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

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Original Research

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

J Fam Pract. 2000 March;49(3):255-264

References

REFERENCE

1. Helgason S, Sigurdsson JA, Gudmundsson S. The clinical course of herpes zoster: a prospective study in primary care. Eur J Gen Pract 1996;2:12-6.

2. Burgoon CF, Burgoon JS, Baldridge GD. The natural history of herpes zoster. JAMA 1957;164:265-9.

3. Volmink J, Lancaster T, Gray S, Silagy C. Treatments for postherpetic neuralgia—a systematic review of randomized controlled trials. Fam Pract 1996;13:84-91.

4. Lancaster T, Silagy C, Gray S. Primary care mangement of acute herpes zoster: systematic review of evidence from randomized controlled trials. Br J Gen Pract 1995;45:39-45.

5. Schmader KE, Studenski S. Are current therapies useful for the prevention of postherpetic neuralgia? A critical analysis of the literature. J Gen Intern Med 1989;4:83-9.

6. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:89-96.

7. Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ. Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995;39:1546-53.

8. Bowsher D. The effects of preemptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 1997;13:327-31.

9. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:1837-42.

10. Lycka BAS. Postherpetic neuralgia and systemic corticosteroid therapy: efficacy and safety. Int J Dermatol 1990;29:523-7.

11. Post BT, Philbrick JT. Do corticosteroids prevent postherpetic neuralgia? A review of the evidence. J AM Acad Dermatol 1988;18:605-10.

12. Dwyer DE. Management issues in herpes zoster. Aust Fam Physician 1996;25:299-307.

13. Wood MJ. How should we measure pain in herpes zoster? Neurology 1995;45(suppl):S61-2.

14. Emerson JD, Burdick E, Hoaglin DC, Mosteller F, Chalmers TC. An empirical study of the possible relation of treatment differences to quality scores in controlled randomized clinical trials. Control Clin Trials 1990;11:339-52.

15. Mulrow CD, Oxman, AD, eds. “Quality” scales and checklists. Cochrane Collaboration handbook, section 6.7.2. In: The Cochrane library. The Cochrane Collaboration. Oxford, England: Update Software; 1997, issue 4.

16. Wood MJ, Ogan PH, McKendrick MW, Care CD, McGill JI, Webb EM. Efficacy of oral acyclovir treatment of acute herpes zoster. Am J Med 1988;85:79-83.

17. Cobo LM, Foulks GN, Liesegang T, et al. Oral acyclovir in the treatment of acute herpes zoster ophthalmicus. Ophthalmology 1986;93:763-70.

18. McKendrick MW, McGill JI, Wood MJ. Lack of effect of acyclovir on postherpetic neuralgia. BMJ 1989;298:431.-

19. McKendrick MW, McGill JI, White JE, Wood MJ. Oral acyclovir in acute herpes zoster. BMJ 1986;293:1529-32.

20. Wood MJ, McKendrick MW, McGill JI. Oral acyclovir for acute herpes zoster infections in immune-competent adults. Infection 1987;15(suppl):S9-13.

21. McGill JI, White JE. Acyclovir and post-herpetic neuralgia and ocular involvement. BMJ 1994;309:1124.-

22. McKendrick MW, Wood MJ. Acyclovir and post-herpetic neuralgia two other participating study centres report different results. BMJ 1995;310:1005.-

23. Crooks RJ, Jones DA, Fiddian AP. Zoster-associated chronic pain: an overview of clinical trials with acyclovir. Scand J Infect Dis 1991;78(suppl):62-8.

24. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis 1996;22:341-7.

25. Huff JC, Bean B, Balfour HH, et al. Therapy of herpes zoster with oral acyclovir. Am J Med 1988;85:84-9.

26. Huff JC. Oral acyclovir therapy of acute herpes zoster: a mutlicentre study. Res Clin Forums 1987;9:37-45.

27. Huff JC, Drucker JL, Clemmer A, Laskin OL, Connor JD, Bryson YJ, et al. Effect of oral acyclovir on pain resolution in herpes zoster: a reanalysis. J Med Virol 1993;Suppl 1:93-6.

