Does Treatment of Acute Herpes Zoster Prevent or Shorten Postherpetic Neuralgia? A Systematic Review of the Literature

Postherpetic neuralgia (PHN) is the most common complication of zoster and is much more prevalent among older patients.^1,2 The results of the largest English-language prospective study of patients presenting with zoster,¹ involving 457 patients from 62 general practitioners in Iceland, suggest that the average family physician caring for 2000 patients would expect to see 4 cases of zoster per year and one case of PHN lasting more than 3 months once in 3 years. Among patients older than 60 years in this study, 19% had pain at 3 months, and 8% had pain at 12 months. Among the 183 patients younger than 40 years, only one had pain at 3 months. The authors of the second largest prospective study of zoster,² involving 206 patients from multiple specialty services in Philadelphia, Pennsylvania, found that 14% of patients older than 50 years had pain at 3 months, and 7% had pain at 6 months. In this study, no patients younger than 50 years had pain at 3 months. In comparison, randomized controlled trials of zoster treatment have reported ranges of 16.7% to 60% of patients receiving placebo having pain at 3 months and 5% to 39.1% having pain at 6 months.

Several systematic reviews have addressed treatment or prevention of PHN.^3-5 New trial data^6-9 and discrepancies in the literature^4,10,11 prompted our paper. Differences in the definition of PHN complicated our review of the medical literature.^12,13 For this review, PHN is defined as any pain after cutaneous healing of zoster, and zoster-associated pain (ZAP) is defined as any pain associated with zoster (acute zoster pain and PHN). This review is limited to randomized controlled trials performed at the time of zoster with follow-up addressing the incidence or duration of PHN or ZAP.

Methods

MEDLINE (1966 to present) was searched on December 29, 1998, using PubMed and combining the terms “zoster” or “post-herpetic neuralgia” or “postherpetic neuralgia” or “post-herpetic pain” or “postherpetic pain,” and publication type “clinical trial” (including phases I-IV) or “controlled clinical trial” or “randomized controlled trial.” We searched The Cochrane Controlled Trials Register 1998, issue 4, using the same terms. We also identified trials through article reference lists and Web-based searches. One author conducted independent searches and was unable to identify any additional randomized controlled trials.

For our review we included randomized controlled trials published in English that enrolled primarily immunocompetent subjects with acute herpes zoster and addressed relevant end points (incidence of pain at any time after rash healing in zoster patients or duration of ZAP or PHN). The two authors independently evaluated the trials meeting these inclusion criteria for quality of randomization, allocation concealment, blinding, baseline difference assessment, methods of data collection, adequacy of follow-up (duration and methods), accounting for dropouts, and intention-to-treat analysis. We rated methodologic quality as good, fair, or poor on the basis of an overall assessment of these features. We did not use explicit validity checklists with summary scores, because they have not been shown to predict the effect of bias on treatment differences (ie, they have not been shown to provide more reliable assessments of validity).^14,15 Discordant ratings of trial quality were resolved through the consensus of both investigators.

Results

Our literature search identified 74 appropriate trials. Of the 74 trials reviewed, 42 pertained to treatment at the time of acute zoster to prevent PHN, and 32 pertained to treatment of established PHN.* Of the 42 prevention trials reviewed, 6 were rated as good quality, 22 as fair, and 14 as poor.

Acyclovir

Nucleoside analogues represent the mainstay of acute herpes zoster treatment and produce a faster rate of cutaneous healing and decreased risk of ophthalmic complications.^16,17 A limited subset of acute zoster treatment trials have reported data on PHN incidence or duration.

Four placebo-controlled trials have been conducted using oral acyclovir 800 mg 5 times daily for 7 to 10 days within 72 hours of zoster rash (Table 1).

The largest placebo-controlled trial of acyclovir involved 376 patients from 3 United Kingdom centers and has been reported in multiple publications.^16,18-22 Acyclovir had no effect on the incidence or severity of PHN. Follow-up was monthly to 6 months or until there was no pain during the previous month; this loss to follow-up after the first cessation of pain is the major criticism of this trial, because PHN is known to relapse.^22,23 With this loss to follow-up, the amount of time to complete cessation of pain could not be determined.^23,24 Ten-year follow-up of 132 patients from this trial who reported resolution of pain found that pain returned in 16 cases (12%).²² In subsequent publications, investigators have reported conflicting results in terms of the long-term incidence of PHN. A statistically significant difference in the incidence of PHN was reported in 57 patients from Southampton contacted at 5 years (7% acyclovir patients vs 37% placebo patients, P = .01),²¹ but not in 160 patients from the Sheffield and Birmingham centers contacted at 9 to 10 years.²²

A smaller US multicenter placebo-controlled trial of oral acyclovir reported decreased pain at 1 to 3 months posttreatment, but no differences in analgesic use were reported.^25,26 A reanalysis of 166 patients with pain at enrollment found a reduction in the median duration of ZAP from 62 days to 20 days with acyclovir (P = .02).²⁷ However, of the 21 patients with no pain on enrollment, 15 later developed pain and 4 of those patients continued to report pain through the seventh month. It is possible that inclusion of these patients in the analysis would materially change the results.

In a third trial²⁸ consisting of 83 patients presenting to general practitioners, acyclovir was associated with statistically significant less pain to 3 months. Total analgesic use, however, was reduced in the acyclovir group for only the first 4 weeks.

The fourth trial,²⁹ consisting of 46 patients with acute herpes zoster ophthalmicus, acyclovir was associated with a reduction in pain incidence that was statistically significant at 2 months (P = .04), but not at 6 months (P = .07). Pain severity was significantly reduced from 2 through 6 months, although this analysis is based on only 6 patients having pain at 6 months.

These 4 trials provided all or most of the data for several reviews and meta-analyses.^4,23,24,30 Summary results among these reviews varied because of different methods used, different subgroups assessed, and different efficacy end points reported but generally supported short-term benefit for oral acyclovir. A key issue affecting the overall results of these reviews was consideration of time to complete cessation of pain. This end point was clearly recorded in the 3 smaller trials with positive results but not reported in the large trial with negative results as discussed above.

Crooks and colleagues²³ performed a pooled analysis and reported that oral acyclovir reduced the incidence of PHN from 19% to 11% at 3 to 6 months. We (as well as Lancaster and colleagues⁴) were unable to verify the placebo group incidence rates reported by Crooks and coworkers which appear to have overestimated any acyclovir benefit, and therefore cannot substantiate these findings. Analysis for time to first cessation of pain was reported as a nonsignificant trend toward benefit with acyclovir, while analysis for time to complete cessation of pain (which excluded the largest trial with the negative results) was reported as a statistically significant reduction from an average 86 to 49 days.

Lancaster and colleagues⁴ found a statistically significant reduction in pain at 3 months but no statistically significant benefit at 1 month or 6 months. They commented that analgesic use was not significantly different in 2 of the positive studies.

Wood and coworkers²⁴ derived results from previously unpublished data from these 4 trials and reported that acyclovir significantly accelerated pain resolution. Significant reductions in incidence of pain with acyclovir were reported at 3 and 6 months, but it is unclear if the largest of the 4 trials was included in this analysis.

In the most recent meta-analysis,³⁰ Jackson and colleagues included a fifth trial³¹ and reported an absolute risk reduction of 16% for the incidence of any pain at 6 months (P <.05; number needed to treat [NNT] = 6.3). Multiple methodologic flaws in that meta-analysis, detailed in the Cochrane Review Database,³² make application of the results unclear.

Additional oral acyclovir trials are summarized in Table 1.* Extending the duration of treatment to 14 or 21 days did not provide benefit over 7 days.^33,34 Lower doses of acyclovir had no effect on incidence, severity, or duration of PHN.^17,35,36 There is no evidence to support use of intravenous or topical acyclovir for prevention of PHN.*

Marginal evidence exists to suggest that oral acyclovir 800 mg 5 times daily may reduce the incidence of pain at 1 to 3 months. Information regarding effects on quality of life were generally lacking.

