Antiviral treatment for preventing postherpetic neuralgia

  • Review
  • Intervention

Authors


Abstract

Background

Postherpetic neuralgia (PHN) is a painful and refractory complication of herpes zoster. Treatments are either partially or totally ineffective for many people with PHN. Antiviral agents, used at the time of the rash, have been proposed as an intervention to prevent the development of PHN. This is the first update since the first publication of the review in 2009.

Objectives

To assess the effectiveness of antiviral agents in preventing PHN.

Search methods

On 26 April 2013, we updated the searches in the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and the Chinese Biomedical Retrieval System. We checked the references of published studies to identify additional trials, and contacted authors to obtain additional data. We searched other databases in The Cochrane Library for information for the Discussion and two clinical trials registries for ongoing trials.

Selection criteria

We considered all randomised controlled trials (RCTs) of antiviral treatment given within 72 hours after the onset of herpes zoster for preventing PHN. There were no language restrictions.

Data collection and analysis

Two authors independently selected trials, evaluated the risk of bias in included trials, and extracted and analysed data.

Main results

Six RCTs with a total of 1211 participants were eligible; five trials evaluated oral aciclovir, and one, with 419 participants, evaluated oral famciclovir. We were able to conduct meta-analyses as there were sufficient similarities in the included studies, such as the reporting of the presence of PHN, duration of rash before treatment initiation and treatment regimen. For our primary outcome, based on three trials (609 participants) we found no significant difference between the aciclovir and control groups in the incidence of PHN four months after the onset of the acute herpetic rash (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.51 to 1.11), nor was there a significant difference at six months (RR 1.05, 95% CI 0.87 to 1.27, two trials, 476 participants). In four of the trials (692 participants), there was some evidence for a reduction in the incidence of pain four weeks after the onset of rash. In the trial of famciclovir versus placebo, neither 500 mg nor 750 mg doses of famciclovir reduced the incidence of herpetic neuralgia significantly. The most commonly reported adverse events were nausea, vomiting, diarrhoea and headache for aciclovir, and headache and nausea for famciclovir. For neither treatment was the incidence of adverse events significantly different from placebo. None of the studies were at high risk of bias, although the risk of bias was unclear in at least one domain for all but one study. We found no new RCTs when we updated the searches in April 2013.

Authors' conclusions

There is high quality evidence that oral aciclovir does not reduce the incidence of PHN significantly. In addition, there is insufficient evidence to determine the effect of other antiviral treatments; therefore, further well-designed RCTs are needed to investigate famciclovir or other new antiviral agents in preventing PHN. Future trials should pay more attention to the severity of pain and quality of life of participants, and should be conducted among different subgroups of people, such as people who are immunocompromised.

Résumé scientifique

Traitement antiviral pour la prévention de la névralgie post-herpétique

Contexte

La névralgie post-herpétique (NPH) est une complication douloureuse et réfractaire de l'herpès zoster. Les traitements sont partiellement ou totalement inefficaces pour de nombreuses personnes atteintes de NPH. Les agents antiviraux, utilisés au moment de l'éruption cutanée, ont été proposés comme intervention pour prévenir le développement de la NPH. Ceci est la première mise à jour depuis la première publication de la revue en 2009.

Objectifs

Évaluer l'efficacité des agents antiviraux dans la prévention de la NPH.

Stratégie de recherche documentaire

Le 26 avril 2013, nous avons mis à jour les recherches dans le registre spécialisé du groupe Cochrane sur les affections neuromusculaires, CENTRAL, MEDLINE, EMBASE, LILACS, et le Chinese Biomedical Retrieval System. Nous avons examiné les références bibliographiques des études publiées afin d'identifier d'autres essais, et contacté les auteurs pour obtenir des données supplémentaires. Nous avons effectué des recherches dans d'autres bases de données dans la Bibliothèque Cochrane pour obtenir des informations pour la partie Discussion et dans deux registres d'essais cliniques pour trouver des essais en cours.

Critères de sélection

Nous avons pris en compte tous les essais contrôlés randomisés (ECR) sur le traitement antiviral administré dans les 72 heures après l'apparition de l'herpès zoster pour la prévention de la NPH. Il n'y avait aucune restriction concernant la langue.

