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Natural History and Treatment of Herpes Zoster
The Journal of Pain, Vol 9, No 1 (January), Supplement 1, 2008: pp S3-S9 Available online at www.sciencedirect.com
Natural History and Treatment of Herpes Zoster Kenneth E. Schmader* and Robert H. Dworkin† *Division of Geriatrics, Department of Medicine and the Center for the Study of Aging and Human Development, Duke University Medical Center and Geriatric Research, Education and Clinical Center, Durham VA Medical Center, Durham, North Carolina. † Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Abstract: The objective of this article is to provide an overview of the natural history and treatment of herpes zoster, with a focus on pain management. Herpes zoster has the highest incidence of all neurological diseases, occurring annually in approximately 1 million people in the United States. A basic feature of herpes zoster is a marked increase in incidence with aging and with diseases and drugs that impair cellular immunity. Herpes zoster begins with reactivation of varicella zoster virus in dorsal root or cranial nerve ganglia, which is often accompanied by a prodrome of dermatomal pain or abnormal sensations. Varicella zoster virus spreads in the affected primary afferent nerve to the skin and produces a characteristic dermatomal maculopapular and vesicular rash and pain. Herpes zoster acute pain lowers quality of life and interferes with activities of daily living. Antiviral therapy and scheduled analgesics form the pharmacotherapeutic foundation for herpes zoster acute pain reduction. If moderate to severe herpes zoster pain is not adequately relieved by antiviral agents in combination with oral analgesic medications, then corticosteroids, anticonvulsants (eg, gabapentin or pregabalin), tricyclic antidepressants (eg, nortriptyline or desipramine), or neural blockade can be considered. Perspective: This article presents information on the clinical features and treatment of herpes zoster. This information will help clinicians diagnose and manage herpes zoster pain. © 2008 by the American Pain Society Key words: Herpes zoster, pain, aged.
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fter a primary varicella (chickenpox) infection, the varicella zoster virus (VZV) establishes latency in dorsal root and cranial nerve ganglia. Herpes zoster (“shingles”) is the reactivation of the virus and its spread from a single ganglion to the corresponding dermatome and neural tissue of the same segment.24,29,30,53,59 Herpes zoster has the highest incidence of all neurological diseases, occurring annually in KES has received grants/research support, consulting fees, or honoraria in the past year from Merck & Co., Inc. and RHD has received grants/research support, consulting fees, or honoraria in the past year from Allergan, Balboa, Cara, CombinatoRx, Dara, Eli Lilly, Endo, EpiCept, Fralex, GlaxoSmithKline, Grünenthal, GW Pharmaceuticals, Johnson & Johnson, KAI Pharmaceuticals, Merck & Co., Inc., NeurogesX, Ono, Organon, Pfizer, Supernus, US Food and Drug Administration, US National Institutes of Health, US Veterans Administration, Wyeth, and XTL Development. Address reprint requests to Dr. Kenneth Schmader, 182 GRECC, 508 Fulton Street, Durham VA Medical Center, Durham, NC 27705. E-mail: [email protected] 1526-5900/$34.00 © 2008 by the American Pain Society doi:10.1016/j.jpain.2007.10.002
approximately 1 million people in the United States,48 during the lifetimes of as much as 20% to 30% of the population, and in as many as 50% of those living until 85 years of age.30,37 The objective of this article is to provide an overview of the natural history and treatment of herpes zoster, with a focus on pain management. The natural history of herpes zoster is ultimately determined by the transmission and spread of VZV in populations. The most important condition in the spread of VZV is the primary infection, but latent and reactivated VZV infections also play important roles in maintaining VZV infection in populations.2 Latently infected elderly adults and immunosuppressed patients are important reservoirs of virus because VZV is more likely to reactivate in these groups, as discussed below. When herpes zoster occurs, VZV can be transmitted during the vesicular phase of the rash and cause primary infection when there is contact with a seronegative individual. A herpes S3
S4 zoster exposure with a seropositive, latently infected individual may result in a subclinical reinfection and boost of humoral and cellular VZV immunity, but it is unlikely to cause varicella or herpes zoster.2 In population-based studies, the incidence of herpes zoster in persons of all ages is 1.2 to 4.8 cases per 1000 persons per year, whereas the incidence of herpes zoster in persons older than 60 years is 7.2 to 11.8 cases per thousand per year.52 A fundamental epidemiological feature of herpes zoster is a marked increase in incidence with aging and with diseases and drugs that impair cellular immunity. The age at which the sharpest increase in herpes zoster occurs is 50 to 60 years of age, although the slope continues a marked upward course in the decades above 60 years.30,49 The diseases most associated with herpes zoster include human immunodeficiency virus infection, acquired immunodeficiency syndrome (AIDS), hematologic malignancies, organ transplants (especially bone marrow transplant), and immune-mediated diseases.24 Even among those who are immunocompromised, greater age increases the risk of herpes zoster. Other possible risk factors for herpes zoster include physical trauma at the involved dermatome,55 psychological stress,44,50,51 and white race.50,54 The live, attenuated varicella vaccine and the zoster vaccine may alter the epidemiology and natural history of herpes zoster.
Natural History of Herpes Zoster The clinical presentation of herpes zoster is variable. In the majority of patients, a prodrome of dermatomal pain or abnormal sensations precedes the appearance of the characteristic rash.14,26,27 This prodrome may also present with fatigue, headache, and other flu-like symptoms. It begins several days before rash onset in almost all cases, but a series of patients with prodromal pain preceding the appearance of the rash by 7 to more than 100 days has been reported.19 Unfortunately, it is not possible to reliably identify individuals with a herpes zoster prodrome. In a series of 57 patients presenting to their general practitioners with acute unilateral pain, only 2 developed a herpes zoster rash, and there was no correlation between clinical evaluations and VZV reactivation as determined by the development of a rash or the results of serology and polymerase chain reaction.43 The unilateral dermatomal rash of herpes zoster begins with the appearance of macules and papules on an erythematous base. The resulting clustered vesicles progress to pustules and crusts over the next 7 to 10 days, and complete loss of scabs occurs within 2 to 3 weeks.6 Thoracic dermatomes are the most commonly affected sites in herpes zoster and account for up to 50% of all cases.6,30,49 Cranial (especially the ophthalmic division of the trigeminal nerve), cervical, and lumbar dermatomes each account for 10% to 20% of cases, and sacral dermatomes are affected in 2% to 8% of cases.6,30,49 Because herpes zoster can occur in any dermatome, it may be misdiagnosed as herpes simplex when it affects der-
Natural History and Treatment of Zoster matomes in which such infections are common, especially lumbar, sacral, maxillary, and mandibular dermatomes.47 In addition to involvement of the primary dermatome, patients commonly develop lesions in adjacent dermatomes. Older age is associated with a greater likelihood of a more severe herpes zoster rash,45 but cutaneous dissemination— defined as ⬎20 lesions outside the primary and immediately adjacent dermatomes—is rare in immunocompetent patients.42 Cutaneous dissemination and atypical or prolonged rash can occur in immunocompromised patients, and a substantial number of these patients also have evidence of visceral involvement.23,24 Pain in the affected dermatome accompanies the rash in most patients.14,26,27 Those who do not have a painful prodrome typically begin to experience pain at rash onset or shortly afterward. This herpes zoster acute pain, which may be accompanied by itch and other paresthesias and dysesthesias,46 can have several different qualities, including constant burning and throbbing, intermittent shooting or stabbing, and allodynia, which is pain in response to normally innocuous stimuli, such as the touch of light clothing. The acute pain associated with herpes zoster gradually resolves before or shortly after rash healing in most patients, and the results of recent research provide support for distinguishing between 3 phases of pain—acute pain occurring within 30 days after rash onset; subacute herpetic neuralgia (pain that persists beyond the acute phase but that resolves before the diagnosis of PHN can be made); and postherpetic neuralgia (PHN; pain that persists 120 days or more after rash onset).1,11,16,33 Herpes zoster without a rash but with dermatomal pain, referred to as zoster sine herpete, has also been described.20,38 Although the finding of VZV DNA, but not herpes simplex virus DNA, in the cerebrospinal fluid of 2 patients with prolonged and recurrent radicular pain and no rash provides support for the existence of this condition,22 its prevalence is currently unknown. Because of the difficulty of diagnosing herpes zoster (and its complications, especially PHN) in the absence of the characteristic rash, this diagnosis should be reserved for patients who have been evaluated in specialist centers with a diagnosis confirmed by the results of laboratory tests such as acute and convalescent serology. The morbidity of herpes zoster includes neurological disorders and ophthalmologic, cutaneous, and visceral complications. Specific types of neurologic complications include granulomatous arteritis, which occurs more often in immunocompetent patients; small-vessel encephalitis, which has become the most common central nervous system complication of herpes zoster as a result of the increased numbers of immunocompromised patients; and myelitis, which occurs in both immunocompromised and immunocompetent patients.21 It has been recognized for some time that a motor neuropathy can occur in patients with herpes zoster, but this may be more common than generally appreciated. The authors of a study of 40 patients with herpes zoster in