Newer Antivirals

Famciclovir, a prodrug of penciclovir, did not affect the incidence of PHN measured at the time of cutaneous healing in a placebo-controlled trial of 419 patients6 (Table 2). Among the 186 patients (44%) who developed PHN, famciclovir significantly reduced its duration by a median of 2 months, 3.5 months in patients older than 50 years. No dose-response difference was noted. In a subsequent publication presenting monthly prevalence data,³⁷ pain 6 months after enrollment was reported in 15% of patients assigned famciclovir 500 mg and 23.8% of the patients assigned placebo (NNT = 11.4). Similar results were stated for the 750-mg group. Results were reported as statistically significant but P values were not given.

Valacyclovir, a prodrug of acyclovir, has not been studied in a placebo-controlled trial in patients older than 50 years, based on published reports. In a comparison trial with acyclovir,⁷ valacyclovir for 7 or 14 days did not reduce the incidence of PHN (pain after rash healing) but did accelerate its resolution by 1 to 2 weeks. Pain persisting for 6 months was found in 25.7% of the acyclovir group and 18.6% of the combined valacyclovir group (P = .02; NNT = 15.6). The actual benefit of valacyclovir cannot be determined, since the evidence for acyclovir is inconclusive.

Steroids

Inflammation of peripheral nervous system structures has been identified in specimens from patients with PHN.³⁸ Because of this, corticosteroids have been used in the treatment of herpes zoster in hopes of preventing PHN. Trials evaluating steroids are heterogeneous, involving different drugs, doses, routes, durations, and follow-up methods, thus hampering pooling of trial data (Table 3).

Esmann and coworkers³⁹ compared a 21-day oral prednisolone treatment with placebo in 84 patients, all of whom received acyclovir for the first 7 days. Pretrial calculation demonstrated that 324 patients would be required to detect an 80% change in incidence of PHN at 6 months with statistical significance. Enrollment was stopped early when an interim analysis did not show any treatment effect at 3 months at the P <.10 level. No benefit was seen at 6 months. Data points before 6 months were not reported. This is the methodologically strongest of the 4 early steroid trials.

Clemmensen and Andersen⁴⁰ randomized 60 patients to adrenocorticotropic hormone, prednisone, or placebo. No benefit was found for prednisone, and both active treatments may have increased pain at 1 month. No data were reported beyond 6 weeks.

Keczkes and Basheer⁴¹ randomized 40 patients with “severe, painful” zoster to prednisolone or carbamazepine for 4 weeks. A decreased incidence in pain was reported with prednisolone at 8 weeks, but statistics were not reported. Of the 4 early steroid trials, this shows the greatest benefit but is methodologically the weakest study. Without a placebo group, the purported benefit of prednisolone due to a detrimental effect of carbamazepine cannot be excluded.

Eaglstein and colleagues⁴² randomized 35 patients with “severely painful” zoster to triamcinolone versus placebo. No patients younger than 60 years developed neuralgia. Pain reduction with triamcinolone was reported at 8 weeks but not at 6 months for the 24 patients who developed neuralgia. Statistics were not reported.

These 4 trials have undergone several reviews. In a meta-analysis, Lycka10 reported statistically significant reductions in pain at 6 and 12 weeks after zoster onset but not at 6 months. That meta-analysis incorporated unpublished data obtained from the original investigators. NNTs of 4.5 to prevent pain at 6 weeks and 3.5 to prevent pain at 12 weeks were reported, although an intention-to-treat analysis was not performed. The authors of 2 other reviews^4,11 concluded that there was insufficient evidence to support a benefit from steroids, finding the trials too heterogeneous to appropriately combine in meta-analysis.⁴

A later placebo-controlled trial³¹ randomized 201 patients to acyclovir, prednisone, both, or neither for 21 days. That trial had good methodology and may have been large enough to provide the evidence to support or refute the benefit of steroids. No differences in pain incidence were found at 3 or 6 months. Benefit during the first month was found, but results were reported only as risk reductions.With no incidence or duration data reported, these results are not clinically applicable. Follow-up commentary⁴³ pointed out the need for actual data instead of risk ratios. The authors’ response provided limited data showing reductions in median time to cessation of analgesic use (from 28 to 14 days), return to normal activity (from 21 to 3 days), and uninterrupted sleep (from 26 to 5 days) for the combined acyclovir and prednisone treatment group compared with the placebo group. No data were provided for the acyclovir-only or prednisone-only groups.

Wood and colleagues³⁴ randomized 400 patients to prednisolone or placebo for 21 days. Patients were also randomized to acyclovir for 7 days or 21 days, so there was no placebo-only group. There was no benefit to extending acyclovir to 21 days or to adding prednisolone with respect to incidence or duration of PHN.

A recent review⁴⁴ incorporating these newer trials concluded that steroids can reduce acute herpes zoster pain and improve short-term (1-month) quality of life and suggested that steroids are reasonable to use in patients older than 50 years. No effect, however, was demonstrated on the incidence, severity, or duration of PHN.

Tricyclic Antidepressants

Amitriptyline exerts a pain-modulating effect separate from its antidepressant properties⁴⁵ and has been widely used in neuropathic and other chronic pain states. Amitriptyline (25 mg nightly) used preemptively for 90 days starting within 48 hours of rash onset showed a statistically significant reduction in pain incidence at 6 months in a single placebo-controlled trial of fair quality.⁸ Blinding may have been inadequate, because patients were warned of potential dry mouth. Follow-up was a single contact by telephone or mail at 6 to 8 months. Acyclovir given by general practitioners was not controlled. Twenty-four percent of the amitriptyline group and 50% of the placebo group received acyclovir. Among amitriptyline-treated patients, there was a nonsignificant trend toward reduced pain with acyclovir use, while placebo patients who received acyclovir experienced a nonsignificant trend toward increased pain.

Percutaneous Electrical Nerve Stimulation

Percutaneous electrical nerve stimulation (PENS) compared favorably with famciclovir in a single blind randomized trial of 50 adults with zoster.⁴⁶ A 12% absolute risk reduction in pain was reported at 3 and 6 months (but not at 9 months), but no statistical analysis was reported for this measure. Statistically significant reductions in severity of pain were found at 3 and 6 months. Costs and availability of PENS were not reported.

Discussion

There are limited data from randomized controlled trials that indicate that early treatment of acute herpes zoster decreases the incidence or duration of PHN. Acyclovir was the most-studied agent, but there is no convincing evidence that acyclovir alters the course of PHN. There is some evidence that oral acyclovir 800 mg 5 times daily for 7 to 10 days reduces the incidence of pain in the short term (1 to 3 months). Valacyclovir was somewhat more effective than acyclovir in the single largest antiviral trial, but without a placebo control, the actual efficacy of either drug is indeterminate. Famciclovir did not alter the incidence of PHN (at the time of rash healing) but did significantly reduce the duration of PHN in a single placebo-controlled trial of good methodology.

Randomized antiviral trials have been limited totrials including patients presenting within 72 hours of rash onset. No data are available to address the use of antivirals initiated more than 72 hours after rash onset. In the largest prospective study of patients presenting to general practitioners with zoster,¹ only 44% presented within 72 hours of rash onset.

For immunocompetent subjects, oral acyclovir, famciclovir, and valacyclovir were free of major toxicities and demonstrated side effects comparable with placebo in the clinical trials presented. According to the package inserts, posttrial case reports of more serious reactions, including anaphylaxis and renal failure, have been cited. These medications require dose adjustment in patients with compromised renal function.

Steroids, like antivirals, are widely prescribed for the treatment of acute herpes zoster. Although useful for reduction of early pain, there is no evidence that systemic steroids prevent or shorten the course of PHN. No further trials are needed in this regard. The largest and best designed trial involving corticosteroids for the treatment of zoster is rendered clinically inapplicable by the presentation of relative risk reduction rather than incidence and duration data for placebo and treatment groups.

