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Background Acyclovir given for 7 to 10 days is of proved benefit in acute herpes zoster, but studies of its effectiveness in preventing postherpetic neuralgia have had conflicting results. The role of corticosteroids in the treatment of herpes zoster is also controversial.
Methods We conducted a double-blind, controlled trial in patients with acute herpes zoster to determine whether either 21 days of acyclovir therapy or the addition of prednisolone offered any improvement over 7 days of acyclovir therapy. Patients with a rash of less than 72 hours' duration were assigned to receive acyclovir (800 mg orally, five times daily) for 7 days with either prednisolone or placebo, or acyclovir for 21 days with either prednisolone or placebo. Prednisolone therapy was initiated at a dose of 40 mg per day and tapered over a three-week period. Patients were assessed frequently through day 28 and then monthly through month 6 to assess postherpetic neuralgia.
Results Of 400 patients recruited, 349 completed the study. No significant differences were detected between the four groups in the progression of the rash (P>0.1). With steroid therapy, a significantly higher proportion of the rash area had healed on days 7 and 14 (P = 0.02). Pain reduction was greater during the acute phase of disease in patients treated with steroids or 21 days of acyclovir (P<0.01 and P = 0.02, respectively, on day 7; P<0.01 for steroid therapy on day 14). However, on follow-up there were no significant differences between any of the groups in the time to a first or a complete cessation of pain. The steroid recipients reported more adverse events.
Conclusions In acute herpes zoster, treatment with acyclovir for 21 days or the addition of prednisolone to acyclovir therapy confers only slight benefits over standard 7-day treatment with acyclovir. Neither additional treatment reduces the frequency of postherpetic neuralgia.
In controlled trials, intravenous and oral acyclovir in immunocompetent patients are associated with significant improvements in the rate of healing and the severity of the acute pain of herpes zoster7,8,9,10,11. The effects of acyclovir on postherpetic neuralgia are less clear-cut. In three studies comparing oral acyclovir (800 mg five times daily for 7 or 10 days) with placebo,9,10,11 the incidence of prolonged pain was lower in the acyclovir recipients. In contrast, other studies evaluating the effects of five to seven days of intravenous or oral acyclovir7,8 found no benefit with respect to prolonged pain. It has been hypothesized that longer courses of acyclovir may be more effective. Corticosteroids have also been advocated to treat herpes zoster and prevent postherpetic neuralgia, but studies of oral corticosteroids have had conflicting results12,13,14,15.
The present study was designed to clarify the effects on herpes zoster of a longer course of antiviral therapy and concurrent steroid administration. Because the benefits of acyclovir therapy during the acute phase are established,7,8,9,10,11 it was considered unethical to include a placebo group. Thus, all the patients were given at least a seven-day course of acyclovir; further acyclovir therapy, concomitant treatment with prednisolone, or both were added to this basic regimen.
Methods
Selection of Patients
The trial was a double-blind, randomized study conducted in four centers in the United Kingdom. Adults over 18 years of age without immune dysfunction due to cancer or immunosuppressive therapy, who presented with a clinical diagnosis of herpes zoster as confirmed by one of the investigators and had a rash for 72 hours or less and at least moderate pain, were enrolled. The following patients were excluded from the study: pregnant women and women of childbearing potential who were not adequately protected by contraception; patients with renal insufficiency (serum creatinine concentration, more than 1.8 mg per deciliter [159 µmol per liter]), hypertension (diastolic pressure, >110 mm Hg), insulin-dependent diabetes, or a random blood glucose determination exceeding 216 mg per deciliter (12 mmol per liter); patients with a history of peptic ulceration, severe psoriasis, or hypersensitivity to acyclovir; and patients receiving barbiturates, anticonvulsant drugs, systemic steroids, rifampin, or specific antiviral therapy for the present infection.
The study was approved by the ethics review committee at each participating institution. All patients gave written informed consent to participation.
Treatment Regimens
With a computer-generated randomization code, patients were randomized according to center and assigned in blocks of eight to one of four treatments: 7 days of acyclovir therapy; 7 days of acyclovir therapy and 21 days of prednisolone; 21 days of acyclovir therapy; or 21 days of acyclovir therapy and 21 days of prednisolone.
