrical nerve stimulation for postherpetic neuralgia treatment.

Barbarisi M, Pace MC, Passavanti MB, Maisto M, Mazzariello L, Pota V, et al. Clin J Pain 2010; 26: 567–72.

Pregabalin has demonstrated better efficacy in reducing PHN pain when combined with transcutaneous electrical nerve stimulation.

Gabapentin for the treatment of post-herpetic neuralgia: a randomized controlled trial.

Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. JAMA 1998; 280: 1837–42.

Gabapentin is effective in the treatment of pain and sleep interference associated with PHN.

Incidence of postherpetic neuralgia after combination treatment with gabapentin and valacyclovir in patients with acute herpes zoster: open-label study.

Lapolla W, Digiorgio C, Haitz K, Magel G, Mendoza N, Grady J, et al. Arch Dermatol 2011; 147: 901–7.

A recent study demonstrated a significant reduction in PHN with the addition of gabapentin to valacyclovir in acute herpes zoster patients. Therefore it is recommended that gabapentin be initiated in addition to antivirals for the treatment of acute herpes zoster patients with moderate to severe pain at presentation.

Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double blind clinical trial: The GONIP Trial.

Chandra K, Shafiq N, Pandhi P, Gupta S, Malhotra S. Int J Clin Pharmacol Ther 2006; 44: 358–63.

Gabapentin and nortriptyline are equally efficacious, but gabapentin is better tolerated.

Nortriptyline versus amitriptyline in post-herpetic neuralgia: a randomized trial.

Watson CP, Vernich L, Chipman M, Reed K. Neurology 1998; 51: 1166–71.

Nortriptyline is equally as effective as amitriptyline but is better tolerated.

The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial.

Bowsher D. J Pain Symptom Manage 1997; 13: 327–31.

Low-dose amitriptyline given at the time of the acute zoster rash may reduce the incidence of PHN.

Topical lidocaine for the treatment of postherpetic neuralgia.

Khaliq W, Alam S, Puri N. Cochrane Database Syst Rev 2007; 2: CD004846.

A meta-analysis combining two studies found that lidocaine is more effective than placebo, but there is insufficient evidence to recommend it as a first-line therapy. The studies cited in the review used 5% lidocaine gel applied for 8–24 hours, or 5% lidocaine patch applied up to three times daily.

Efficacy of oxycodone in neuropathic pain: a randomized trial in post-herpetic neuralgia.

Watson CPN, Babul N. Neurology 1998; 50: 1837–41.

Patients on slow-release oxycodone had significantly greater pain relief and reduction in allodynia and disability.

Third-line therapies

Vaccination of adults	A
Corticosteroids	E
Contact with varicella or with children	C
Topical capsaicin	A
Topical non-steroidal anti-inflammatory cream	C
Tramadol	B
Sympathetic nerve block	B
Transcutaneous electrical stimulation	C

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. N Engl J Med 2005; 352: 2271.

A randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine enrolled 38 546 immunocompetent adults aged 60 years or over. The vaccine significantly reduced morbidity from herpes zoster and PHN. It was also shown to be safe and well tolerated.

Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50–59 years.

Schmader KE, Levin MJ, Gnann Jr, JW, McNeil SA, Vesikari T, Betts RF, et al. Clin Infect Dis 2012; 54: 922–8.

In a recent trial, the Merck Zostavax vaccine was shown to reduce the incidence of herpes zoster by 69.8% in patients aged 50–59 years. The vaccine was also well tolerated. The randomized, double-blind, placebo-controlled trial enrolled 22 439 subjects aged 50–59 years.

Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized placebo-controlled trial.

Whitley RJ, Weiss H, Gnann Jr, JW, Tyring S, Mertz GJ, Pappas PG, et al. Ann Intern Med 1996; 125: 376–83.

There was no statistical difference between acyclovir plus prednisone or acyclovir alone in the resolution of pain.

A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster.

Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J. N Engl J Med 1994; 330: 896–900.

There was no statistical difference between acyclovir plus prednisolone or acyclovir alone in the resolution of pain.

Contacts with varicella or with children and protection against herpes zoster in adults: a case controlled study.

Thomas SL, Wheeler JG, Hall AJ. Lancet 2002; 360: 678–82.

Social contact with many children outside the household, or occupational contacts with children ill with chickenpox, results in a graded protection against zoster.

A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia.

Watson CP, Tyler KL, Bickers DR, Millikan LE, Smith S, Coleman E. Clin Ther 1993; 15: 510–26.

A double-blind study with 143 patients comparing capsaicin 0.075% cream with vehicle. Capsaicin applied three to four times per day was effective. The only side effect was burning or stinging at sites of application.

Benzydamine cream for the treatment of post-herpetic neuralgia: minimum duration of treatment periods in a cross-over trial.

McQuay HJ, Carroll D, Moxon A, Glynn CJ, Moore RA. Pain 1990; 40: 131–5.

Some patients benefit from 3% benzydamine hydrochloride cream applied six times daily.

Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial.

Boureau F, Legallicier P, Kabir-Ahmadi M. Pain 2003; 104: 323–31.

A double-blind study with 127 patients found tramadol to be effective in reducing pain intensity and increasing the percentage of pain relief compared to placebo. All patients were treated for 6 weeks with doses ranging from 100 to 400 mg based on therapeutic response. Patients over 75 years of age received divided doses (morning and night); others received single dose regimen.

Neuraxial and sympathetic blocks in herpes zoster and postherpetic neuralgia: an appraisal of current evidence.

Kumar V, Krone K, Mathieu A. Regional Anesth Pain Med 2004; 29: 454–61.

A review of the literature found that sympathetic blocks for herpes zoster and PHN appear to be useful, but require randomized control trials for validation.

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Herpes zoster

Herpes zoster

Management strategy

Specific investigations

First-line therapies

Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults.

Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older.

Factors influencing pain outcome in herpes zoster: an observational study with valacyclovir.

Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo controlled trial.

Double-blind, randomized, acyclovir-controlled, parallel-group trial comparing the safety and efficacy of famciclovir and acyclovir in patients with uncomplicated herpes zoster.

Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials.

Antiviral treatment for preventing postherpetic neuralgia.

Second-line therapies

Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.

Pregabalin and transcutaneous electrical nerve stimulation for postherpetic neuralgia treatment.

Gabapentin for the treatment of post-herpetic neuralgia: a randomized controlled trial.

Incidence of postherpetic neuralgia after combination treatment with gabapentin and valacyclovir in patients with acute herpes zoster: open-label study.

Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double blind clinical trial: The GONIP Trial.

Nortriptyline versus amitriptyline in post-herpetic neuralgia: a randomized trial.

The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial.

Topical lidocaine for the treatment of postherpetic neuralgia.

Efficacy of oxycodone in neuropathic pain: a randomized trial in post-herpetic neuralgia.

Third-line therapies

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50–59 years.

Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized placebo-controlled trial.

A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster.

Contacts with varicella or with children and protection against herpes zoster in adults: a case controlled study.

A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia.

Benzydamine cream for the treatment of post-herpetic neuralgia: minimum duration of treatment periods in a cross-over trial.

Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial.

Neuraxial and sympathetic blocks in herpes zoster and postherpetic neuralgia: an appraisal of current evidence.

Modified Jaipur block for the treatment of post- herpetic neuralgia.

Transcutaneous electrical nerve stimulation for chronic pain.

Cryoanalgesia for post-herpetic neuralgia: a new treatment.

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