Recueil et analyse des données

Deux auteurs ont indépendamment sélectionné les essais, évalué le risque de biais dans les essais inclus et extrait et analysé les données.

Résultats principaux

Six ECR portant sur un total de 1 211 participants étaient éligibles ; cinq d'entre eux évaluaient l'aciclovir par voie orale et le dernier, avec 419 participants, évaluait le famciclovir par voie orale. Nous avons été en mesure de réaliser des méta-analyses car des similarités suffisantes existaient entre les études incluses, telles que la notification de la présence de NPH, la durée de l'éruption cutanée avant l'instauration du traitement et le schéma thérapeutique. Pour notre critère de jugement principal, sur la base de trois essais (609 participants), nous n'avons trouvé aucune différence significative entre les groupes sous aciclovir et témoins dans l'incidence de la NPH quatre mois après l'apparition de l'éruption herpétique aiguë (risque relatif (RR) 0,75, intervalle de confiance à 95 % (IC) de 0,51 à 1,11), ni après six mois (RR 1,05, IC à 95 % 0,87 à 1,27, deux essais, 476 participants). Dans quatre essais (692 participants), il y avait des preuves d'une réduction dans l'incidence de la douleur quatre semaines après l'apparition de l'éruption. Dans l'essai sur le famciclovir versus placebo, ni les doses de 500 mg ou de 750 mg de famciclovir n'ont réduit de façon significative l'incidence de la névralgie herpétique. Les événements indésirables les plus couramment signalés étaient nausées, vomissements, diarrhées et céphalées pour l'aciclovir, et céphalées et nausées pour le famciclovir. Pour aucun des deux traitements, l'incidence des événements indésirables n'était significativement différente du placebo. Aucune des études n'était à risque élevé de biais, bien que le risque de biais ait été imprécis dans au moins un domaine pour toutes les études à l'exception d'une. Nous n'avons pas trouvé de nouveaux ECR lorsque nous avons mis à jour les recherches en avril 2013.

Conclusions des auteurs

Il existe des preuves de qualité élevée que l'aciclovir par voie orale ne permet pas de réduire significativement l'incidence de la NPH. En outre, il n'existe pas suffisamment de preuves pour déterminer l'effet d'autres traitements antiviraux ; par conséquent, d'autres ECR bien conçus sont nécessaires pour étudier le famciclovir ou d'autres nouveaux agents antiviraux pour la prévention de la NPH. Les futurs essais devront prêter plus d'attention à la gravité de la douleur et la qualité de vie des participants, et devraient être menés dans différents sous-groupes de patients, tels que les personnes immunodéprimées.

Plain language summary

Antiviral treatment for preventing nerve pain after shingles (postherpetic neuralgia)

Review question

We reviewed the evidence about the effect of antiviral medicines for preventing postherpetic neuralgia (PHN).

Background

PHN is a painful condition that can occur after shingles (herpes zoster) in the area where the rash occurred. Many people with PHN find that treatments work only a little or not at all. Attention has therefore turned to stopping the development of PHN. Some people suggested that medicines that target the virus that causes shingles (antiviral medicines), given at the time of the rash, might prevent PHN. The aim of this review was to assess the whether antiviral medicines are able to prevent PHN.

Study characteristics

We identified six clinical trials that met our standards for inclusion in the review. They included a total of 1319 participants. We decided that our main measure of whether antiviral medicines work in preventing PHN would be whether or not PHN had developed six months after a first attack of shingles (some of the studies we included of aciclovir measured PHN at four months).

Key results and quality of the evidence

Aciclovir, which is an antiviral medicine, was used in five trials (900 participants) and was not better than a placebo (dummy pill) in preventing PHN. In the other trial (419 participants), famciclovir, which is another antiviral drug, was no better than placebo in preventing pain following healing of the shingles rash. The number of side effects with aciclovir and famciclovir was not very different from the number with placebo. The trials did not have any major problems of design or conduct that put the results in doubt, although most of the reports did not provide enough information to fully assess every aspect. We conclude that according to high quality evidence, oral aciclovir was ineffective in reducing the incidence of PHN and there is not enough evidence on other antiviral treatments. There need to be further well-designed trials of famciclovir or other new antiviral agents with a greater number of participants. Future trials should pay more attention to the severity of pain and quality of life of participants, and should include different groups of people, such as those who have lowered immunity.