Preemptive amitriptyline and PENS appear promising on the basis of single trials of fair quality. Potentially promising agents based on poor quality trials* include amantadine and Clinacanthus nutans cream. On the basis of the quality of available evidence, availability of therapy, and costs (Table 5), amitriptyline is the most promising of these agents. Anticholinergic side effects are likely to be of greatest significance in the population at risk for PHN (the elderly), although only 3 of 41 patients (7%) withdrew from therapy in the amitriptyline trial.⁸

Limitations

A systematic review of PHN is hampered by different definitions of PHN (ranging from pain immediately following rash healing to 6 months after rash onset), differences in primary end points measured, and differences in study follow-up methods and duration. Although we stated our definition of PHN (pain following rash healing), we have not restricted our analysis to studies employing the same definition or attempted to analyze only study data using that definition. There is debate about whether a pain continuum (ZAP) or subdivision (acute, subacute, and chronic) of zoster-related pain is most suitable for randomized controlled trials examining the impact of treatments on PHN.^47,48 Although the pain that often heralds and more frequently accompanies zoster may merit treatment, we are particularly interested in whether such treatment will have an impact on the pain incidence, duration, and severity that follow rash healing.

We used a comprehensive literature-based search. Searches for unpublished literature and contact with investigators were generally not undertaken. There is a strong chance of publication bias because of our methods of searching. For example, the product information for valacyclovir notes a placebo-controlled trial in patients younger than 50 years presenting with 72 hours of zoster that found no difference with respect to the duration of pain after rash healing. We were unable to locate this trial in a published format, so it did not meet our inclusion criteria.

Language bias is another source of publication basis. We only included studies published in English. Sixteen non–English-language studies identified were potentially pertinent to the prevention of PHN.*

Quality-of-life measures may be ultimately more important than measures of incidence or duration for assessing the impact of treatment on patients. Few trials^7,31,34,46 addressed quality-of-life measures, and these were generally reported only for the short term. Even in the newer antirviral trials demonstrating reduction in the duration of PHN,^6,7 a significant impact on quality of life was not well documented.

Analysis of the power of trials with negative results was not performed, so potential benefits of treatments not studied adequately cannot be excluded.

The expected outcome without treatment is an important consideration in decisions regarding prevention of PHN. There is an inherent selection bias in randomized controlled trials because an unknown number of patients with zoster will not present for medical attention. There is also a reporting bias with identification of PHN in subjects who would otherwise not be troubled enough by symptoms to present for medical care. Therefore, natural history data derived from placebo cohorts of randomized controlled trials is likely to overestimate the true incidence of clinically significant PHN.

Recommendations for future research

Trials of patients with acute herpes zoster should include all the standard criteria for good methodology (adequate randomization, blinding, and so forth), adequate numbers to detect significant differences determined a priori, continued follow-up of all randomized patients for at least 6 months, and detailed descriptions of the studied population. Trials should be limited to subjects older than 50 years, since this is the age group most likely to be afflicted with PHN. Trials should also evaluate patient-oriented end points other than pain, such as quality of life and time to return to usual activity, and should consider analgesic use as a surrogate pain measure. Cost, compliance, and tolerability should be assessed. For clinical applications, P values and NNT should be reported.

A comparison trial of famciclovir and valacyclovir is recommended. Future use of placebo arms in zoster trials is a matter of continued debate,^34,49 especially for trials enrolling patients with ophthalmic zoster.

Future trials of amitriptyline should extend enrollment to 96 hours or more. Inclusion in the amitriptyline trial was limited to subjects presenting within 48 hours of rash onset. This limitation would be very restrictive in clinical practice.

Further investigation of PENS and possibly Clinacanthus nutans cream and amantadine should be considered.

Primary prevention of PHN may best be achieved through prevention of varicella and subsequent zoster through vaccinations. It has been demonstrated in 2 immunized populations (children with leukemia and renal transplant patients) that zoster occurs 5 to 7 times less frequently after vaccination than after natural varicella.⁵⁰ Follow-up of immunocompromised and immunocompetent vaccine recipients is warranted to evaluate the vaccine’s impact on the natural history of zoster and PHN. Waning cell-mediated immunity to varicella-zoster virus with age has been associated with zoster, and booster vaccinations in the elderly have been shown to improve laboratory markers of cell-mediated immunity. Thus, there is a possibility that vaccinations of elderly patients may reduce the impact of zoster and subsequent PHN.⁵¹ Such a trial is currently recruiting 37,000 volunteers older than 60 years who have had chickenpox but have never had shingles.⁵² It should be noted that theoretical arguments have been made that primary vaccination of varicella could lead to subsequent increases in zoster incidence.⁵³

Recommendations for clinical practice

When acute herpes zoster occurs, providers should restrict their attention regarding PHN prevention to patients older than 50 years. According to the available evidence, antiviral therapy (famciclovir or valacyclovir for 7 days) started within 72 hours of rash onset and/or low-dose amitriptyline (for 90 days) may be offered in an effort to reduce PHN incidence or duration. Patients should be informed of the natural history of zoster and PHN, expected benefits for medications, potential for adverse effects, and expected costs. Other treatments, such as steroids or analgesics, may be offered to alter the acute course of zoster but would have no effect on preventing PHN.

Acknowledgments

The authors wish to thank Dehorah Lovett, Karen J. Alper, and Stacey Raulzhan for their assistance.

Postherpetic neuralgia (PHN) is the most common complication of zoster and is much more prevalent among older patients.^1,2 The results of the largest English-language prospective study of patients presenting with zoster,¹ involving 457 patients from 62 general practitioners in Iceland, suggest that the average family physician caring for 2000 patients would expect to see 4 cases of zoster per year and one case of PHN lasting more than 3 months once in 3 years. Among patients older than 60 years in this study, 19% had pain at 3 months, and 8% had pain at 12 months. Among the 183 patients younger than 40 years, only one had pain at 3 months. The authors of the second largest prospective study of zoster,² involving 206 patients from multiple specialty services in Philadelphia, Pennsylvania, found that 14% of patients older than 50 years had pain at 3 months, and 7% had pain at 6 months. In this study, no patients younger than 50 years had pain at 3 months. In comparison, randomized controlled trials of zoster treatment have reported ranges of 16.7% to 60% of patients receiving placebo having pain at 3 months and 5% to 39.1% having pain at 6 months.

Several systematic reviews have addressed treatment or prevention of PHN.^3-5 New trial data^6-9 and discrepancies in the literature^4,10,11 prompted our paper. Differences in the definition of PHN complicated our review of the medical literature.^12,13 For this review, PHN is defined as any pain after cutaneous healing of zoster, and zoster-associated pain (ZAP) is defined as any pain associated with zoster (acute zoster pain and PHN). This review is limited to randomized controlled trials performed at the time of zoster with follow-up addressing the incidence or duration of PHN or ZAP.

Methods

MEDLINE (1966 to present) was searched on December 29, 1998, using PubMed and combining the terms “zoster” or “post-herpetic neuralgia” or “postherpetic neuralgia” or “post-herpetic pain” or “postherpetic pain,” and publication type “clinical trial” (including phases I-IV) or “controlled clinical trial” or “randomized controlled trial.” We searched The Cochrane Controlled Trials Register 1998, issue 4, using the same terms. We also identified trials through article reference lists and Web-based searches. One author conducted independent searches and was unable to identify any additional randomized controlled trials.

For our review we included randomized controlled trials published in English that enrolled primarily immunocompetent subjects with acute herpes zoster and addressed relevant end points (incidence of pain at any time after rash healing in zoster patients or duration of ZAP or PHN). The two authors independently evaluated the trials meeting these inclusion criteria for quality of randomization, allocation concealment, blinding, baseline difference assessment, methods of data collection, adequacy of follow-up (duration and methods), accounting for dropouts, and intention-to-treat analysis. We rated methodologic quality as good, fair, or poor on the basis of an overall assessment of these features. We did not use explicit validity checklists with summary scores, because they have not been shown to predict the effect of bias on treatment differences (ie, they have not been shown to provide more reliable assessments of validity).^14,15 Discordant ratings of trial quality were resolved through the consensus of both investigators.