ORIGINAL REPORT/Schmader and Dworkin whom electromyography and motor nerve conduction velocity were prospectively examined concluded that motor involvement can be widespread, extending ipsilaterally and contralaterally several segments above and below the dermatome affected by the rash, and that these changes can worsen over time and persist for months.25 Different types of ophthalmologic complications have been described in 2% to 46% of cases with ophthalmic zoster.39 These include ptosis, scleritis, iridocyclitis, secondary glaucoma, cataract, and keratitis, the most common ocular complication of herpes zoster. The complications of ophthalmic zoster can be sight-threatening, and these patients should therefore be evaluated and managed by an ophthalmologist. Ramsay-Hunt syndrome refers to herpes zoster of the facial nerve accompanied by ear pain, hearing loss, vertigo, and facial paresis. Importantly, elderly and especially immunosuppressed patients are at greater risk of most of the complications of herpes zoster. Herpes zoster is often accompanied by decreased quality of life.7,8,34,40,41 Severe acute pain in herpes zoster interferes with patients’ abilities to carry out normal activities of daily living (ADLs) and is, not surprisingly, associated with greater use of analgesic medications.7,8,34,40,41 In a sample of 50 patients with herpes zoster, the greatest impact on quality of life occurred during the third to fourth week after rash onset, with effects at least as large as those seen in chronic diseases such as diabetes and congestive heart failure.40 Greater acute pain was associated with greater interference in ADLs, and pain intensity was the most robust determinant of decreased quality of life in a multivariate analysis that controlled for age, rash severity, comorbid illnesses, and general health. In a prospective observational study of 121 older adults with herpes zoster, pain at 30 to 35 days after rash onset significantly interfered with multiple ADLs, reduced health-related quality of life (HRQL), and impaired mental and physical health.8 Interference with ADLs and reduced HRQL increased significantly as pain severity increased. In a study of 110 patients with herpes zoster, the impact of herpes zoster acute pain burden was determined using an area-under-the-curve approach in which a pain intensity composite score was multiplied by the number of days in pain.34 Multiple regression analyses showed that the overall pain burden was significantly correlated with poorer physical, role, and emotional functioning and contributed to decreased role and social functioning. These studies indicate that acute herpetic pain can cause significant suffering. In some patients, pain does not resolve when the herpes zoster rash heals but can continue for months or years. This persisting pain is the most common complication of herpes zoster. Patients typically describe several different types of pain, including continuous burning or throbbing pain, intermittent sharp or electric-shock–like pain, and allodynia. Chronic pain has substantial effects on quality of life, and physical disability and emotional distress are common in patients with PHN. Unfortu-
S5 nately, there have been no systematic attempts to investigate the prevalence of PHN, and estimates of the number of cases have ranged up to 1 million in the United States.48 Numerous studies have established that older age is a potent risk factor for PHN; greater acute pain intensity, greater severity of the rash, and presence and greater severity of a painful prodrome preceding the rash are additional well-replicated risk factors.17,33
Treatment of Herpes Zoster In immunocompetent patients, the primary goal of the treatment of herpes zoster is to reduce pain, while cessation of viral replication is the primary goal in immunocompromised patients and those with ophthalmic zoster.13 Nonpharmacologic approaches are generally beneficial to patient well-being—for example, providing reassurance and education can dispel myths and fears about zoster and its implications. Social support, maintaining optimal levels of mental and physical activity, adequate nutrition, and a caring attitude can also help patients cope with this illness. Pharmacologic approaches to herpes zoster include use of antiviral therapy, systemic corticosteroids, and analgesics. Detailed management guidelines for herpes zoster have been recently published.13
Antiviral Therapy Acyclovir, famciclovir, and valacyclovir are guanosine analogs that are phosphorylated by viral thymidine kinase and cellular kinases to a triphosphate form that inhibits VZV DNA polymerase. In general, these drugs are safe and well tolerated, and the most common adverse effects are nausea and headache, which occur in no more than 10% to 20% of patients, which is generally similar to what was found in patients treated with placebo.4,57 These antiviral drugs are excreted by the kidneys, and dosages must be adjusted to allow for renal insufficiency. Infection with VZV resistant to acyclovir (mediated by the lack of thymidine kinase) has been reported in patients with AIDS32 and in transplant patients who received prolonged acyclovir therapy, but not in immunocompetent elderly patients. In patients with acyclovirresistant herpes zoster, alternative treatments are available (eg, foscarnet). Treatment of herpes zoster patients with orally administered acyclovir (800 mg 5 times daily for 7 days), famciclovir (500 mg 3 times daily for 7 days), and valacyclovir (1 g 3 times daily for 7 days) inhibits viral replication and has been shown to reduce the duration of viral shedding and hasten rash healing.4,35,56 Antiviral therapy also decreases the severity and duration of acute pain, and so it is likely that treatment with these drugs reduces the adverse impact of herpes zoster on quality of life discussed above. Antiviral therapy is especially important in immunocompromised patients, because of their increased risk of cutaneous and visceral dissemination and neurologic complications, and in patients with ophthalmic zoster, because of their risk of ocular complications.
S6 Because PHN is the most common complication of herpes zoster in immunocompetent patients, the prevention of PHN has been considered a very important clinical objective. For this reason, the effect of antiviral therapy on the development of PHN has attracted particular attention. By inhibiting viral replication, antiviral therapy limits the degree of neural damage caused by zoster, and such damage likely contributes prominently to the development of PHN. The results of randomized, controlled trials and meta-analyses have demonstrated that antiviral therapy in herpes zoster significantly reduces the risk of prolonged pain.4,10,31,56,57,62 For example, in the pivotal controlled trials of famciclovir and valacyclovir for 7 days beginning within 72 hours of rash onset, the median time to complete loss of pain in patients with pain at rash healing was 63 days with famciclovir (500 mg 3 times daily) and 119 days with placebo,56 and the median time to complete cessation of pain was 38 days for valacyclovir (1 g 3 times daily) and 51 days for acyclovir (800 mg 5 times daily).4 Although the effect of acyclovir on chronic pain has been less certain because clinical trials have had conflicting results, the results of 2 meta-analyses suggest that acyclovir is superior to placebo in reducing the duration of overall pain and the incidence of PHN.31,62 The results of each of the antiviral clinical trials taken singly can be challenged, but the consistency of the findings provides strong support for the use of antiviral agents in the treatment of herpes zoster. The data suggest that all 3 available drugs are acceptable agents, and factors other than efficacy, such as cost and dosing schedule, should be considered. Famciclovir and valacyclovir, with 3 times daily dosing, are considerably more convenient for patients than acyclovir, which because of its pharmacokinetics should ideally be dosed every 5 hours. Because of this and their beneficial effects on pain, antiviral therapy has been recommended for all herpes zoster patients who are older, have moderate or severe rash, have moderate or severe pain, have ophthalmic involvement, or are immunocompromised.13 All of the controlled antiviral clinical trials have initiated treatment within 72 hours of rash onset, an arbitrary inclusion criterion that may not correspond to the cessation of viral replication. In clinical practice, of course, many patients are not diagnosed this rapidly and are therefore unable to initiate treatment within this narrow window. Unfortunately, because the efficacy of antiviral therapy when initiated 4 or more days after rash onset is unknown, there is no evidence base for such treatment. The results of 2 uncontrolled studies revealed no significant differences in persistence of pain between patients who initiated treatment within 72 hours and those who initiated treatment at a later time.9,36 These data suggest that there may be benefit from antiviral therapy initiated later than 72 hours after rash onset; the presence of new vesicles, which indicates continuing viral replication, may provide a method for identifying which patients are most likely to benefit from such treatment.24 However, cutaneous viral activity may not reflect
Natural History and Treatment of Zoster viral replication in neural tissue, which can be expected to be more relevant to reducing the likelihood of prolonged pain. Accurate methods for identifying which patients benefit from antiviral therapy initiated beyond 72 hours after rash onset should therefore be a priority for research on herpes zoster. Patients with ophthalmic zoster presenting after 72 hours from rash onset should be considered for antiviral therapy because of the importance of preventing visual impairment and the duration of VZV DNA shedding from the ocular surface is highly variable.63 Although the reduction in the risk of PHN that accompanies antiviral therapy in patients with herpes zoster is both statistically and clinically significant, antiviral therapy does not prevent PHN in all patients. Approximately 20% of patients older than 50 years continue to have pain 6 months after the occurrence of rash, despite antiviral treatment beginning within 72 hours of rash onset.4,12,62 How, then, can the risk of chronic pain be further reduced beyond that currently achieved by antiviral therapy? Although it is possible that new antivirals with greater efficacy will be developed, a different strategy for preventing PHN is to supplement antiviral treatment. Potential supplements include corticosteroids, analgesics, anticonvulsants, tricyclic antidepressants, and neural blockade.