The evidence is current to April 2013, when the searches were last updated. Because new evidence on this topic is slow to emerge, we have scheduled the next update of this review for 2017.

Résumé simplifié

Traitement antiviral pour la prévention de la douleur névralgique après le zona (la névralgie post-herpétique)

Question de la revue

Nous avons examiné les preuves concernant l'effet des médicaments antiviraux pour la prévention de la névralgie post-herpétique (NPH).

Contexte

La NPH est une affection douloureuse qui peut se produire après le zona (herpès zoster) dans la zone où les éruptions cutanées sont survenues. De nombreuses personnes atteintes de NPH trouvent que les traitements fonctionnent peu ou pas du tout. L'attention s'est donc tournée vers les façons d'arrêter le développement de la NPH. Certaines personnes ont suggéré que les médicaments ciblant le virus à l'origine du zona (médicaments antiviraux), administrés au moment de l'éruption cutanée, pourraient prévenir la NPH. L'objectif de cette revue était d'évaluer si les médicaments antiviraux sont capables de prévenir la NPH.

Caractéristiques des études

Nous avons identifié six essais cliniques qui répondaient à nos normes pour l'inclusion dans la revue. Ils incluaient un total de 1 319 participants. Nous avons décidé que notre principal critère pour mesurer si les médicaments antiviraux étaient efficaces pour prévenir la NPH serait de savoir si la NPH s'était développée six mois après une première crise de zona (certaines des études que nous avons incluses sur l'aciclovir mesuraient la NPH à quatre mois).

Résultats principaux et qualité des preuves

L'aciclovir, qui est un médicament antiviral, était utilisé dans cinq essais (900 participants) et n'était pas plus efficace qu'un placebo (pilule factice) dans la prévention de la NPH. Dans l'autre essai (419 participants), le famciclovir, qui est un autre médicament antiviral, n'était pas supérieur au placebo dans la prévention de la douleur après la guérison de l'éruption cutanée due au zona. Le nombre d'effets secondaires avec l'aciclovir et le famciclovir n'était pas très différent du nombre sous placebo. Les essais ne présentaient pas de graves problèmes de conception ou de réalisation mettant en doute les résultats, bien que la plupart des rapports ne fournissait pas suffisamment d'informations pour évaluer pleinement chaque aspect. Nous en concluons que, selon des preuves de haute qualité, l'aciclovir par voie orale est inefficace dans la réduction de l'incidence de la NPH, et il n'existe pas suffisamment de preuves sur les autres traitements antiviraux. D'autres essais bien conçus sur le famciclovir ou sur d'autres nouveaux agents antiviraux, avec un nombre plus important de participants, sont nécessaires. Les futurs essais devront prêter plus d'attention à la gravité de la douleur et à la qualité de vie des participants, et devraient inclure différents groupes de personnes, comme des gens à l'immunité diminuée.

Les preuves sont à jour en avril 2013, lorsque les recherches ont été mises à jour la dernière fois. De nouvelles preuves sur ce sujet n'émergeant que lentement, nous avons prévu la prochaine mise à jour de cette revue pour 2017.

Notes de traduction

Traduit par: French Cochrane Centre 29th June, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Summary of findings(Explanation)

Summary of findings for the main comparison. Oral aciclovir for acute herpes zoster to prevent postherpetic neuralgia (PHN)
  1. 1Within 72 hours after the onset of herpes zoster.
    2The number of participants with PHN in Whitley 1996 could not be obtained, so we conducted the meta-analysis in RevMan5 with the inverse variance method, which cannot be totally reported in the SoF table.
    3Some information is from trials at unclear risk of bias, but the potential limitations are unlikely to lower confidence in the estimate of effect.