Acyclovir (800 mg orally) was administered five times daily, beginning on day 0. The patients in the groups assigned to seven days of acyclovir therapy (with or without steroid) received matching placebo beginning on day 7. Prednisolone was administered according to the following schedule: on days 0 through 6, 40 mg per day; days 7 through 10, 30 mg per day; days 11 through 14, 20 mg per day; days 15 through 18, 10 mg per day; and days 19 through 21, 5 mg per day (total dose, 535 mg). Prednisolone was given as 5-mg tablets. The patients in the groups not receiving steroid received matching placebo tablets.
Treatment of Patients
The patients were treated at home and were visited by an investigator or a research assistant to assess the progression of the rash and the intensity of pain on days 0, 1, 2, and 3; then twice weekly until day 21 (or until all lesions were crusted if this required a longer time); and on day 28. The patients were then visited monthly until six months from study entry to assess postherpetic neuralgia.
The area of the rash was evaluated for the presence or absence of new lesions since the previous assessment in the primarily affected, adjacent, and distant dermatomes; lesions with vesiculation or new vesicles since the previous assessment; any vesicles; any crusts; and complete crusting. The percentage of the rash that had healed (with reepithelialization of skin after crusts had fallen off, or regression of lesions) was also estimated. On days 0 through 28 and at weekly intervals thereafter, patients were asked to record in a diary whether they had any pain, whether their pain interfered with sleep, and whether it was constant or intermittent. They also recorded its frequency, its intensity (just noticeable, mild, moderate, strong, or excruciating), and the quality of the pain (sharp, aching, or an abnormal sensation). Patients with both intermittent and constant pain were asked to give severity ratings and descriptions for both. The diary was checked at each visit. Each month from day 28 to month 6, observers reviewed the diaries and interviewed patients in order to combine the weekly assessments of pain into an accurate characterization.
Blood samples were obtained for biochemical and hematologic monitoring before the start of treatment and on days 7 and 21. Any adverse events were recorded.
Statistical Analysis
From the results of a previous study of treatment of herpes zoster with seven days of oral acyclovir,8 it was calculated that an enrollment of 100 patients in each treatment group would provide at least 90 percent power to detect a 25 percent reduction in the prevalence of pain on day 7 or day 21 or a 33 percent reduction in the mean time needed for complete crusting of the rash. It was calculated that an enrollment of 200 patients in each treatment group would provide at least 90 percent power to detect a 50 percent reduction in the prevalence of pain at three months. Provided that no interaction was detected between the effects of steroid and the duration of acyclovir treatment, the goal of 200 patients per group could be achieved through appropriate pooling of treatment groups.
All analyses were carried out with the SAS statistical software package (SAS Institute, Cary, N.C.); analyses of safety were performed with the Wellcome Safety Data System, a program written in SAS for the analysis of laboratory data.
Kaplan-Meier estimates of the median time to an event were made for the following end points: the last day with new lesions, the first day without new vesicles, the first day with full crusting, the time to 100 percent healing of the rash, and the times to the first cessation of pain and the complete cessation of pain. If any end point was not reached in a patient, the final observation for that patient was censored. p values associated with the log-rank test statistic (for measures of rash) or with the Cox proportional-hazards ratio (for measures of pain) were derived as measures of equality between the treatment groups.
The Wilcoxon rank-sum test was used to compare pooled groups with respect to changes from base line in scores for the severity of pain and percentages of healing of the rash. The Kruskal-Wallis test was used as a global test for differences between treatment with acyclovir alone and treatment with prednisolone added. From plots of the mean values, there was no evidence of interactions between groups. The chi-square test was used to compare the proportions of patients with pain at various times.
Summary statistics were used to describe all other analyses.
Results
Demographic Characteristics
A total of 400 patients were enrolled in the study at the four participating centers (Birmingham, 116; Bristol, 116; Manchester, 73; and Sheffield, 95). Ninety-nine patients were assigned to receive acyclovir for 7 days with steroid, 101 to receive acyclovir for 7 days without steroid, 99 to receive acyclovir for 21 days with steroid, and 101 to receive acyclovir for 21 days without steroid. At each center, approximately equal numbers of patients were enrolled in each treatment group. The patients in all four groups were well matched at study entry (Table 1). The mean duration of rash at entry was comparable in each group. The duration of rash was recorded on a categorical scale (<12 hours, 12 to 24 hours, 24 to 48 hours, and 48 to 72 hours), and since a large proportion of patients in the group receiving acyclovir for seven days without steroid had had their rash for 48 to 72 hours, the median duration of rash was greater in this group. In all, 349 patients completed the study as specified, and 51 patients were withdrawn (Table 1). Some patients gave more than one reason for premature termination of the study. Withdrawals of patients were balanced equally across all groups. None of the three deaths among study participants was considered to be related to herpes zoster or to participation in the study.