Results

Our literature search identified 74 appropriate trials. Of the 74 trials reviewed, 42 pertained to treatment at the time of acute zoster to prevent PHN, and 32 pertained to treatment of established PHN.* Of the 42 prevention trials reviewed, 6 were rated as good quality, 22 as fair, and 14 as poor.

Acyclovir

Nucleoside analogues represent the mainstay of acute herpes zoster treatment and produce a faster rate of cutaneous healing and decreased risk of ophthalmic complications.^16,17 A limited subset of acute zoster treatment trials have reported data on PHN incidence or duration.

Four placebo-controlled trials have been conducted using oral acyclovir 800 mg 5 times daily for 7 to 10 days within 72 hours of zoster rash (Table 1).

The largest placebo-controlled trial of acyclovir involved 376 patients from 3 United Kingdom centers and has been reported in multiple publications.^16,18-22 Acyclovir had no effect on the incidence or severity of PHN. Follow-up was monthly to 6 months or until there was no pain during the previous month; this loss to follow-up after the first cessation of pain is the major criticism of this trial, because PHN is known to relapse.^22,23 With this loss to follow-up, the amount of time to complete cessation of pain could not be determined.^23,24 Ten-year follow-up of 132 patients from this trial who reported resolution of pain found that pain returned in 16 cases (12%).²² In subsequent publications, investigators have reported conflicting results in terms of the long-term incidence of PHN. A statistically significant difference in the incidence of PHN was reported in 57 patients from Southampton contacted at 5 years (7% acyclovir patients vs 37% placebo patients, P = .01),²¹ but not in 160 patients from the Sheffield and Birmingham centers contacted at 9 to 10 years.²²

A smaller US multicenter placebo-controlled trial of oral acyclovir reported decreased pain at 1 to 3 months posttreatment, but no differences in analgesic use were reported.^25,26 A reanalysis of 166 patients with pain at enrollment found a reduction in the median duration of ZAP from 62 days to 20 days with acyclovir (P = .02).²⁷ However, of the 21 patients with no pain on enrollment, 15 later developed pain and 4 of those patients continued to report pain through the seventh month. It is possible that inclusion of these patients in the analysis would materially change the results.

In a third trial²⁸ consisting of 83 patients presenting to general practitioners, acyclovir was associated with statistically significant less pain to 3 months. Total analgesic use, however, was reduced in the acyclovir group for only the first 4 weeks.

The fourth trial,²⁹ consisting of 46 patients with acute herpes zoster ophthalmicus, acyclovir was associated with a reduction in pain incidence that was statistically significant at 2 months (P = .04), but not at 6 months (P = .07). Pain severity was significantly reduced from 2 through 6 months, although this analysis is based on only 6 patients having pain at 6 months.

These 4 trials provided all or most of the data for several reviews and meta-analyses.^4,23,24,30 Summary results among these reviews varied because of different methods used, different subgroups assessed, and different efficacy end points reported but generally supported short-term benefit for oral acyclovir. A key issue affecting the overall results of these reviews was consideration of time to complete cessation of pain. This end point was clearly recorded in the 3 smaller trials with positive results but not reported in the large trial with negative results as discussed above.

Crooks and colleagues²³ performed a pooled analysis and reported that oral acyclovir reduced the incidence of PHN from 19% to 11% at 3 to 6 months. We (as well as Lancaster and colleagues⁴) were unable to verify the placebo group incidence rates reported by Crooks and coworkers which appear to have overestimated any acyclovir benefit, and therefore cannot substantiate these findings. Analysis for time to first cessation of pain was reported as a nonsignificant trend toward benefit with acyclovir, while analysis for time to complete cessation of pain (which excluded the largest trial with the negative results) was reported as a statistically significant reduction from an average 86 to 49 days.

Lancaster and colleagues⁴ found a statistically significant reduction in pain at 3 months but no statistically significant benefit at 1 month or 6 months. They commented that analgesic use was not significantly different in 2 of the positive studies.

Wood and coworkers²⁴ derived results from previously unpublished data from these 4 trials and reported that acyclovir significantly accelerated pain resolution. Significant reductions in incidence of pain with acyclovir were reported at 3 and 6 months, but it is unclear if the largest of the 4 trials was included in this analysis.

In the most recent meta-analysis,³⁰ Jackson and colleagues included a fifth trial³¹ and reported an absolute risk reduction of 16% for the incidence of any pain at 6 months (P <.05; number needed to treat [NNT] = 6.3). Multiple methodologic flaws in that meta-analysis, detailed in the Cochrane Review Database,³² make application of the results unclear.

Additional oral acyclovir trials are summarized in Table 1.* Extending the duration of treatment to 14 or 21 days did not provide benefit over 7 days.^33,34 Lower doses of acyclovir had no effect on incidence, severity, or duration of PHN.^17,35,36 There is no evidence to support use of intravenous or topical acyclovir for prevention of PHN.*

Marginal evidence exists to suggest that oral acyclovir 800 mg 5 times daily may reduce the incidence of pain at 1 to 3 months. Information regarding effects on quality of life were generally lacking.

Newer Antivirals

Famciclovir, a prodrug of penciclovir, did not affect the incidence of PHN measured at the time of cutaneous healing in a placebo-controlled trial of 419 patients6 (Table 2). Among the 186 patients (44%) who developed PHN, famciclovir significantly reduced its duration by a median of 2 months, 3.5 months in patients older than 50 years. No dose-response difference was noted. In a subsequent publication presenting monthly prevalence data,³⁷ pain 6 months after enrollment was reported in 15% of patients assigned famciclovir 500 mg and 23.8% of the patients assigned placebo (NNT = 11.4). Similar results were stated for the 750-mg group. Results were reported as statistically significant but P values were not given.

Valacyclovir, a prodrug of acyclovir, has not been studied in a placebo-controlled trial in patients older than 50 years, based on published reports. In a comparison trial with acyclovir,⁷ valacyclovir for 7 or 14 days did not reduce the incidence of PHN (pain after rash healing) but did accelerate its resolution by 1 to 2 weeks. Pain persisting for 6 months was found in 25.7% of the acyclovir group and 18.6% of the combined valacyclovir group (P = .02; NNT = 15.6). The actual benefit of valacyclovir cannot be determined, since the evidence for acyclovir is inconclusive.

Steroids

Inflammation of peripheral nervous system structures has been identified in specimens from patients with PHN.³⁸ Because of this, corticosteroids have been used in the treatment of herpes zoster in hopes of preventing PHN. Trials evaluating steroids are heterogeneous, involving different drugs, doses, routes, durations, and follow-up methods, thus hampering pooling of trial data (Table 3).

Esmann and coworkers³⁹ compared a 21-day oral prednisolone treatment with placebo in 84 patients, all of whom received acyclovir for the first 7 days. Pretrial calculation demonstrated that 324 patients would be required to detect an 80% change in incidence of PHN at 6 months with statistical significance. Enrollment was stopped early when an interim analysis did not show any treatment effect at 3 months at the P <.10 level. No benefit was seen at 6 months. Data points before 6 months were not reported. This is the methodologically strongest of the 4 early steroid trials.

Clemmensen and Andersen⁴⁰ randomized 60 patients to adrenocorticotropic hormone, prednisone, or placebo. No benefit was found for prednisone, and both active treatments may have increased pain at 1 month. No data were reported beyond 6 weeks.

Keczkes and Basheer⁴¹ randomized 40 patients with “severe, painful” zoster to prednisolone or carbamazepine for 4 weeks. A decreased incidence in pain was reported with prednisolone at 8 weeks, but statistics were not reported. Of the 4 early steroid trials, this shows the greatest benefit but is methodologically the weakest study. Without a placebo group, the purported benefit of prednisolone due to a detrimental effect of carbamazepine cannot be excluded.