Oral aciclovir for acute herpes zoster to prevent PHN
Patient or population: people with acute herpes zoster1
Settings: hospitals and clinics
Intervention: oral aciclovir
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Oral aciclovir
Presence of PHN 6 months after the onset of the acute herpetic rash 2
Clinical diagnostic criteria for PHN in any intensity
Follow-up: 6 months
See comment2See comment2See comment476
(2 studies)
⊕⊕⊕⊕
high 3
The relative effect of this outcome calculated using inverse variance method is 1.05 (95% CI 0.87 to 1.27)
Presence of PHN 4 months after the onset of the acute herpetic rash
Clinical diagnostic criteria for PHN in any intensity
Follow-up: 6 months
166 per 1000 125 per 1000
(85 to 184)
RR 0.75
(0.51 to 1.11)
609
(3 studies)
⊕⊕⊕⊕
high 3
-
Adverse events
Clinical manifestations
Follow-up: 6 months
492 per 1000 497 per 1000
(433 to 566)
RR 1.01
(0.88 to 1.15)
709
(4 studies)
⊕⊕⊕⊕
high 3
No serious adverse effects attributable to the experimental treatment were reported
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; PHN postherpetic neuralgia; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Postherpetic neuralgia (PHN) is a condition of persistent pain in the area previously affected by acute herpes zoster infection (shingles). Herpes zoster results from the reactivation of the varicella zoster virus (VZV), which is usually dormant in the cranial sensory and spinal dorsal root ganglia after the onset of chicken pox (Gnann 2002). Immunosuppression, aging, physical and emotional stress, and human immunodeficiency virus (HIV) infection can trigger reactivation of VZV. People who have received an organ transplant and those receiving chemotherapy and steroid therapy are also susceptible to VZV (Fillet 2002). The incidence of herpes zoster ranges from 1.2 to 3.4 per 1000 person years, and rises steeply with age; fewer than one per 1000 person years in children and as many as 12 per 1000 person years in those aged over 65 years (Dworkin 2001). The normal age-related decrease in cell-mediated immunity is thought to account for the increased incidence in the elderly (Stankus 2000). Herpes zoster is initially characterised by a prodromal phase that is associated with pain and paraesthesia in the affected dermatome. Hours to days later, a papular rash appears and progresses to vesicles, then pustules, and finally crusts and heals three to four weeks later. In some people, the pain persists for weeks, months or years after the rash has healed; this is called PHN.

PHN is the most common complication of herpes zoster. Although PHN has been defined in different ways, data support the distinction between acute herpetic neuralgia (within 30 days of rash onset), subacute herpetic neuralgia (30 to 120 days after rash onset), and PHN (defined as pain lasting at least 120 days from rash onset) (Dworkin 1994; Desmond 2002). In a prospective study, PHN with a pain intensity of 4 (rated on a 0 to 10 scale, 0 indicated no pain and 10 indicated very severe pain) was rare (Thyregod 2007). Accordingly, the severity of pain needs to be considered in trials and in this systematic review. Age was an important risk factor for PHN. Forty per cent of individuals older than 50 years and 75% of adults 75 years and older develop PHN after VZV infection and experience the same burning, incapacitating pain endured during the herpes zoster infection (Portenoy 1986; Lancaster 1995; Dworkin 2001). Pain often leads to depression, fatigue, insomnia, altered activities of daily living and decreased socialisation. Individuals may also experience anorexia, physical inactivity and difficulty concentrating (Schmader 2002).

Description of the intervention

Owing to the severity and complexity of the disease, treatment is initiated at the onset of the rash and may be necessary for months, or even years. Treatments with established efficacy for the treatment of the pain of PHN include gabapentin, lidocaine patch, opioid analgesics, pregabalin and tricyclic antidepressants (TCAs) (Dubinsky 2004; Hempenstall 2005; Attal 2006). However, for many people these medications are either partially or totally ineffective, whether administered alone or in combination. With insufficient good quality evidence, there is no recommended first-line topical or systemic management in the treatment of PHN (Khaliq 2007; Wang 2009). Therefore, attention has turned to approaches that may prevent the development of PHN and antiviral agents are the best-established.

Eradication of varicella with a vaccine should result in fewer cases of herpes zoster because the incidence of reactivation of the vaccine is lower than that of the virus. A randomised, double-blind, placebo-controlled trial (the Shingles Prevention Study, SPS) showed that a VZV vaccine administered to adults, 60 years of age or older, reduced the incidence of herpes zoster and PHN (Oxman 2005). However, a recent Cochrane systematic review, which included the SPS trial, concluded that there was insufficient evidence to prove the efficacy of the vaccine for preventing PHN, beyond its effect on reducing herpes zoster (Chen 2011). Further, the vaccine is given to healthy people, not people with herpes zoster. A Cochrane review has found another potential therapy, corticosteroids given acutely during herpes zoster infection, to be ineffective in preventing PHN (Han 2013).