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No significant differences between treatment groups were detected by the log-rank test with respect to any of the four major measures of rash progression (Table 2). A number of subgroup analyses were conducted for patients over 60 years of age, patients enrolled within 48 hours of the onset of rash, and patients enrolled within 96 hours of the start of the prodrome (i.e., pain or abnormal sensation in the affected dermatome before the appearance of the rash); again, no significant differences between groups were observed.
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Acute Zoster-Associated Pain (to Day 28)
During the acute phase of the disease, the proportion of patients with pain was 6 to 8 percent lower on days 14, 21, and 28 in the groups receiving the 21-day course of acyclovir than in the groups receiving the 7-day course (data not shown); these differences were significant by the chi-square test on day 14 (P = 0.03) and day 21 (P = 0.05).
Differences were also evident in the changes from base line in the mean scores for intensity of pain during the acute phase of the disease (Table 3). The patients receiving the seven-day course of acyclovir had the smallest reduction in pain. A significant difference in favor of the longer course of acyclovir therapy was evident on day 7, one day after the end of the seven-day acyclovir regimen (P = 0.02 by the Wilcoxon rank-sum test). The benefit from steroids was more marked; significant differences were found on days 7 and 14 (P<0.01 for both by the Wilcoxon rank-sum test). By day 21 the changes from base line in pain-intensity scores (and the mean scores) were comparable in all groups.
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Prolonged Zoster-Associated Pain (up to Month 6)
No significant differences were detected between any of the four treatment groups in the time to either the first or the complete cessation of pain (by log-rank test of the Kaplan-Meier distributions) (Table 4). There was a trend toward earlier cessation of pain with the longer course of acyclovir therapy (median number of days in both 7-day-acyclovir groups, 147; in both 21-day-acyclovir groups, 120) (Table 4). Conversely, there was no observed benefit in the time to the complete cessation of pain with the concurrent administration of steroids.
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Safety Data
Of the 400 patients enrolled in the study, 64 (16 percent) reported at least one adverse event (Table 5). A higher incidence of adverse events was observed in the steroid recipients (38 patients, or 19 percent) than in the recipients of acyclovir alone (26 patients, or 13 percent) (P>0.1). In addition, many more adverse events were considered to be attributable to the study medication in the steroid recipients than in the patients receiving acyclovir alone (31 vs. 13 events).
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As might be expected, more changes in laboratory measures were recorded in the groups receiving steroid therapy; increases in hemoglobin levels, peripheral-neutrophil counts, platelet counts, and plasma urea concentrations were all noted with steroid therapy, but they returned to normal as the dose was tapered.
Discussion
As compared with the results obtained in herpes zoster with a 7-day course of oral acyclovir (800 mg five times daily), no additional clinical benefit with respect to the zoster rash was derived from an additional 14 days of acyclovir therapy, and only a limited additional benefit, in the form of initially more rapid healing, was gained by the concurrent administration of steroids.
There is a paucity of published data from controlled trials on the effects of steroid therapy on the rash of herpes zoster, although the available data conform with those obtained in this study. In two small, placebo-controlled trials,12,14 no differences were noted between groups with respect to the rash. In a slightly larger trial (of 78 patients) comparing acyclovir with and without concurrent steroid therapy,15 there was a small advantage with steroids in a significantly shorter time to the appearance of the first crust. Any potential advantage of steroids, however, needs to be considered in the light of the increased number of adverse events, some serious, that are associated with steroid use.
Pain is generally the most troublesome feature of herpes zoster, and most of the numerous therapies advocated attempt to relieve acute pain and to prevent or ameliorate prolonged pain. This clinical trial emphasized the accurate recording of various aspects of zoster-associated pain. Several statistically significant differences between the treatment groups were noted. Even though this may be expected, given the multiple analyses of the measures of pain studied, some interesting and consistent trends were apparent.