Eaglstein and colleagues⁴² randomized 35 patients with “severely painful” zoster to triamcinolone versus placebo. No patients younger than 60 years developed neuralgia. Pain reduction with triamcinolone was reported at 8 weeks but not at 6 months for the 24 patients who developed neuralgia. Statistics were not reported.

These 4 trials have undergone several reviews. In a meta-analysis, Lycka10 reported statistically significant reductions in pain at 6 and 12 weeks after zoster onset but not at 6 months. That meta-analysis incorporated unpublished data obtained from the original investigators. NNTs of 4.5 to prevent pain at 6 weeks and 3.5 to prevent pain at 12 weeks were reported, although an intention-to-treat analysis was not performed. The authors of 2 other reviews^4,11 concluded that there was insufficient evidence to support a benefit from steroids, finding the trials too heterogeneous to appropriately combine in meta-analysis.⁴

A later placebo-controlled trial³¹ randomized 201 patients to acyclovir, prednisone, both, or neither for 21 days. That trial had good methodology and may have been large enough to provide the evidence to support or refute the benefit of steroids. No differences in pain incidence were found at 3 or 6 months. Benefit during the first month was found, but results were reported only as risk reductions.With no incidence or duration data reported, these results are not clinically applicable. Follow-up commentary⁴³ pointed out the need for actual data instead of risk ratios. The authors’ response provided limited data showing reductions in median time to cessation of analgesic use (from 28 to 14 days), return to normal activity (from 21 to 3 days), and uninterrupted sleep (from 26 to 5 days) for the combined acyclovir and prednisone treatment group compared with the placebo group. No data were provided for the acyclovir-only or prednisone-only groups.

Wood and colleagues³⁴ randomized 400 patients to prednisolone or placebo for 21 days. Patients were also randomized to acyclovir for 7 days or 21 days, so there was no placebo-only group. There was no benefit to extending acyclovir to 21 days or to adding prednisolone with respect to incidence or duration of PHN.

A recent review⁴⁴ incorporating these newer trials concluded that steroids can reduce acute herpes zoster pain and improve short-term (1-month) quality of life and suggested that steroids are reasonable to use in patients older than 50 years. No effect, however, was demonstrated on the incidence, severity, or duration of PHN.

Tricyclic Antidepressants

Amitriptyline exerts a pain-modulating effect separate from its antidepressant properties⁴⁵ and has been widely used in neuropathic and other chronic pain states. Amitriptyline (25 mg nightly) used preemptively for 90 days starting within 48 hours of rash onset showed a statistically significant reduction in pain incidence at 6 months in a single placebo-controlled trial of fair quality.⁸ Blinding may have been inadequate, because patients were warned of potential dry mouth. Follow-up was a single contact by telephone or mail at 6 to 8 months. Acyclovir given by general practitioners was not controlled. Twenty-four percent of the amitriptyline group and 50% of the placebo group received acyclovir. Among amitriptyline-treated patients, there was a nonsignificant trend toward reduced pain with acyclovir use, while placebo patients who received acyclovir experienced a nonsignificant trend toward increased pain.

Percutaneous Electrical Nerve Stimulation

Percutaneous electrical nerve stimulation (PENS) compared favorably with famciclovir in a single blind randomized trial of 50 adults with zoster.⁴⁶ A 12% absolute risk reduction in pain was reported at 3 and 6 months (but not at 9 months), but no statistical analysis was reported for this measure. Statistically significant reductions in severity of pain were found at 3 and 6 months. Costs and availability of PENS were not reported.

Discussion

There are limited data from randomized controlled trials that indicate that early treatment of acute herpes zoster decreases the incidence or duration of PHN. Acyclovir was the most-studied agent, but there is no convincing evidence that acyclovir alters the course of PHN. There is some evidence that oral acyclovir 800 mg 5 times daily for 7 to 10 days reduces the incidence of pain in the short term (1 to 3 months). Valacyclovir was somewhat more effective than acyclovir in the single largest antiviral trial, but without a placebo control, the actual efficacy of either drug is indeterminate. Famciclovir did not alter the incidence of PHN (at the time of rash healing) but did significantly reduce the duration of PHN in a single placebo-controlled trial of good methodology.

Randomized antiviral trials have been limited totrials including patients presenting within 72 hours of rash onset. No data are available to address the use of antivirals initiated more than 72 hours after rash onset. In the largest prospective study of patients presenting to general practitioners with zoster,¹ only 44% presented within 72 hours of rash onset.

For immunocompetent subjects, oral acyclovir, famciclovir, and valacyclovir were free of major toxicities and demonstrated side effects comparable with placebo in the clinical trials presented. According to the package inserts, posttrial case reports of more serious reactions, including anaphylaxis and renal failure, have been cited. These medications require dose adjustment in patients with compromised renal function.

Steroids, like antivirals, are widely prescribed for the treatment of acute herpes zoster. Although useful for reduction of early pain, there is no evidence that systemic steroids prevent or shorten the course of PHN. No further trials are needed in this regard. The largest and best designed trial involving corticosteroids for the treatment of zoster is rendered clinically inapplicable by the presentation of relative risk reduction rather than incidence and duration data for placebo and treatment groups.

Preemptive amitriptyline and PENS appear promising on the basis of single trials of fair quality. Potentially promising agents based on poor quality trials* include amantadine and Clinacanthus nutans cream. On the basis of the quality of available evidence, availability of therapy, and costs (Table 5), amitriptyline is the most promising of these agents. Anticholinergic side effects are likely to be of greatest significance in the population at risk for PHN (the elderly), although only 3 of 41 patients (7%) withdrew from therapy in the amitriptyline trial.⁸

Limitations

A systematic review of PHN is hampered by different definitions of PHN (ranging from pain immediately following rash healing to 6 months after rash onset), differences in primary end points measured, and differences in study follow-up methods and duration. Although we stated our definition of PHN (pain following rash healing), we have not restricted our analysis to studies employing the same definition or attempted to analyze only study data using that definition. There is debate about whether a pain continuum (ZAP) or subdivision (acute, subacute, and chronic) of zoster-related pain is most suitable for randomized controlled trials examining the impact of treatments on PHN.^47,48 Although the pain that often heralds and more frequently accompanies zoster may merit treatment, we are particularly interested in whether such treatment will have an impact on the pain incidence, duration, and severity that follow rash healing.

We used a comprehensive literature-based search. Searches for unpublished literature and contact with investigators were generally not undertaken. There is a strong chance of publication bias because of our methods of searching. For example, the product information for valacyclovir notes a placebo-controlled trial in patients younger than 50 years presenting with 72 hours of zoster that found no difference with respect to the duration of pain after rash healing. We were unable to locate this trial in a published format, so it did not meet our inclusion criteria.

Language bias is another source of publication basis. We only included studies published in English. Sixteen non–English-language studies identified were potentially pertinent to the prevention of PHN.*

Quality-of-life measures may be ultimately more important than measures of incidence or duration for assessing the impact of treatment on patients. Few trials^7,31,34,46 addressed quality-of-life measures, and these were generally reported only for the short term. Even in the newer antirviral trials demonstrating reduction in the duration of PHN,^6,7 a significant impact on quality of life was not well documented.

Analysis of the power of trials with negative results was not performed, so potential benefits of treatments not studied adequately cannot be excluded.

The expected outcome without treatment is an important consideration in decisions regarding prevention of PHN. There is an inherent selection bias in randomized controlled trials because an unknown number of patients with zoster will not present for medical attention. There is also a reporting bias with identification of PHN in subjects who would otherwise not be troubled enough by symptoms to present for medical care. Therefore, natural history data derived from placebo cohorts of randomized controlled trials is likely to overestimate the true incidence of clinically significant PHN.

