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.