During the acute phase of the illness, patients receiving the minimal treatment of seven days of acyclovir therapy seemed to fare the least well. For example, on days 14 and 21 there were significantly more patients with pain in the groups given acyclovir for only seven days. In addition, the acute pain was more severe in these patients, and more of them reported constant pain and pain that interfered with sleep. The differences in the reduction in pain intensity between 7 days and 21 days of acyclovir therapy were modest and statistically significant only on day 7 (1 day after the discontinuation of acyclovir in the group receiving 7 days of acyclovir therapy). The reason for this difference on day 7 is unclear, but it may reflect a rebound of the acute pain, comparable to that described in 6 of 17 similar patients immediately after the end of five days of therapy with intravenous acyclovir7. Steroids significantly reduced the intensity of the acute pain up to day 14. This may reflect the more rapid healing of the rash in the steroid recipients during this period and would seem to support the contention that the acute pain of herpes zoster is at least partly caused by inflammation resulting from viral replication within the skin or nerves.
When the results of the follow-up from months 1 to 6 were considered, the additional benefits of prolonged acyclovir therapy or concurrent steroid administration observed during the acute phase of the trial were no longer seen. The lack of useful benefit from steroids in the follow-up phase of this study is in accordance with results from Scandinavia15.
In this study, in which all patients received a minimum of 7 days of treatment with acyclovir, the mean duration of pain ranged from 112 to 127 days, substantially longer than the 44 to 66 days reported in previous studies of oral acyclovir8,9,10,11. The principal consistent difference in design between this trial and others was that only patients with at least moderate pain were considered eligible. Previous studies enrolled patients with no pain or mild pain. It is difficult to draw firm conclusions from comparisons between studies, but there may be a correlation between the duration of pain and the severity of pain on presentation. This hypothesis warrants further investigation in a controlled clinical setting.
When optimal therapy for herpes zoster is considered, safety aspects must be taken into account. Longer courses of acyclovir therapy did not appear to result in more clinical side effects than were reported with shorter courses. In sharp contrast, there was an increase in the number of adverse events, including an episode of hematemesis reported in association with steroid therapy, even though patients likely to be at an increased risk of such adverse effects were excluded from the study. A number of laboratory abnormalities, particularly steroid-induced granulocytosis, were also noted.
In conclusion, the results of this study suggest that the addition of prednisolone to acyclovir may confer additional benefit in the healing of rash and in the incidence and severity of pain during the first few weeks of illness but that it has no appreciable influence on the incidence or severity of postherpetic neuralgia. Given that a short course of prednisolone is not without adverse effects, even in patients with no contraindications, the use of this steroid in herpes zoster cannot be recommended. A longer (21-day) course of acyclovir therapy also produced a marginal additional benefit with regard to the incidence and severity of pain during the acute phase of illness. Although this was not associated with any clinical intolerance, the costs of the additional 14 days of acyclovir therapy are considerable, and these results provide insufficient evidence of clinical benefit to support the use of a longer course of acyclovir in the routine treatment of acute herpes zoster in immunocompetent patients.
Supported by a grant from the Wellcome Research Laboratories, Beckenham, United Kingdom.
We are indebted to Mrs. P. Ogan, Mrs. U. Johnson, Mrs. C. Care, Mrs. B. Ball, and Mrs. J. Ellis, the research assistants without whom this study could not have been performed; to Dr. Paul Fiddian for his advice; and to Mrs. Lynda Kellam for statistical analysis.
Source Information
From the Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham (M.J.W.); the Sir Humphry Davy Department of Anaesthesia, Bristol Royal Infirmary, Bristol (R.W.J.); the Department of Infectious Diseases and Medicine, Royal Hallamshire Hospital, Sheffield (M.W.M.); the Wellcome Research Laboratories, Beckenham (J.T., J.C.); and the Department of Infectious Diseases and Tropical Medicine, Monsall Hospital, Manchester (B.K.M.) -- all in the United Kingdom. Presented in part at the meeting "Herpes -- a Global Challenge," sponsored by the Wellcome Foundation, Ltd., Berlin, Germany, June 4-6, 1992.
Address reprint requests to Dr. Wood at the Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Bordesley Green E., Birmingham B9 5ST, United Kingdom.
References
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Related Letters:
Acyclovir for Herpes Zoster
van den Broek P. J., Stuyt P. M.J., van der Meer J. W.M., Tangeman J. C., Kuzminski A. M., Svahn D. S., Wood M. J., McKendrick M. W., Johnson R. W.
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Full Text
N Engl J Med 1994;
331:481, Aug 18, 1994.
Correspondence
This article has been cited by other articles:
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