OBJECTIVE: Our goal was to determine if any treatment of acute herpes zoster alters the incidence or duration of postherpetic neuralgia (PHN), a common sequela in elderly patients.
SEARCH STRATEGY: We systematically searched MEDLINE and The Cochrane Library. We also examined the reference lists of identified trials and reviews.
SELECTION CRITERIA: We included all randomized controlled trials of treatments of zoster published in English that included assessment of pain at any time after rash healing.
DATA COLLECTION/ANALYSIS: Forty-two trials met inclusion criteria, and 2 reviewers independently evaluated them for methodologic quality and the statistical and clinical significance of results.
MAIN RESULTS: Four placebo-controlled trials of oral acyclovir with 692 patients provided marginal evidence for reduction in pain incidence at 1 to 3 months following zoster onset. Famciclovir significantly reduced duration but not incidence of PHN in one placebo-controlled trial of 419 patients. Valacyclovir significantly reduced duration but not incidence of PHN in one acyclovir-controlled trial of 1141 patients. Steroids had no effect on PHN. Amitriptyline for 90 days reduced pain incidence at 6 months in one placebo-controlled trial of 80 patients. A single trial of percutaneous electrical nerve stimulation (PENS) in 50 patients suggested a decrease in pain incidence at 3 and 6 months compared with famciclovir.
CONCLUSIONS: There is limited evidence that current interventions prevent or shorten PHN. Famciclovir and valacyclovir have been shown to reduce the duration of PHN in single published trials. Well-designed and larger trials of amitriptyline and PENS should be conducted.
Clinical question
What can be done at the time of acute herpes zoster treatment toprevent or reduce postherpetic neuralgia?
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 data6-9 and discrepancies in the literature4,10,11 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.