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 Searches for unpublished literature and contact with investigators were generally not undertaken.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 trials7,31,34,46 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