Corticosteroids Two well-designed clinical trials of acyclovir with or without corticosteroids demonstrated that the addition of corticosteroids did not contribute significantly beyond the benefits achieved by acyclovir in reducing prolonged pain.60,61 Therefore, corticosteroids do not seem to hasten the resolution of pain after herpes zoster. The most common adverse effects in these trials were gastrointestinal symptoms (dyspepsia, nausea, and vomiting), edema, and granulocytosis. Although these data contradict the routine use of corticosteroids in herpes zoster, the more recent trial demonstrated that time to uninterrupted sleep, return to normal daily activity, and cessation of analgesic therapy were all significantly accelerated in patients who received combination therapy relative to patients who received placebo.60 The patients in the trial had an average age of 60 years and no contraindications to corticosteroids, such as hypertension, diabetes mellitus, or osteoporosis. On the basis of these results, orally administered corticosteroids in combination with an antiviral drug could be considered for otherwise healthy older adults with moderate to severe pain or rash unrelieved by antiviral agents and analgesics and no contraindications to their use. Importantly, the use of corticosteroids without concomitant antiviral therapy cannot be recommended,24 except possibly in rare cases in which patients are unable to tolerate antiviral therapy but have no contraindications to corticosteroids. Some clinicians use corticosteroids especially for VZV-induced facial paralysis and cranial polyneuritis to improve motor outcomes and relieve pain.
ORIGINAL REPORT/Schmader and Dworkin
Analgesics It has been predicted that combining antiviral therapy with effective relief of acute pain in herpes zoster will further reduce the risk of PHN beyond that achieved by antiviral therapy alone.15,18 The basis for this hypothesis is provided by the well-replicated relationship between acute pain severity and PHN and by recent research on the pathophysiology of PHN. The efficacy of opioid analgesics, anticonvulsants, tricyclic antidepressants, or nerve blocks during the acute phase of herpes zoster in reducing the risk of PHN requires investigation in randomized placebo-controlled clinical trials. Even if there were no benefit of aggressive analgesic treatment in patients with herpes zoster in reducing their likelihood of developing PHN, the effective relief of acute pain in herpes zoster is clearly a desirable treatment goal in itself. Clinicians should use the principles of state-of-the-art pain management for herpes zoster acute pain, such as scheduled analgesia, use of standardized pain measures, and consistent and frequent follow-up. The choice of analgesic treatment approaches depends on the patient’s pain severity, underlying conditions, and response to the drug.13 Patients with mild pain may be treated adequately with acetaminophen or nonsteroidal agents, whereas patients with moderate to severe pain usually require treatment with a strong opioid analgesic. One approach to the use of opioids in herpes zoster pain is to start with a short-acting medication scheduled 4 times daily and titrating the dose until pain reduction and tolerability are achieved.13 Long-acting opioids are more convenient and may also provide a more consistent level of pain relief, so treatment can be switched from a short-acting to a longacting medication if an effective and tolerable dose is found, depending on cost and patient preference. Providers can prescribe rescue doses of a short-acting opioid for exacerbations of pain as needed with the longacting opioid. Opioids have multiple adverse effects including nausea, constipation, and sedation that may be intolerable in some older adults. In most cases, constipation should be anticipated and managed with laxative therapy. If moderate to severe herpes zoster pain is not adequately relieved by antiviral agents in combination with oral analgesic medications and/or corticosteroids, then adjuvant agents such as anticonvulsants (eg, gabapentin or pregabalin) or tricyclic antidepressants (eg, nortriptyline or desipramine) can be considered.13 Although neither gabapentin nor pregabalin has been tested for the prevention of PHN or relief of acute pain in herpes zoster in randomized, controlled trials, these agents have known efficacy in relieving chronic neuropathic pain, and a single-dose (900 mg) gabapentin trial in herpes zoster acute pain showed pain reduction.3,28 If prescribed, gabapentin and pregabalin must be dose-adjusted for renal insufficiency and can cause sedation, dizziness, ataxia, and peripheral edema, which can be particularly problematic in frail elderly patients.13,28 It is best to give starting doses at bedtime and carefully in-
S7 crease subsequent doses to 3 times daily for gabapentin and twice daily for pregabalin. Tricyclic antidepressants have not been tested for relief of herpes zoster acute pain in randomized, controlled trials. However, tricyclic antidepressants have known efficacy in relieving chronic neuropathic pain and a small study that used amitriptyline 25-mg daily during acute herpes zoster was associated with lower rates of pain at 6 months from rash onset.5 Amitriptyline has greater anticholinergic properties and associated adverse effects than nortriptyline or desipramine. The use of tricyclic antidepressants must be weighed carefully against significant potential adverse effects, particularly in frail elderly patients. These agents should be used with extreme caution, if at all, in patients with QT prolongation, with atrioventricular block or bundle-branch block, or with a recent acute myocardial infarction. Baseline and follow-up electrocardiograms are necessary when prescribing these agents. Other important anticholinergic adverse effects include urinary retention, dry mouth, constipation, dizziness, orthostatic hypotension, visual impairment, drowsiness, cognitive impairment, and balance problems.
Neural Blockade Another option for patients with severe herpes zoster acute pain unrelieved by pharmacotherapeutic approaches is the use of neural blockade. A recent randomized, controlled trial of a single epidural block with bupivacaine and methylprednisolone in combination with antiviral therapy and oral analgesics compared with antiviral therapy and oral analgesics alone demonstrated that neural blockade reduces acute pain but does not prevent PHN.58 This modality requires referral to a pain specialist or pain management center. In some cases, patients will experience severe, unrelenting pain despite the above outpatient treatments. These individuals require hospitalization for parenteral opioids and/or epidural analgesia along with supportive care.
Conclusions Herpes zoster is a common problem, occurring in about 1 million people each year in the United States. The cardinal problem posed by herpes zoster in immunocompetent adults is pain. Herpes zoster acute pain lowers quality of life and interferes with activities of daily living. A clinician can reduce pain and improve quality of life with early antiviral therapy and scheduled analgesics. In patients who continue to have moderate to severe herpes zoster acute pain not adequately relieved by these measures, then supplemental treatments with corticosteroids, anticonvulsants (eg, gabapentin or pregabalin), tricyclic antidepressants (eg, nortriptyline or desipramine), or neural blockade can be considered. However, the evidence base for the effectiveness of these supplemental treatments in herpes zoster acute pain is weak. Further research is needed to better understand the proper roles of these treatments.