Recommendations for future research

Trials of patients with acute herpes zoster should include all the standard criteria for good methodology (adequate randomization, blinding, and so forth), adequate numbers to detect significant differences determined a priori, continued follow-up of all randomized patients for at least 6 months, and detailed descriptions of the studied population. Trials should be limited to subjects older than 50 years, since this is the age group most likely to be afflicted with PHN. Trials should also evaluate patient-oriented end points other than pain, such as quality of life and time to return to usual activity, and should consider analgesic use as a surrogate pain measure. Cost, compliance, and tolerability should be assessed. For clinical applications, P values and NNT should be reported.

A comparison trial of famciclovir and valacyclovir is recommended. Future use of placebo arms in zoster trials is a matter of continued debate,^34,49 especially for trials enrolling patients with ophthalmic zoster.

Future trials of amitriptyline should extend enrollment to 96 hours or more. Inclusion in the amitriptyline trial was limited to subjects presenting within 48 hours of rash onset. This limitation would be very restrictive in clinical practice.

Further investigation of PENS and possibly Clinacanthus nutans cream and amantadine should be considered.

Primary prevention of PHN may best be achieved through prevention of varicella and subsequent zoster through vaccinations. It has been demonstrated in 2 immunized populations (children with leukemia and renal transplant patients) that zoster occurs 5 to 7 times less frequently after vaccination than after natural varicella.⁵⁰ Follow-up of immunocompromised and immunocompetent vaccine recipients is warranted to evaluate the vaccine’s impact on the natural history of zoster and PHN. Waning cell-mediated immunity to varicella-zoster virus with age has been associated with zoster, and booster vaccinations in the elderly have been shown to improve laboratory markers of cell-mediated immunity. Thus, there is a possibility that vaccinations of elderly patients may reduce the impact of zoster and subsequent PHN.⁵¹ Such a trial is currently recruiting 37,000 volunteers older than 60 years who have had chickenpox but have never had shingles.⁵² It should be noted that theoretical arguments have been made that primary vaccination of varicella could lead to subsequent increases in zoster incidence.⁵³

Recommendations for clinical practice

When acute herpes zoster occurs, providers should restrict their attention regarding PHN prevention to patients older than 50 years. According to the available evidence, antiviral therapy (famciclovir or valacyclovir for 7 days) started within 72 hours of rash onset and/or low-dose amitriptyline (for 90 days) may be offered in an effort to reduce PHN incidence or duration. Patients should be informed of the natural history of zoster and PHN, expected benefits for medications, potential for adverse effects, and expected costs. Other treatments, such as steroids or analgesics, may be offered to alter the acute course of zoster but would have no effect on preventing PHN.

Acknowledgments

The authors wish to thank Dehorah Lovett, Karen J. Alper, and Stacey Raulzhan for their assistance.

Postherpetic neuralgia (PHN) is the most common complication of zoster and is much more prevalent among older patients.^1,2 The results of the largest English-language prospective study of patients presenting with zoster,¹ involving 457 patients from 62 general practitioners in Iceland, suggest that the average family physician caring for 2000 patients would expect to see 4 cases of zoster per year and one case of PHN lasting more than 3 months once in 3 years. Among patients older than 60 years in this study, 19% had pain at 3 months, and 8% had pain at 12 months. Among the 183 patients younger than 40 years, only one had pain at 3 months. The authors of the second largest prospective study of zoster,² involving 206 patients from multiple specialty services in Philadelphia, Pennsylvania, found that 14% of patients older than 50 years had pain at 3 months, and 7% had pain at 6 months. In this study, no patients younger than 50 years had pain at 3 months. In comparison, randomized controlled trials of zoster treatment have reported ranges of 16.7% to 60% of patients receiving placebo having pain at 3 months and 5% to 39.1% having pain at 6 months.

Several systematic reviews have addressed treatment or prevention of PHN.^3-5 New trial data^6-9 and discrepancies in the literature^4,10,11 prompted our paper. Differences in the definition of PHN complicated our review of the medical literature.^12,13 For this review, PHN is defined as any pain after cutaneous healing of zoster, and zoster-associated pain (ZAP) is defined as any pain associated with zoster (acute zoster pain and PHN). This review is limited to randomized controlled trials performed at the time of zoster with follow-up addressing the incidence or duration of PHN or ZAP.

Methods

MEDLINE (1966 to present) was searched on December 29, 1998, using PubMed and combining the terms “zoster” or “post-herpetic neuralgia” or “postherpetic neuralgia” or “post-herpetic pain” or “postherpetic pain,” and publication type “clinical trial” (including phases I-IV) or “controlled clinical trial” or “randomized controlled trial.” We searched The Cochrane Controlled Trials Register 1998, issue 4, using the same terms. We also identified trials through article reference lists and Web-based searches. One author conducted independent searches and was unable to identify any additional randomized controlled trials.

For our review we included randomized controlled trials published in English that enrolled primarily immunocompetent subjects with acute herpes zoster and addressed relevant end points (incidence of pain at any time after rash healing in zoster patients or duration of ZAP or PHN). The two authors independently evaluated the trials meeting these inclusion criteria for quality of randomization, allocation concealment, blinding, baseline difference assessment, methods of data collection, adequacy of follow-up (duration and methods), accounting for dropouts, and intention-to-treat analysis. We rated methodologic quality as good, fair, or poor on the basis of an overall assessment of these features. We did not use explicit validity checklists with summary scores, because they have not been shown to predict the effect of bias on treatment differences (ie, they have not been shown to provide more reliable assessments of validity).^14,15 Discordant ratings of trial quality were resolved through the consensus of both investigators.

Results

Our literature search identified 74 appropriate trials. Of the 74 trials reviewed, 42 pertained to treatment at the time of acute zoster to prevent PHN, and 32 pertained to treatment of established PHN.* Of the 42 prevention trials reviewed, 6 were rated as good quality, 22 as fair, and 14 as poor.

Acyclovir

Nucleoside analogues represent the mainstay of acute herpes zoster treatment and produce a faster rate of cutaneous healing and decreased risk of ophthalmic complications.^16,17 A limited subset of acute zoster treatment trials have reported data on PHN incidence or duration.

Four placebo-controlled trials have been conducted using oral acyclovir 800 mg 5 times daily for 7 to 10 days within 72 hours of zoster rash (Table 1).

The largest placebo-controlled trial of acyclovir involved 376 patients from 3 United Kingdom centers and has been reported in multiple publications.^16,18-22 Acyclovir had no effect on the incidence or severity of PHN. Follow-up was monthly to 6 months or until there was no pain during the previous month; this loss to follow-up after the first cessation of pain is the major criticism of this trial, because PHN is known to relapse.^22,23 With this loss to follow-up, the amount of time to complete cessation of pain could not be determined.^23,24 Ten-year follow-up of 132 patients from this trial who reported resolution of pain found that pain returned in 16 cases (12%).²² In subsequent publications, investigators have reported conflicting results in terms of the long-term incidence of PHN. A statistically significant difference in the incidence of PHN was reported in 57 patients from Southampton contacted at 5 years (7% acyclovir patients vs 37% placebo patients, P = .01),²¹ but not in 160 patients from the Sheffield and Birmingham centers contacted at 9 to 10 years.²²

A smaller US multicenter placebo-controlled trial of oral acyclovir reported decreased pain at 1 to 3 months posttreatment, but no differences in analgesic use were reported.^25,26 A reanalysis of 166 patients with pain at enrollment found a reduction in the median duration of ZAP from 62 days to 20 days with acyclovir (P = .02).²⁷ However, of the 21 patients with no pain on enrollment, 15 later developed pain and 4 of those patients continued to report pain through the seventh month. It is possible that inclusion of these patients in the analysis would materially change the results.

In a third trial²⁸ consisting of 83 patients presenting to general practitioners, acyclovir was associated with statistically significant less pain to 3 months. Total analgesic use, however, was reduced in the acyclovir group for only the first 4 weeks.