28. Morton P, Thomson AN. Oral acyclovir in the treatment of herpes zoster in general practice. N Z Med J 1989;102:93-5.

29. Harding SP, Porter SM. Oral acyclovir in herpes zoster ophthalmicus. Curr Eye Res 1991;10(suppl):177-82.

30. Jackson JL, Gibbons R, Meyer G, Inouye L. The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia: a meta-analysis. Arch Intern Med 1997;157:909-12.

31. Whitley RJ, Weiss H, Gnann JW, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized, placebo-controlled trial. Ann Intern Med 1996;125:376-83.

32. The Cochrane Collaboration. The database of abstracts of reviews of effectiveness. DARE-978103. In: The Cochrane library. Oxford, England: Update Software; 1998, issue 4.

33. Hoang-Xuan T, Buchi EB, Herbort CP, et al. Oral acyclovir for herpes zoster ophthalmicus. Ophthalmology 1992;99:1062-71.

34. Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks J. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994;330:896-900.

35. Wassilew SW, Reimlinger S, Nasemann T, Jones D. Oral acyclovir for herpes zoster: a double-blind controlled trial in normal subjects. Br J Dermatol 1987;117:495-501.

36. McKendrick MW, Care C, Burke C, Hickmott E, McKendrick GDW. Oral acyclovir in herpes zoster. J Antimicrob Chemother 1984;14:661-5.

37. Dworkin RH, Boon RJ, Griffin DRG, Phung D. Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis 1998;178(suppl):S76-80.

38. Watson CP, Deck JH, Morshead C, Van der Koody D, Evans RJ. Post-herpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 1991;44:105-17.

39. Esmann V, Kroon S, Peterslund NA, et al. Prednisolone does not prevent post-herpetic neuralgia. Lancet 1987;2:126-9.

40. Clemmensen OJ, Andersen KE. ACTH versus prednisone and placebo in herpes zoster treatment. Clin Exp Dermatol 1984;9:557-63.

41. Keczkes K, Basheer AM. Do corticosteroids prevent post-her-petic neuralgia? Br J Dermatol 1980;102:551-5.

42. Eaglstein WH, Katz R, Brown JA. The effects of early corticosteroid therapy on the skin eruption and pain of herpes zoster. JAMA 1970;211:1681-3.

43. Herbert DA, Carson MP. Acyclovir plus steroids for herpes zoster. Ann Intern Med 1997;126:831-2.

44. MacFarlane LL, Simmons MM, Hunter MH. The use of corticosteroids in the management of herpes zoster. J Am Board Fam Pract 1998;11:224-8.

45. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 1987;37:589-96.

46. Ahmed HE, Craig WF, White PF, et al. Percutaneous electrical nerve stimulation: an alternative to antiviral drugs for acute herpes zoster. Anesth Analg 1998;87:911-4.

47. Wood MJ, Balfour H, Beutner K, et al. How should zoster trials be conducted? J Antimicrob Chemother 1995;36:1089-101.

48. Dworkin RH, Portenoy RK. Proposed classification of herpes zoster pain. Lancet 1994;343:1648.-

49. Van den Broek PJ, Stuyt PM, van der Meer JW. Acyclovir for herpes zoster. N Engl J Med 1994;331:481.-

50. Gershon A. Varicella: to vaccinate or not to vaccinate? Arch Dis in Childhood 1998;79:470-1.

51. Oxman MN. Immunization to reduce the frequency and serverity of herpes zoster and its complications. Neurology 1995;45(suppl):S41-6.

52. Stephenson J. Shingles vaccine trial in health agencies update. JAMA 1999;282:625.-Available on the World Wide Web at http://jama.ama-assn.org/issues/v282p7/full/jha90006-4.html.

53. Garnett GP, Grenfell BT. The epidemiology of varicella-zoster virus infections: the influence of varicella on the prevalence of herpes zoster. Epidemiol Infect 1992;108:513-28.

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.