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References 1. Arani RB, Soong S-J, Weiss HL, Wood MJ, Fiddian PA, Gnann JW, Whitley R: Phase specific analysis of herpes zoster associated pain data: A new statistical approach. Stat Med 20:2429-2439, 2001 2. Arvin AM: Varicella-zoster virus. Clin Microbiol Rev 9:361381, 1996 3. Berry JD, Petersen KL: A single dose of gabapentin reduces acute pain and allodynia in patients with herpes zoster. Neurology 65:444-447, 2005 4. 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 39:1546-1553, 1995 5. Bowsher D: The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: A randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 13:327-331, 1997 6. Burgoon CF Jr, Burgoon JS, Baldridge GD: The natural history of herpes zoster. JAMA 164:265-269, 1957 7. Chidiac C, Bruxelle J, Daures JP, Hoang-Xuan T, Morel P, Leplége A, El Hasnaouri A, de Labareyre C: Characteristics of patients with herpes zoster on presentation to practitioners in France. Clin Infect Dis 33:62-69, 2001 8. Coplan PM, Schmader K, Nikas A, Chan IS, Choo P, Levin MJ, Johnson G, Bauer M, Williams HM, Kaplan KM, Guess HA, Oxman MN: Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the brief pain inventory. J Pain 5:344-356, 2004 9. Decroix J, Partsch H, Gonzalez R, Mobacken H, Gohs CL, Walsh JB, Shuklaz S, Naisbett B, on behalf of the Valaciclovir International Zoster Assessment Group (VIZA): Factors influencing pain outcome in herpes zoster: An observational study with valaciclovir. J Eur Acad Dermatol Venereol 14:2333, 2000 10. Degreef H, Famciclovir Herpes Zoster Clinical Study Group: Famciclovir, a new oral antiherpes drug: Results of the first controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int J Antimicrob Agents 4:241-246, 1994 11. Desmond RA, Weiss HL, Arani RB, Soong S-J, Wood MJ, Fiddian PA, Gnann JW, Whitley RJ: Clinical applications for change-point analysis of herpes zoster pain. J Pain Symptom Manage 23:510-516, 2002 12. Dworkin RH, Boon RJ, Griffin DR, Phung D: Postherpetic neuralgia: Impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis 178(suppl 1):S76-S80, 1998 13. Dworkin RH, Johnson RW, Breuer J, Gnann JW, Levin MJ, Backonja M, Betts RF, Gershon AA, Haanpää ML, McKendrick MW, Nurmikko TJ, Oaklander AL, Oxman MN, PavanLangston D, Petersen KL, Rowbotham MC, Schmader KE, Stacy BR, Tyring SK, von Wijck AJ, Wallace MS, Wassilew SW, Whitley RJ: Recommendations for the management of herpes zoster. Clin Infect Dis 44(suppl 1):S1-26, 2007 14. Dworkin RH, Nagasako EM, Johnson RW, Griffin DR: Acute pain in herpes zoster: The famciclovir database project. Pain 94:113-119, 2001
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15. Dworkin RH, Perkins FM, Nagasako EM: Prospects for the prevention of postherpetic neuralgia in herpes zoster patients. Clin J Pain 16:S90-S100, 2000 16. Dworkin RH, Portenoy RK: Proposed classification of herpes zoster pain. Lancet 343:1648, 1994 17. Dworkin RH, Schmader KE: The epidemiology and natural history of herpes zoster and postherpetic neuralgia, in Watson CP, Gershon AA (eds): Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York, Elsevier, 2001, pp 39-64 18. Dworkin RH, Schmader KE: Treatment and prevention of postherpetic neuralgia. Clin Infect Dis 36:877-882, 2003 19. Gilden DH, Dueland AN, Cohrs R, Martin JR, Kleinschmidt-DeMasters BK, Mahalingam R: Preherpetic neuralgia. Neurology 41:1215-1218, 1991 20. Gilden DH, Dueland AN, Devlin ME, Mahalingam R, Cohrs R: Varicella-zoster virus reactivation without rash. J Infect Dis 166(suppl 1):S30-S34, 1992 21. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ: Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med 342:635645, 2000 22. Gilden DH, Wright RR, Schneck SA, Gwaltney JM Jr, Mahalingam R: Zoster sine herpete, a clinical variant. Ann Neurol 35:530-533, 1994 23. Glesby MJ, Moore RD, Chaisson RE: Clinical spectrum of herpes zoster in adults infected with human immunodeficiency virus. Clin Infect Dis 21:370-375, 1995 24. Gnann JW Jr, Whitley RJ: Clinical practice: Herpes zoster. N Engl J Med 347:340-346, 2002 25. Haanpää M, Häkkinen V, Nurmikko T: Motor involvement in acute herpes zoster. Muscle Nerve 20:1433-1438, 1997 26. Haanpää M, Laippala P, Nurmikko T: Pain and somatosensory dysfunction in acute herpes zoster. Clin J Pain 15:7884, 1999 27. Haanpää M, Laippala P, Nurmikko T: Allodynia and pinprick hypesthesia in acute herpes zoster, and the development of postherpetic neuralgia. J Pain Symptom Manage 20:50-58, 2000 28. Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS: Analgesic therapy in postherpetic neuralgia: A quantitative systematic review. PLoS Med 2:e164, 2005 29. Hope-Simpson R: Studies on shingles: Is the virus ordinary chicken pox virus? Lancet 1299-1302, 1954 30. Hope-Simpson R: The nature of herpes zoster: A longterm study and a new hypothesis. Proc R Soc Med 58:9-20, 1965 31. Jackson JL, Gibbons R, Meyer G, Inouye L: The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia: A meta-analysis. Arch Intern Med 157: 909-912, 1997 32. Jacobson MA, Berger TG, Fikrig S, Beckerer P, Moohr JW, Stanat SC, Biran KK: Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 112:187-191, 1990 33. Jung BF, Johnson RW, Griffin DR, Dworkin RH: Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 62:1545-1551, 2004
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34. Katz J, Cooper EM, Walther RR, Sweeney EW, Dworkin RH: Acute pain in herpes zoster and its impact on healthrelated quality of life. Clin Infect Dis 39:342-348, 2004
50. Schmader K, George LK, Burchett BM, Hamilton JD, Pieper CF: Race and stress in the incidence of herpes zoster in older adults. J Am Geriatr Soc 46:973-977, 1998
35. Kost RG, Straus SE: Postherpetic neuralgia: pathogenesis, treatment, and prevention. N Engl J Med 335:32-42, 1996
51. Schmader K, Studenski S, MacMillan J, Grufferman S, Cohen HJ: Are stressful life events risk factors for herpes zoster? J Am Geriatr Soc 38:1188-1194, 1990
36. Kurokawa I, Kumano K, Murakawa K: Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster. J Int Med Res 30:56-65, 2002 37. Kurtzke JF: Neuroepidemiology. Ann Neurol 16:265-277, 1984 38. Lewis GW: Zoster sine herpete. Br Med J 2:418-421, 1958 39. Liesegang TJ: Varicella-zoster virus eye disease. Cornea 18:511-531, 1999 40. Lydick E, Epstein RS, Himmelberger D, White CJ: Herpes zoster and quality of life: A self-limited disease with severe impact. Neurology 45:S52-S53, 1995 41. Mauskopf J, Austin R, Dix L, Berzon R: The Nottingham Health Profile as a measure of quality of life in zoster patients: Convergent and discriminant validity. Qual Life Res 3:431-435, 1994 42. McCrary ML, Severson J, Tyring SK: Varicella zoster virus. J Am Acad Dermatol 41:1-14, 1999 43. 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 39:209-212, 1999 44. Mehta SK, Cohrs RJ, Forghani B, Zerbe G, Gilden DH, Pierson DL: Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol 72:174-179, 2004 45. Nagasako EM, Johnson RW, Griffin DR, Dworkin RH: Rash severity in herpes zoster: Correlates and relationship to postherpetic neuralgia. J Am Acad Dermatol 46:834-839, 2002 46. Oaklander AL, Bowsher D, Galer B, Haanpää M, Jensen MP: Herpes zoster itch: Preliminary epidemiologic data. J Pain 4:338-343, 2003 47. Oaklander AL, Rissmiller JG: Postherpetic neuralgia after shingles: An under-recognized cause of chronic vulvar pain. Obstet Gynecol 99:625-628, 2002 48. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh S-S, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL, for the Shingles Prevention Study Group: A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352:2271-2284, 2005 49. Ragozzino MW, Melton LJ III, Kurland LT, Chu CP, Perry HO: Population-based study of herpes zoster and its sequelae. Medicine (Baltimore) 61:310-316, 1982
52. Schmader KE, Watson CP, Gnann JW: Epidemiological and clinical rationale for the herpes zoster vaccine. J Infect Dis 2007; In press 53. Straus SE, Reinhold W, Smith HA, Ruyechan WT, Henderson DK, Blaese RM, Hay J: Endonuclease analysis of viral DNA from varicella and subsequent zoster infections in the same patient. N Engl J Med 311:1362-1364, 1984 54. Thomas SL, Hall AJ: What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis 4:2633, 2004 55. Thomas SL, Wheeler JG, Hall AJ: Case-control study of the effect of mechanical trauma on the risk of herpes zoster. BMJ 328:439, 2004 56. Tyring S, Barbarash RA, Nahlik JE, Cunningham A, Marley J, Heng M, Jones T, Rea T, Boon R, Saltzman R, and the Collaborative Famciclovir Herpes Zoster Study Group: Famciclovir for the treatment of acute herpes zoster: Effects on acute disease and postherpetic neuralgia: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 123: 89-96, 1995 57. Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ: Antiviral therapy for herpes zoster: Randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 9:863-869, 2000 58. van Wijck AJ, Opstelten W, Moons KG, van Essen GA, Stalker RJ, Kalkman CJ, Verheij TJ: The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: A randomised controlled trial. Lancet 367:219-224, 2006 59. Weller T, Witton H, Bell E: The etiologic agents of varicella and herpes zoster: Isolation, propagation, and cultural characteristics in vitro. J Exp Med 108:843-868, 1958 60. Whitley RJ, Weiss H, Gnann JW Jr, Tyring S, Mertz GJ, Pappas PG, Schleupner CJ, Hayden F, Wolf J, Soong S-J: Acyclovir with and without prednisone for the treatment of herpes zoster: A randomized, placebo-controlled trial. Ann Intern Med 125:376-383, 1996 61. Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J: A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 330:896-900, 1994 62. 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 22:341-347, 1996 63. Zaal MJ, Völker-Dieben HJ, Wienesen M, D’Amaro JD, Kijlstra A: Longitudinal analysis of varicella-zoster virus DNA on the ocular surface associated with herpes zoster ophthalmicus. Am J Ophthalmol 131:25-29, 2001
Natural History and Treatment of Herpes Zoster Kenneth E. Schmader* and Robert H. Dworkin† *Division of Geriatrics, Department of Medicine and the Center for the Study of Aging and Human Development, Duke University Medical Center and Geriatric Research, Education and Clinical Center, Durham VA Medical Center, Durham, North Carolina. † Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Abstract: The objective of this article is to provide an overview of the natural history and treatment of herpes zoster, with a focus on pain management. Herpes zoster has the highest incidence of all neurological diseases, occurring annually in approximately 1 million people in the United States. A basic feature of herpes zoster is a marked increase in incidence with aging and with diseases and drugs that impair cellular immunity. Herpes zoster begins with reactivation of varicella zoster virus in dorsal root or cranial nerve ganglia, which is often accompanied by a prodrome of dermatomal pain or abnormal sensations. Varicella zoster virus spreads in the affected primary afferent nerve to the skin and produces a characteristic dermatomal maculopapular and vesicular rash and pain. Herpes zoster acute pain lowers quality of life and interferes with activities of daily living. Antiviral therapy and scheduled analgesics form the pharmacotherapeutic foundation for herpes zoster acute pain reduction. If moderate to severe herpes zoster pain is not adequately relieved by antiviral agents in combination with oral analgesic medications, then corticosteroids, anticonvulsants (eg, gabapentin or pregabalin), tricyclic antidepressants (eg, nortriptyline or desipramine), or neural blockade can be considered. Perspective: This article presents information on the clinical features and treatment of herpes zoster. This information will help clinicians diagnose and manage herpes zoster pain. © 2008 by the American Pain Society Key words: Herpes zoster, pain, aged.