The fourth trial,²⁹ consisting of 46 patients with acute herpes zoster ophthalmicus, acyclovir was associated with a reduction in pain incidence that was statistically significant at 2 months (P = .04), but not at 6 months (P = .07). Pain severity was significantly reduced from 2 through 6 months, although this analysis is based on only 6 patients having pain at 6 months.

These 4 trials provided all or most of the data for several reviews and meta-analyses.^4,23,24,30 Summary results among these reviews varied because of different methods used, different subgroups assessed, and different efficacy end points reported but generally supported short-term benefit for oral acyclovir. A key issue affecting the overall results of these reviews was consideration of time to complete cessation of pain. This end point was clearly recorded in the 3 smaller trials with positive results but not reported in the large trial with negative results as discussed above.

Crooks and colleagues²³ performed a pooled analysis and reported that oral acyclovir reduced the incidence of PHN from 19% to 11% at 3 to 6 months. We (as well as Lancaster and colleagues⁴) were unable to verify the placebo group incidence rates reported by Crooks and coworkers which appear to have overestimated any acyclovir benefit, and therefore cannot substantiate these findings. Analysis for time to first cessation of pain was reported as a nonsignificant trend toward benefit with acyclovir, while analysis for time to complete cessation of pain (which excluded the largest trial with the negative results) was reported as a statistically significant reduction from an average 86 to 49 days.

Lancaster and colleagues⁴ found a statistically significant reduction in pain at 3 months but no statistically significant benefit at 1 month or 6 months. They commented that analgesic use was not significantly different in 2 of the positive studies.

Wood and coworkers²⁴ derived results from previously unpublished data from these 4 trials and reported that acyclovir significantly accelerated pain resolution. Significant reductions in incidence of pain with acyclovir were reported at 3 and 6 months, but it is unclear if the largest of the 4 trials was included in this analysis.

In the most recent meta-analysis,³⁰ Jackson and colleagues included a fifth trial³¹ and reported an absolute risk reduction of 16% for the incidence of any pain at 6 months (P <.05; number needed to treat [NNT] = 6.3). Multiple methodologic flaws in that meta-analysis, detailed in the Cochrane Review Database,³² make application of the results unclear.

Additional oral acyclovir trials are summarized in Table 1.* Extending the duration of treatment to 14 or 21 days did not provide benefit over 7 days.^33,34 Lower doses of acyclovir had no effect on incidence, severity, or duration of PHN.^17,35,36 There is no evidence to support use of intravenous or topical acyclovir for prevention of PHN.*

Marginal evidence exists to suggest that oral acyclovir 800 mg 5 times daily may reduce the incidence of pain at 1 to 3 months. Information regarding effects on quality of life were generally lacking.

Newer Antivirals

Famciclovir, a prodrug of penciclovir, did not affect the incidence of PHN measured at the time of cutaneous healing in a placebo-controlled trial of 419 patients6 (Table 2). Among the 186 patients (44%) who developed PHN, famciclovir significantly reduced its duration by a median of 2 months, 3.5 months in patients older than 50 years. No dose-response difference was noted. In a subsequent publication presenting monthly prevalence data,³⁷ pain 6 months after enrollment was reported in 15% of patients assigned famciclovir 500 mg and 23.8% of the patients assigned placebo (NNT = 11.4). Similar results were stated for the 750-mg group. Results were reported as statistically significant but P values were not given.

Valacyclovir, a prodrug of acyclovir, has not been studied in a placebo-controlled trial in patients older than 50 years, based on published reports. In a comparison trial with acyclovir,⁷ valacyclovir for 7 or 14 days did not reduce the incidence of PHN (pain after rash healing) but did accelerate its resolution by 1 to 2 weeks. Pain persisting for 6 months was found in 25.7% of the acyclovir group and 18.6% of the combined valacyclovir group (P = .02; NNT = 15.6). The actual benefit of valacyclovir cannot be determined, since the evidence for acyclovir is inconclusive.

Steroids

Inflammation of peripheral nervous system structures has been identified in specimens from patients with PHN.³⁸ Because of this, corticosteroids have been used in the treatment of herpes zoster in hopes of preventing PHN. Trials evaluating steroids are heterogeneous, involving different drugs, doses, routes, durations, and follow-up methods, thus hampering pooling of trial data (Table 3).

Esmann and coworkers³⁹ compared a 21-day oral prednisolone treatment with placebo in 84 patients, all of whom received acyclovir for the first 7 days. Pretrial calculation demonstrated that 324 patients would be required to detect an 80% change in incidence of PHN at 6 months with statistical significance. Enrollment was stopped early when an interim analysis did not show any treatment effect at 3 months at the P <.10 level. No benefit was seen at 6 months. Data points before 6 months were not reported. This is the methodologically strongest of the 4 early steroid trials.

Clemmensen and Andersen⁴⁰ randomized 60 patients to adrenocorticotropic hormone, prednisone, or placebo. No benefit was found for prednisone, and both active treatments may have increased pain at 1 month. No data were reported beyond 6 weeks.

Keczkes and Basheer⁴¹ randomized 40 patients with “severe, painful” zoster to prednisolone or carbamazepine for 4 weeks. A decreased incidence in pain was reported with prednisolone at 8 weeks, but statistics were not reported. Of the 4 early steroid trials, this shows the greatest benefit but is methodologically the weakest study. Without a placebo group, the purported benefit of prednisolone due to a detrimental effect of carbamazepine cannot be excluded.

Eaglstein and colleagues⁴² randomized 35 patients with “severely painful” zoster to triamcinolone versus placebo. No patients younger than 60 years developed neuralgia. Pain reduction with triamcinolone was reported at 8 weeks but not at 6 months for the 24 patients who developed neuralgia. Statistics were not reported.

These 4 trials have undergone several reviews. In a meta-analysis, Lycka10 reported statistically significant reductions in pain at 6 and 12 weeks after zoster onset but not at 6 months. That meta-analysis incorporated unpublished data obtained from the original investigators. NNTs of 4.5 to prevent pain at 6 weeks and 3.5 to prevent pain at 12 weeks were reported, although an intention-to-treat analysis was not performed. The authors of 2 other reviews^4,11 concluded that there was insufficient evidence to support a benefit from steroids, finding the trials too heterogeneous to appropriately combine in meta-analysis.⁴

A later placebo-controlled trial³¹ randomized 201 patients to acyclovir, prednisone, both, or neither for 21 days. That trial had good methodology and may have been large enough to provide the evidence to support or refute the benefit of steroids. No differences in pain incidence were found at 3 or 6 months. Benefit during the first month was found, but results were reported only as risk reductions.With no incidence or duration data reported, these results are not clinically applicable. Follow-up commentary⁴³ pointed out the need for actual data instead of risk ratios. The authors’ response provided limited data showing reductions in median time to cessation of analgesic use (from 28 to 14 days), return to normal activity (from 21 to 3 days), and uninterrupted sleep (from 26 to 5 days) for the combined acyclovir and prednisone treatment group compared with the placebo group. No data were provided for the acyclovir-only or prednisone-only groups.

Wood and colleagues³⁴ randomized 400 patients to prednisolone or placebo for 21 days. Patients were also randomized to acyclovir for 7 days or 21 days, so there was no placebo-only group. There was no benefit to extending acyclovir to 21 days or to adding prednisolone with respect to incidence or duration of PHN.

A recent review⁴⁴ incorporating these newer trials concluded that steroids can reduce acute herpes zoster pain and improve short-term (1-month) quality of life and suggested that steroids are reasonable to use in patients older than 50 years. No effect, however, was demonstrated on the incidence, severity, or duration of PHN.