A
fter a primary varicella (chickenpox) infection, the varicella zoster virus (VZV) establishes latency in dorsal root and cranial nerve ganglia. Herpes zoster (“shingles”) is the reactivation of the virus and its spread from a single ganglion to the corresponding dermatome and neural tissue of the same segment.24,29,30,53,59 Herpes zoster has the highest incidence of all neurological diseases, occurring annually in KES has received grants/research support, consulting fees, or honoraria in the past year from Merck & Co., Inc. and RHD has received grants/research support, consulting fees, or honoraria in the past year from Allergan, Balboa, Cara, CombinatoRx, Dara, Eli Lilly, Endo, EpiCept, Fralex, GlaxoSmithKline, Grünenthal, GW Pharmaceuticals, Johnson & Johnson, KAI Pharmaceuticals, Merck & Co., Inc., NeurogesX, Ono, Organon, Pfizer, Supernus, US Food and Drug Administration, US National Institutes of Health, US Veterans Administration, Wyeth, and XTL Development. Address reprint requests to Dr. Kenneth Schmader, 182 GRECC, 508 Fulton Street, Durham VA Medical Center, Durham, NC 27705. E-mail: [email protected] 1526-5900/$34.00 © 2008 by the American Pain Society doi:10.1016/j.jpain.2007.10.002
approximately 1 million people in the United States,48 during the lifetimes of as much as 20% to 30% of the population, and in as many as 50% of those living until 85 years of age.30,37 The objective of this article is to provide an overview of the natural history and treatment of herpes zoster, with a focus on pain management. The natural history of herpes zoster is ultimately determined by the transmission and spread of VZV in populations. The most important condition in the spread of VZV is the primary infection, but latent and reactivated VZV infections also play important roles in maintaining VZV infection in populations.2 Latently infected elderly adults and immunosuppressed patients are important reservoirs of virus because VZV is more likely to reactivate in these groups, as discussed below. When herpes zoster occurs, VZV can be transmitted during the vesicular phase of the rash and cause primary infection when there is contact with a seronegative individual. A herpes S3
S4 zoster exposure with a seropositive, latently infected individual may result in a subclinical reinfection and boost of humoral and cellular VZV immunity, but it is unlikely to cause varicella or herpes zoster.2 In population-based studies, the incidence of herpes zoster in persons of all ages is 1.2 to 4.8 cases per 1000 persons per year, whereas the incidence of herpes zoster in persons older than 60 years is 7.2 to 11.8 cases per thousand per year.52 A fundamental epidemiological feature of herpes zoster is a marked increase in incidence with aging and with diseases and drugs that impair cellular immunity. The age at which the sharpest increase in herpes zoster occurs is 50 to 60 years of age, although the slope continues a marked upward course in the decades above 60 years.30,49 The diseases most associated with herpes zoster include human immunodeficiency virus infection, acquired immunodeficiency syndrome (AIDS), hematologic malignancies, organ transplants (especially bone marrow transplant), and immune-mediated diseases.24 Even among those who are immunocompromised, greater age increases the risk of herpes zoster. Other possible risk factors for herpes zoster include physical trauma at the involved dermatome,55 psychological stress,44,50,51 and white race.50,54 The live, attenuated varicella vaccine and the zoster vaccine may alter the epidemiology and natural history of herpes zoster.
Natural History of Herpes Zoster The clinical presentation of herpes zoster is variable. In the majority of patients, a prodrome of dermatomal pain or abnormal sensations precedes the appearance of the characteristic rash.14,26,27 This prodrome may also present with fatigue, headache, and other flu-like symptoms. It begins several days before rash onset in almost all cases, but a series of patients with prodromal pain preceding the appearance of the rash by 7 to more than 100 days has been reported.19 Unfortunately, it is not possible to reliably identify individuals with a herpes zoster prodrome. In a series of 57 patients presenting to their general practitioners with acute unilateral pain, only 2 developed a herpes zoster rash, and there was no correlation between clinical evaluations and VZV reactivation as determined by the development of a rash or the results of serology and polymerase chain reaction.43 The unilateral dermatomal rash of herpes zoster begins with the appearance of macules and papules on an erythematous base. The resulting clustered vesicles progress to pustules and crusts over the next 7 to 10 days, and complete loss of scabs occurs within 2 to 3 weeks.6 Thoracic dermatomes are the most commonly affected sites in herpes zoster and account for up to 50% of all cases.6,30,49 Cranial (especially the ophthalmic division of the trigeminal nerve), cervical, and lumbar dermatomes each account for 10% to 20% of cases, and sacral dermatomes are affected in 2% to 8% of cases.6,30,49 Because herpes zoster can occur in any dermatome, it may be misdiagnosed as herpes simplex when it affects der-
Natural History and Treatment of Zoster matomes in which such infections are common, especially lumbar, sacral, maxillary, and mandibular dermatomes.47 In addition to involvement of the primary dermatome, patients commonly develop lesions in adjacent dermatomes. Older age is associated with a greater likelihood of a more severe herpes zoster rash,45 but cutaneous dissemination— defined as ⬎20 lesions outside the primary and immediately adjacent dermatomes—is rare in immunocompetent patients.42 Cutaneous dissemination and atypical or prolonged rash can occur in immunocompromised patients, and a substantial number of these patients also have evidence of visceral involvement.23,24 Pain in the affected dermatome accompanies the rash in most patients.14,26,27 Those who do not have a painful prodrome typically begin to experience pain at rash onset or shortly afterward. This herpes zoster acute pain, which may be accompanied by itch and other paresthesias and dysesthesias,46 can have several different qualities, including constant burning and throbbing, intermittent shooting or stabbing, and allodynia, which is pain in response to normally innocuous stimuli, such as the touch of light clothing. The acute pain associated with herpes zoster gradually resolves before or shortly after rash healing in most patients, and the results of recent research provide support for distinguishing between 3 phases of pain—acute pain occurring within 30 days after rash onset; subacute herpetic neuralgia (pain that persists beyond the acute phase but that resolves before the diagnosis of PHN can be made); and postherpetic neuralgia (PHN; pain that persists 120 days or more after rash onset).1,11,16,33 Herpes zoster without a rash but with dermatomal pain, referred to as zoster sine herpete, has also been described.20,38 Although the finding of VZV DNA, but not herpes simplex virus DNA, in the cerebrospinal fluid of 2 patients with prolonged and recurrent radicular pain and no rash provides support for the existence of this condition,22 its prevalence is currently unknown. Because of the difficulty of diagnosing herpes zoster (and its complications, especially PHN) in the absence of the characteristic rash, this diagnosis should be reserved for patients who have been evaluated in specialist centers with a diagnosis confirmed by the results of laboratory tests such as acute and convalescent serology. The morbidity of herpes zoster includes neurological disorders and ophthalmologic, cutaneous, and visceral complications. Specific types of neurologic complications include granulomatous arteritis, which occurs more often in immunocompetent patients; small-vessel encephalitis, which has become the most common central nervous system complication of herpes zoster as a result of the increased numbers of immunocompromised patients; and myelitis, which occurs in both immunocompromised and immunocompetent patients.21 It has been recognized for some time that a motor neuropathy can occur in patients with herpes zoster, but this may be more common than generally appreciated. The authors of a study of 40 patients with herpes zoster in
ORIGINAL REPORT/Schmader and Dworkin whom electromyography and motor nerve conduction velocity were prospectively examined concluded that motor involvement can be widespread, extending ipsilaterally and contralaterally several segments above and below the dermatome affected by the rash, and that these changes can worsen over time and persist for months.25 Different types of ophthalmologic complications have been described in 2% to 46% of cases with ophthalmic zoster.39 These include ptosis, scleritis, iridocyclitis, secondary glaucoma, cataract, and keratitis, the most common ocular complication of herpes zoster. The complications of ophthalmic zoster can be sight-threatening, and these patients should therefore be evaluated and managed by an ophthalmologist. Ramsay-Hunt syndrome refers to herpes zoster of the facial nerve accompanied by ear pain, hearing loss, vertigo, and facial paresis. Importantly, elderly and especially immunosuppressed patients are at greater risk of most of the complications of herpes zoster. Herpes zoster is often accompanied by decreased quality of life.7,8,34,40,41 Severe acute pain in herpes zoster interferes with patients’ abilities to carry out normal activities of daily living (ADLs) and is, not surprisingly, associated with greater use of analgesic medications.7,8,34,40,41 In a sample of 50 patients with herpes zoster, the greatest impact on quality of life occurred during the third to fourth week after rash onset, with effects at least as large as those seen in chronic diseases such as diabetes and congestive heart failure.40 Greater acute pain was associated with greater interference in ADLs, and pain intensity was the most robust determinant of decreased quality of life in a multivariate analysis that controlled for age, rash severity, comorbid illnesses, and general health. In a prospective observational study of 121 older adults with herpes zoster, pain at 30 to 35 days after rash onset significantly interfered with multiple ADLs, reduced health-related quality of life (HRQL), and impaired mental and physical health.8 Interference with ADLs and reduced HRQL increased significantly as pain severity increased. In a study of 110 patients with herpes zoster, the impact of herpes zoster acute pain burden was determined using an area-under-the-curve approach in which a pain intensity composite score was multiplied by the number of days in pain.34 Multiple regression analyses showed that the overall pain burden was significantly correlated with poorer physical, role, and emotional functioning and contributed to decreased role and social functioning. These studies indicate that acute herpetic pain can cause significant suffering. In some patients, pain does not resolve when the herpes zoster rash heals but can continue for months or years. This persisting pain is the most common complication of herpes zoster. Patients typically describe several different types of pain, including continuous burning or throbbing pain, intermittent sharp or electric-shock–like pain, and allodynia. Chronic pain has substantial effects on quality of life, and physical disability and emotional distress are common in patients with PHN. Unfortu-
S5 nately, there have been no systematic attempts to investigate the prevalence of PHN, and estimates of the number of cases have ranged up to 1 million in the United States.48 Numerous studies have established that older age is a potent risk factor for PHN; greater acute pain intensity, greater severity of the rash, and presence and greater severity of a painful prodrome preceding the rash are additional well-replicated risk factors.17,33
Treatment of Herpes Zoster In immunocompetent patients, the primary goal of the treatment of herpes zoster is to reduce pain, while cessation of viral replication is the primary goal in immunocompromised patients and those with ophthalmic zoster.13 Nonpharmacologic approaches are generally beneficial to patient well-being—for example, providing reassurance and education can dispel myths and fears about zoster and its implications. Social support, maintaining optimal levels of mental and physical activity, adequate nutrition, and a caring attitude can also help patients cope with this illness. Pharmacologic approaches to herpes zoster include use of antiviral therapy, systemic corticosteroids, and analgesics. Detailed management guidelines for herpes zoster have been recently published.13
Antiviral Therapy Acyclovir, famciclovir, and valacyclovir are guanosine analogs that are phosphorylated by viral thymidine kinase and cellular kinases to a triphosphate form that inhibits VZV DNA polymerase. In general, these drugs are safe and well tolerated, and the most common adverse effects are nausea and headache, which occur in no more than 10% to 20% of patients, which is generally similar to what was found in patients treated with placebo.4,57 These antiviral drugs are excreted by the kidneys, and dosages must be adjusted to allow for renal insufficiency. Infection with VZV resistant to acyclovir (mediated by the lack of thymidine kinase) has been reported in patients with AIDS32 and in transplant patients who received prolonged acyclovir therapy, but not in immunocompetent elderly patients. In patients with acyclovirresistant herpes zoster, alternative treatments are available (eg, foscarnet). Treatment of herpes zoster patients with orally administered acyclovir (800 mg 5 times daily for 7 days), famciclovir (500 mg 3 times daily for 7 days), and valacyclovir (1 g 3 times daily for 7 days) inhibits viral replication and has been shown to reduce the duration of viral shedding and hasten rash healing.4,35,56 Antiviral therapy also decreases the severity and duration of acute pain, and so it is likely that treatment with these drugs reduces the adverse impact of herpes zoster on quality of life discussed above. Antiviral therapy is especially important in immunocompromised patients, because of their increased risk of cutaneous and visceral dissemination and neurologic complications, and in patients with ophthalmic zoster, because of their risk of ocular complications.
S6 Because PHN is the most common complication of herpes zoster in immunocompetent patients, the prevention of PHN has been considered a very important clinical objective. For this reason, the effect of antiviral therapy on the development of PHN has attracted particular attention. By inhibiting viral replication, antiviral therapy limits the degree of neural damage caused by zoster, and such damage likely contributes prominently to the development of PHN. The results of randomized, controlled trials and meta-analyses have demonstrated that antiviral therapy in herpes zoster significantly reduces the risk of prolonged pain.4,10,31,56,57,62 For example, in the pivotal controlled trials of famciclovir and valacyclovir for 7 days beginning within 72 hours of rash onset, the median time to complete loss of pain in patients with pain at rash healing was 63 days with famciclovir (500 mg 3 times daily) and 119 days with placebo,56 and the median time to complete cessation of pain was 38 days for valacyclovir (1 g 3 times daily) and 51 days for acyclovir (800 mg 5 times daily).4 Although the effect of acyclovir on chronic pain has been less certain because clinical trials have had conflicting results, the results of 2 meta-analyses suggest that acyclovir is superior to placebo in reducing the duration of overall pain and the incidence of PHN.31,62 The results of each of the antiviral clinical trials taken singly can be challenged, but the consistency of the findings provides strong support for the use of antiviral agents in the treatment of herpes zoster. The data suggest that all 3 available drugs are acceptable agents, and factors other than efficacy, such as cost and dosing schedule, should be considered. Famciclovir and valacyclovir, with 3 times daily dosing, are considerably more convenient for patients than acyclovir, which because of its pharmacokinetics should ideally be dosed every 5 hours. Because of this and their beneficial effects on pain, antiviral therapy has been recommended for all herpes zoster patients who are older, have moderate or severe rash, have moderate or severe pain, have ophthalmic involvement, or are immunocompromised.13 All of the controlled antiviral clinical trials have initiated treatment within 72 hours of rash onset, an arbitrary inclusion criterion that may not correspond to the cessation of viral replication. In clinical practice, of course, many patients are not diagnosed this rapidly and are therefore unable to initiate treatment within this narrow window. Unfortunately, because the efficacy of antiviral therapy when initiated 4 or more days after rash onset is unknown, there is no evidence base for such treatment. The results of 2 uncontrolled studies revealed no significant differences in persistence of pain between patients who initiated treatment within 72 hours and those who initiated treatment at a later time.9,36 These data suggest that there may be benefit from antiviral therapy initiated later than 72 hours after rash onset; the presence of new vesicles, which indicates continuing viral replication, may provide a method for identifying which patients are most likely to benefit from such treatment.24 However, cutaneous viral activity may not reflect
Natural History and Treatment of Zoster viral replication in neural tissue, which can be expected to be more relevant to reducing the likelihood of prolonged pain. Accurate methods for identifying which patients benefit from antiviral therapy initiated beyond 72 hours after rash onset should therefore be a priority for research on herpes zoster. Patients with ophthalmic zoster presenting after 72 hours from rash onset should be considered for antiviral therapy because of the importance of preventing visual impairment and the duration of VZV DNA shedding from the ocular surface is highly variable.63 Although the reduction in the risk of PHN that accompanies antiviral therapy in patients with herpes zoster is both statistically and clinically significant, antiviral therapy does not prevent PHN in all patients. Approximately 20% of patients older than 50 years continue to have pain 6 months after the occurrence of rash, despite antiviral treatment beginning within 72 hours of rash onset.4,12,62 How, then, can the risk of chronic pain be further reduced beyond that currently achieved by antiviral therapy? Although it is possible that new antivirals with greater efficacy will be developed, a different strategy for preventing PHN is to supplement antiviral treatment. Potential supplements include corticosteroids, analgesics, anticonvulsants, tricyclic antidepressants, and neural blockade.