Tricyclic Antidepressants

Amitriptyline exerts a pain-modulating effect separate from its antidepressant properties⁴⁵ and has been widely used in neuropathic and other chronic pain states. Amitriptyline (25 mg nightly) used preemptively for 90 days starting within 48 hours of rash onset showed a statistically significant reduction in pain incidence at 6 months in a single placebo-controlled trial of fair quality.⁸ Blinding may have been inadequate, because patients were warned of potential dry mouth. Follow-up was a single contact by telephone or mail at 6 to 8 months. Acyclovir given by general practitioners was not controlled. Twenty-four percent of the amitriptyline group and 50% of the placebo group received acyclovir. Among amitriptyline-treated patients, there was a nonsignificant trend toward reduced pain with acyclovir use, while placebo patients who received acyclovir experienced a nonsignificant trend toward increased pain.

Percutaneous Electrical Nerve Stimulation

Percutaneous electrical nerve stimulation (PENS) compared favorably with famciclovir in a single blind randomized trial of 50 adults with zoster.⁴⁶ A 12% absolute risk reduction in pain was reported at 3 and 6 months (but not at 9 months), but no statistical analysis was reported for this measure. Statistically significant reductions in severity of pain were found at 3 and 6 months. Costs and availability of PENS were not reported.

Discussion

There are limited data from randomized controlled trials that indicate that early treatment of acute herpes zoster decreases the incidence or duration of PHN. Acyclovir was the most-studied agent, but there is no convincing evidence that acyclovir alters the course of PHN. There is some evidence that oral acyclovir 800 mg 5 times daily for 7 to 10 days reduces the incidence of pain in the short term (1 to 3 months). Valacyclovir was somewhat more effective than acyclovir in the single largest antiviral trial, but without a placebo control, the actual efficacy of either drug is indeterminate. Famciclovir did not alter the incidence of PHN (at the time of rash healing) but did significantly reduce the duration of PHN in a single placebo-controlled trial of good methodology.

Randomized antiviral trials have been limited totrials including patients presenting within 72 hours of rash onset. No data are available to address the use of antivirals initiated more than 72 hours after rash onset. In the largest prospective study of patients presenting to general practitioners with zoster,¹ only 44% presented within 72 hours of rash onset.

For immunocompetent subjects, oral acyclovir, famciclovir, and valacyclovir were free of major toxicities and demonstrated side effects comparable with placebo in the clinical trials presented. According to the package inserts, posttrial case reports of more serious reactions, including anaphylaxis and renal failure, have been cited. These medications require dose adjustment in patients with compromised renal function.

Steroids, like antivirals, are widely prescribed for the treatment of acute herpes zoster. Although useful for reduction of early pain, there is no evidence that systemic steroids prevent or shorten the course of PHN. No further trials are needed in this regard. The largest and best designed trial involving corticosteroids for the treatment of zoster is rendered clinically inapplicable by the presentation of relative risk reduction rather than incidence and duration data for placebo and treatment groups.

Preemptive amitriptyline and PENS appear promising on the basis of single trials of fair quality. Potentially promising agents based on poor quality trials* include amantadine and Clinacanthus nutans cream. On the basis of the quality of available evidence, availability of therapy, and costs (Table 5), amitriptyline is the most promising of these agents. Anticholinergic side effects are likely to be of greatest significance in the population at risk for PHN (the elderly), although only 3 of 41 patients (7%) withdrew from therapy in the amitriptyline trial.⁸

Limitations

A systematic review of PHN is hampered by different definitions of PHN (ranging from pain immediately following rash healing to 6 months after rash onset), differences in primary end points measured, and differences in study follow-up methods and duration. Although we stated our definition of PHN (pain following rash healing), we have not restricted our analysis to studies employing the same definition or attempted to analyze only study data using that definition. There is debate about whether a pain continuum (ZAP) or subdivision (acute, subacute, and chronic) of zoster-related pain is most suitable for randomized controlled trials examining the impact of treatments on PHN.^47,48 Although the pain that often heralds and more frequently accompanies zoster may merit treatment, we are particularly interested in whether such treatment will have an impact on the pain incidence, duration, and severity that follow rash healing.

We used a comprehensive literature-based search. Searches for unpublished literature and contact with investigators were generally not undertaken. There is a strong chance of publication bias because of our methods of searching. For example, the product information for valacyclovir notes a placebo-controlled trial in patients younger than 50 years presenting with 72 hours of zoster that found no difference with respect to the duration of pain after rash healing. We were unable to locate this trial in a published format, so it did not meet our inclusion criteria.

Language bias is another source of publication basis. We only included studies published in English. Sixteen non–English-language studies identified were potentially pertinent to the prevention of PHN.*

Quality-of-life measures may be ultimately more important than measures of incidence or duration for assessing the impact of treatment on patients. Few trials^7,31,34,46 addressed quality-of-life measures, and these were generally reported only for the short term. Even in the newer antirviral trials demonstrating reduction in the duration of PHN,^6,7 a significant impact on quality of life was not well documented.

Analysis of the power of trials with negative results was not performed, so potential benefits of treatments not studied adequately cannot be excluded.

The expected outcome without treatment is an important consideration in decisions regarding prevention of PHN. There is an inherent selection bias in randomized controlled trials because an unknown number of patients with zoster will not present for medical attention. There is also a reporting bias with identification of PHN in subjects who would otherwise not be troubled enough by symptoms to present for medical care. Therefore, natural history data derived from placebo cohorts of randomized controlled trials is likely to overestimate the true incidence of clinically significant PHN.

Recommendations for future research

Trials of patients with acute herpes zoster should include all the standard criteria for good methodology (adequate randomization, blinding, and so forth), adequate numbers to detect significant differences determined a priori, continued follow-up of all randomized patients for at least 6 months, and detailed descriptions of the studied population. Trials should be limited to subjects older than 50 years, since this is the age group most likely to be afflicted with PHN. Trials should also evaluate patient-oriented end points other than pain, such as quality of life and time to return to usual activity, and should consider analgesic use as a surrogate pain measure. Cost, compliance, and tolerability should be assessed. For clinical applications, P values and NNT should be reported.

A comparison trial of famciclovir and valacyclovir is recommended. Future use of placebo arms in zoster trials is a matter of continued debate,^34,49 especially for trials enrolling patients with ophthalmic zoster.

Future trials of amitriptyline should extend enrollment to 96 hours or more. Inclusion in the amitriptyline trial was limited to subjects presenting within 48 hours of rash onset. This limitation would be very restrictive in clinical practice.

Further investigation of PENS and possibly Clinacanthus nutans cream and amantadine should be considered.

Primary prevention of PHN may best be achieved through prevention of varicella and subsequent zoster through vaccinations. It has been demonstrated in 2 immunized populations (children with leukemia and renal transplant patients) that zoster occurs 5 to 7 times less frequently after vaccination than after natural varicella.⁵⁰ Follow-up of immunocompromised and immunocompetent vaccine recipients is warranted to evaluate the vaccine’s impact on the natural history of zoster and PHN. Waning cell-mediated immunity to varicella-zoster virus with age has been associated with zoster, and booster vaccinations in the elderly have been shown to improve laboratory markers of cell-mediated immunity. Thus, there is a possibility that vaccinations of elderly patients may reduce the impact of zoster and subsequent PHN.⁵¹ Such a trial is currently recruiting 37,000 volunteers older than 60 years who have had chickenpox but have never had shingles.⁵² It should be noted that theoretical arguments have been made that primary vaccination of varicella could lead to subsequent increases in zoster incidence.⁵³

Recommendations for clinical practice

When acute herpes zoster occurs, providers should restrict their attention regarding PHN prevention to patients older than 50 years. According to the available evidence, antiviral therapy (famciclovir or valacyclovir for 7 days) started within 72 hours of rash onset and/or low-dose amitriptyline (for 90 days) may be offered in an effort to reduce PHN incidence or duration. Patients should be informed of the natural history of zoster and PHN, expected benefits for medications, potential for adverse effects, and expected costs. Other treatments, such as steroids or analgesics, may be offered to alter the acute course of zoster but would have no effect on preventing PHN.

Acknowledgments

The authors wish to thank Dehorah Lovett, Karen J. Alper, and Stacey Raulzhan for their assistance.