Corticosteroids Two well-designed clinical trials of acyclovir with or without corticosteroids demonstrated that the addition of corticosteroids did not contribute significantly beyond the benefits achieved by acyclovir in reducing prolonged pain.60,61 Therefore, corticosteroids do not seem to hasten the resolution of pain after herpes zoster. The most common adverse effects in these trials were gastrointestinal symptoms (dyspepsia, nausea, and vomiting), edema, and granulocytosis. Although these data contradict the routine use of corticosteroids in herpes zoster, the more recent trial demonstrated that time to uninterrupted sleep, return to normal daily activity, and cessation of analgesic therapy were all significantly accelerated in patients who received combination therapy relative to patients who received placebo.60 The patients in the trial had an average age of 60 years and no contraindications to corticosteroids, such as hypertension, diabetes mellitus, or osteoporosis. On the basis of these results, orally administered corticosteroids in combination with an antiviral drug could be considered for otherwise healthy older adults with moderate to severe pain or rash unrelieved by antiviral agents and analgesics and no contraindications to their use. Importantly, the use of corticosteroids without concomitant antiviral therapy cannot be recommended,24 except possibly in rare cases in which patients are unable to tolerate antiviral therapy but have no contraindications to corticosteroids. Some clinicians use corticosteroids especially for VZV-induced facial paralysis and cranial polyneuritis to improve motor outcomes and relieve pain.
ORIGINAL REPORT/Schmader and Dworkin
Analgesics It has been predicted that combining antiviral therapy with effective relief of acute pain in herpes zoster will further reduce the risk of PHN beyond that achieved by antiviral therapy alone.15,18 The basis for this hypothesis is provided by the well-replicated relationship between acute pain severity and PHN and by recent research on the pathophysiology of PHN. The efficacy of opioid analgesics, anticonvulsants, tricyclic antidepressants, or nerve blocks during the acute phase of herpes zoster in reducing the risk of PHN requires investigation in randomized placebo-controlled clinical trials. Even if there were no benefit of aggressive analgesic treatment in patients with herpes zoster in reducing their likelihood of developing PHN, the effective relief of acute pain in herpes zoster is clearly a desirable treatment goal in itself. Clinicians should use the principles of state-of-the-art pain management for herpes zoster acute pain, such as scheduled analgesia, use of standardized pain measures, and consistent and frequent follow-up. The choice of analgesic treatment approaches depends on the patient’s pain severity, underlying conditions, and response to the drug.13 Patients with mild pain may be treated adequately with acetaminophen or nonsteroidal agents, whereas patients with moderate to severe pain usually require treatment with a strong opioid analgesic. One approach to the use of opioids in herpes zoster pain is to start with a short-acting medication scheduled 4 times daily and titrating the dose until pain reduction and tolerability are achieved.13 Long-acting opioids are more convenient and may also provide a more consistent level of pain relief, so treatment can be switched from a short-acting to a longacting medication if an effective and tolerable dose is found, depending on cost and patient preference. Providers can prescribe rescue doses of a short-acting opioid for exacerbations of pain as needed with the longacting opioid. Opioids have multiple adverse effects including nausea, constipation, and sedation that may be intolerable in some older adults. In most cases, constipation should be anticipated and managed with laxative therapy. If moderate to severe herpes zoster pain is not adequately relieved by antiviral agents in combination with oral analgesic medications and/or corticosteroids, then adjuvant agents such as anticonvulsants (eg, gabapentin or pregabalin) or tricyclic antidepressants (eg, nortriptyline or desipramine) can be considered.13 Although neither gabapentin nor pregabalin has been tested for the prevention of PHN or relief of acute pain in herpes zoster in randomized, controlled trials, these agents have known efficacy in relieving chronic neuropathic pain, and a single-dose (900 mg) gabapentin trial in herpes zoster acute pain showed pain reduction.3,28 If prescribed, gabapentin and pregabalin must be dose-adjusted for renal insufficiency and can cause sedation, dizziness, ataxia, and peripheral edema, which can be particularly problematic in frail elderly patients.13,28 It is best to give starting doses at bedtime and carefully in-
S7 crease subsequent doses to 3 times daily for gabapentin and twice daily for pregabalin. Tricyclic antidepressants have not been tested for relief of herpes zoster acute pain in randomized, controlled trials. However, tricyclic antidepressants have known efficacy in relieving chronic neuropathic pain and a small study that used amitriptyline 25-mg daily during acute herpes zoster was associated with lower rates of pain at 6 months from rash onset.5 Amitriptyline has greater anticholinergic properties and associated adverse effects than nortriptyline or desipramine. The use of tricyclic antidepressants must be weighed carefully against significant potential adverse effects, particularly in frail elderly patients. These agents should be used with extreme caution, if at all, in patients with QT prolongation, with atrioventricular block or bundle-branch block, or with a recent acute myocardial infarction. Baseline and follow-up electrocardiograms are necessary when prescribing these agents. Other important anticholinergic adverse effects include urinary retention, dry mouth, constipation, dizziness, orthostatic hypotension, visual impairment, drowsiness, cognitive impairment, and balance problems.
Neural Blockade Another option for patients with severe herpes zoster acute pain unrelieved by pharmacotherapeutic approaches is the use of neural blockade. A recent randomized, controlled trial of a single epidural block with bupivacaine and methylprednisolone in combination with antiviral therapy and oral analgesics compared with antiviral therapy and oral analgesics alone demonstrated that neural blockade reduces acute pain but does not prevent PHN.58 This modality requires referral to a pain specialist or pain management center. In some cases, patients will experience severe, unrelenting pain despite the above outpatient treatments. These individuals require hospitalization for parenteral opioids and/or epidural analgesia along with supportive care.
Conclusions Herpes zoster is a common problem, occurring in about 1 million people each year in the United States. The cardinal problem posed by herpes zoster in immunocompetent adults is pain. Herpes zoster acute pain lowers quality of life and interferes with activities of daily living. A clinician can reduce pain and improve quality of life with early antiviral therapy and scheduled analgesics. In patients who continue to have moderate to severe herpes zoster acute pain not adequately relieved by these measures, then supplemental treatments with corticosteroids, anticonvulsants (eg, gabapentin or pregabalin), tricyclic antidepressants (eg, nortriptyline or desipramine), or neural blockade can be considered. However, the evidence base for the effectiveness of these supplemental treatments in herpes zoster acute pain is weak. Further research is needed to better understand the proper roles of these treatments.
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References 1. Arani RB, Soong S-J, Weiss HL, Wood MJ, Fiddian PA, Gnann JW, Whitley R: Phase specific analysis of herpes zoster associated pain data: A new statistical approach. Stat Med 20:2429-2439, 2001 2. Arvin AM: Varicella-zoster virus. Clin Microbiol Rev 9:361381, 1996 3. Berry JD, Petersen KL: A single dose of gabapentin reduces acute pain and allodynia in patients with herpes zoster. Neurology 65:444-447, 2005 4. 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 39:1546-1553, 1995 5. Bowsher D: The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: A randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 13:327-331, 1997 6. Burgoon CF Jr, Burgoon JS, Baldridge GD: The natural history of herpes zoster. JAMA 164:265-269, 1957 7. Chidiac C, Bruxelle J, Daures JP, Hoang-Xuan T, Morel P, Leplége A, El Hasnaouri A, de Labareyre C: Characteristics of patients with herpes zoster on presentation to practitioners in France. Clin Infect Dis 33:62-69, 2001 8. Coplan PM, Schmader K, Nikas A, Chan IS, Choo P, Levin MJ, Johnson G, Bauer M, Williams HM, Kaplan KM, Guess HA, Oxman MN: Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the brief pain inventory. J Pain 5:344-356, 2004 9. Decroix J, Partsch H, Gonzalez R, Mobacken H, Gohs CL, Walsh JB, Shuklaz S, Naisbett B, on behalf of the Valaciclovir International Zoster Assessment Group (VIZA): Factors influencing pain outcome in herpes zoster: An observational study with valaciclovir. J Eur Acad Dermatol Venereol 14:2333, 2000 10. Degreef H, Famciclovir Herpes Zoster Clinical Study Group: Famciclovir, a new oral antiherpes drug: Results of the first controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int J Antimicrob Agents 4:241-246, 1994 11. Desmond RA, Weiss HL, Arani RB, Soong S-J, Wood MJ, Fiddian PA, Gnann JW, Whitley RJ: Clinical applications for change-point analysis of herpes zoster pain. J Pain Symptom Manage 23:510-516, 2002 12. Dworkin RH, Boon RJ, Griffin DR, Phung D: Postherpetic neuralgia: Impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis 178(suppl 1):S76-S80, 1998 13. Dworkin RH, Johnson RW, Breuer J, Gnann JW, Levin MJ, Backonja M, Betts RF, Gershon AA, Haanpää ML, McKendrick MW, Nurmikko TJ, Oaklander AL, Oxman MN, PavanLangston D, Petersen KL, Rowbotham MC, Schmader KE, Stacy BR, Tyring SK, von Wijck AJ, Wallace MS, Wassilew SW, Whitley RJ: Recommendations for the management of herpes zoster. Clin Infect Dis 44(suppl 1):S1-26, 2007 14. Dworkin RH, Nagasako EM, Johnson RW, Griffin DR: Acute pain in herpes zoster: The famciclovir database project. Pain 94:113-119, 2001
Natural History and Treatment of Zoster
15. Dworkin RH, Perkins FM, Nagasako EM: Prospects for the prevention of postherpetic neuralgia in herpes zoster patients. Clin J Pain 16:S90-S100, 2000 16. Dworkin RH, Portenoy RK: Proposed classification of herpes zoster pain. Lancet 343:1648, 1994 17. Dworkin RH, Schmader KE: The epidemiology and natural history of herpes zoster and postherpetic neuralgia, in Watson CP, Gershon AA (eds): Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York, Elsevier, 2001, pp 39-64 18. Dworkin RH, Schmader KE: Treatment and prevention of postherpetic neuralgia. Clin Infect Dis 36:877-882, 2003 19. Gilden DH, Dueland AN, Cohrs R, Martin JR, Kleinschmidt-DeMasters BK, Mahalingam R: Preherpetic neuralgia. Neurology 41:1215-1218, 1991 20. Gilden DH, Dueland AN, Devlin ME, Mahalingam R, Cohrs R: Varicella-zoster virus reactivation without rash. J Infect Dis 166(suppl 1):S30-S34, 1992 21. Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ: Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med 342:635645, 2000 22. Gilden DH, Wright RR, Schneck SA, Gwaltney JM Jr, Mahalingam R: Zoster sine herpete, a clinical variant. Ann Neurol 35:530-533, 1994 23. Glesby MJ, Moore RD, Chaisson RE: Clinical spectrum of herpes zoster in adults infected with human immunodeficiency virus. Clin Infect Dis 21:370-375, 1995 24. Gnann JW Jr, Whitley RJ: Clinical practice: Herpes zoster. N Engl J Med 347:340-346, 2002 25. Haanpää M, Häkkinen V, Nurmikko T: Motor involvement in acute herpes zoster. Muscle Nerve 20:1433-1438, 1997 26. Haanpää M, Laippala P, Nurmikko T: Pain and somatosensory dysfunction in acute herpes zoster. Clin J Pain 15:7884, 1999 27. Haanpää M, Laippala P, Nurmikko T: Allodynia and pinprick hypesthesia in acute herpes zoster, and the development of postherpetic neuralgia. J Pain Symptom Manage 20:50-58, 2000 28. Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS: Analgesic therapy in postherpetic neuralgia: A quantitative systematic review. PLoS Med 2:e164, 2005 29. Hope-Simpson R: Studies on shingles: Is the virus ordinary chicken pox virus? Lancet 1299-1302, 1954 30. Hope-Simpson R: The nature of herpes zoster: A longterm study and a new hypothesis. Proc R Soc Med 58:9-20, 1965 31. Jackson JL, Gibbons R, Meyer G, Inouye L: The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia: A meta-analysis. Arch Intern Med 157: 909-912, 1997 32. Jacobson MA, Berger TG, Fikrig S, Beckerer P, Moohr JW, Stanat SC, Biran KK: Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 112:187-191, 1990 33. Jung BF, Johnson RW, Griffin DR, Dworkin RH: Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 62:1545-1551, 2004
ORIGINAL REPORT/Schmader and Dworkin
S9
34. Katz J, Cooper EM, Walther RR, Sweeney EW, Dworkin RH: Acute pain in herpes zoster and its impact on healthrelated quality of life. Clin Infect Dis 39:342-348, 2004
50. Schmader K, George LK, Burchett BM, Hamilton JD, Pieper CF: Race and stress in the incidence of herpes zoster in older adults. J Am Geriatr Soc 46:973-977, 1998
35. Kost RG, Straus SE: Postherpetic neuralgia: pathogenesis, treatment, and prevention. N Engl J Med 335:32-42, 1996
51. Schmader K, Studenski S, MacMillan J, Grufferman S, Cohen HJ: Are stressful life events risk factors for herpes zoster? J Am Geriatr Soc 38:1188-1194, 1990
36. Kurokawa I, Kumano K, Murakawa K: Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster. J Int Med Res 30:56-65, 2002 37. Kurtzke JF: Neuroepidemiology. Ann Neurol 16:265-277, 1984 38. Lewis GW: Zoster sine herpete. Br Med J 2:418-421, 1958 39. Liesegang TJ: Varicella-zoster virus eye disease. Cornea 18:511-531, 1999 40. Lydick E, Epstein RS, Himmelberger D, White CJ: Herpes zoster and quality of life: A self-limited disease with severe impact. Neurology 45:S52-S53, 1995 41. Mauskopf J, Austin R, Dix L, Berzon R: The Nottingham Health Profile as a measure of quality of life in zoster patients: Convergent and discriminant validity. Qual Life Res 3:431-435, 1994 42. McCrary ML, Severson J, Tyring SK: Varicella zoster virus. J Am Acad Dermatol 41:1-14, 1999 43. 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 39:209-212, 1999 44. Mehta SK, Cohrs RJ, Forghani B, Zerbe G, Gilden DH, Pierson DL: Stress-induced subclinical reactivation of varicella zoster virus in astronauts. J Med Virol 72:174-179, 2004 45. Nagasako EM, Johnson RW, Griffin DR, Dworkin RH: Rash severity in herpes zoster: Correlates and relationship to postherpetic neuralgia. J Am Acad Dermatol 46:834-839, 2002 46. Oaklander AL, Bowsher D, Galer B, Haanpää M, Jensen MP: Herpes zoster itch: Preliminary epidemiologic data. J Pain 4:338-343, 2003 47. Oaklander AL, Rissmiller JG: Postherpetic neuralgia after shingles: An under-recognized cause of chronic vulvar pain. Obstet Gynecol 99:625-628, 2002 48. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh S-S, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL, for the Shingles Prevention Study Group: A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352:2271-2284, 2005 49. Ragozzino MW, Melton LJ III, Kurland LT, Chu CP, Perry HO: Population-based study of herpes zoster and its sequelae. Medicine (Baltimore) 61:310-316, 1982
52. Schmader KE, Watson CP, Gnann JW: Epidemiological and clinical rationale for the herpes zoster vaccine. J Infect Dis 2007; In press 53. Straus SE, Reinhold W, Smith HA, Ruyechan WT, Henderson DK, Blaese RM, Hay J: Endonuclease analysis of viral DNA from varicella and subsequent zoster infections in the same patient. N Engl J Med 311:1362-1364, 1984 54. Thomas SL, Hall AJ: What does epidemiology tell us about risk factors for herpes zoster? Lancet Infect Dis 4:2633, 2004 55. Thomas SL, Wheeler JG, Hall AJ: Case-control study of the effect of mechanical trauma on the risk of herpes zoster. BMJ 328:439, 2004 56. Tyring S, Barbarash RA, Nahlik JE, Cunningham A, Marley J, Heng M, Jones T, Rea T, Boon R, Saltzman R, and the Collaborative Famciclovir Herpes Zoster Study Group: Famciclovir for the treatment of acute herpes zoster: Effects on acute disease and postherpetic neuralgia: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 123: 89-96, 1995 57. Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ: Antiviral therapy for herpes zoster: Randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 9:863-869, 2000 58. van Wijck AJ, Opstelten W, Moons KG, van Essen GA, Stalker RJ, Kalkman CJ, Verheij TJ: The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: A randomised controlled trial. Lancet 367:219-224, 2006 59. Weller T, Witton H, Bell E: The etiologic agents of varicella and herpes zoster: Isolation, propagation, and cultural characteristics in vitro. J Exp Med 108:843-868, 1958 60. Whitley RJ, Weiss H, Gnann JW Jr, Tyring S, Mertz GJ, Pappas PG, Schleupner CJ, Hayden F, Wolf J, Soong S-J: Acyclovir with and without prednisone for the treatment of herpes zoster: A randomized, placebo-controlled trial. Ann Intern Med 125:376-383, 1996 61. Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J: A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 330:896-900, 1994 62. 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 22:341-347, 1996 63. Zaal MJ, Völker-Dieben HJ, Wienesen M, D’Amaro JD, Kijlstra A: Longitudinal analysis of varicella-zoster virus DNA on the ocular surface associated with herpes zoster ophthalmicus. Am J Ophthalmol 131:25-29, 2001