How the intervention might work

VZV is a highly contagious DNA virus. It is thought that VZV passes to the dorsal root ganglion via the skin during the initial infection (chicken pox) and lies dormant. Although the pathophysiology of PHN remains unclear, pathological analysis of ganglia from people with PHN has revealed diffuse and focal infiltration by chronic inflammatory cells (Smith 1978; Watson 1991). The detection of VZV DNA and proteins in peripheral blood mononuclear cells of people with PHN further supports the notion that low-grade viral ganglionitis contributes to PHN (Vafai 1988; Mahalingam 1995). If chronic pain reflects active infection, there may be a rationale for aggressive treatment with antiviral agents to prevent PHN. The antiviral agents inhibit VZV replication and accelerate cessation of viral shedding, hasten rash healing, and reduce the duration of acute pain (Gnann 2002), but their roles in preventing PHN remain controversial.

Many studies have demonstrated no benefit from aciclovir in reducing the duration or incidence of PHN (Kost 1996). However, two meta-analysis studies of all placebo-controlled trials with aciclovir for herpes zoster suggested a significant reduction in zoster-associated pain in people who received aciclovir (Wood 1996; Jackson 1997). In 2000 a systematic review suggested, from the limited evidence then available from randomised controlled trials (RCTs), that early treatment of acute herpes zoster with famciclovir or valaciclovir started within 72 hours of rash onset for seven days might reduce PHN incidence or duration (Alper 2000).

Why it is important to do this review

There have been numerous trials and reviews to assess the effects of various antiviral treatments for preventing PHN; however, their results have been inconsistent and we still have no clear evidence. We therefore carried out this Cochrane systematic review. The review was first published in 2009 and we updated the searches in 2013.

Objectives

To assess the effectiveness of antiviral agents in preventing PHN.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs, blinded and unblinded were eligible for this review. There were no language restrictions.

Types of participants

We considered participants with herpes zoster of all ages, of all degrees of severity, within 72 hours after the onset of herpes zoster.

Types of interventions

We considered antiviral agents, including but not limited to aciclovir, valaciclovir, famciclovir and brivudin, given by oral or intravenous routes within 72 hours of the onset of herpes zoster. We excluded other forms of administration of antiviral treatment, such as topical administration.

We investigated the following treatment comparisons.

  1. Antiviral agents alone compared with no treatment.

  2. Antiviral agents alone compared with placebo.

  3. Antiviral agents plus another treatment compared with the same other treatment alone.

  4. Antiviral agents plus another treatment compared with placebo plus the same other treatment.

Comparisons of antiviral agents and corticosteroids with double placebo or no treatment were not included. A separate review includes vaccines for preventing PHN.

Types of outcome measures

Primary outcomes

The primary outcome was the presence of PHN six months after the onset of the acute herpetic rash.

We defined PHN according to clinical diagnostic criteria as pain persisting or recurring at the site of shingles and lasting at least 120 days from rash onset (Desmond 2002). Where pain severity was described, we categorised pain as mild (less than a score of 4 on a scale of 0 to 10) or moderate (4 out of 10 or higher).

Secondary outcomes
  1. Pain severity measured by a validated visual analogue scale (VAS) (e.g. VAS of pain intensity from 0 cm to 10 cm) (Stratton Hill 1997), or numerical descriptive scale after 3, 6 and 12 months.

  2. Quality of life measured with a validated scale, such as the Short Form 36 Health Survey questionnaire (SF-36) (Ware 1998), after six months.

  3. Adverse events during treatment or within two weeks of stopping treatment. Adverse events were categorised as 'serious' or 'not serious'. Serious adverse events were those which led to death; were life-threatening; required inpatient hospitalisation or prolongation of existing hospitalisation; resulted in persistent or significant disability; or any important medical event that might have jeopardised the person or required preventive intervention. All other adverse events were considered to be non-serious (ICHEWG 2007).

Outcomes for inclusion in a 'Summary of findings' table

We included a 'Summary of findings' table to present the quality of evidence for these key outcomes:

  1. presence of PHN six or four months after the onset of the acute herpetic rash; and

  2. adverse events.

We graded the quality of the evidence for included RCTs as high, moderate, low, or very low based on the GRADE criteria. RCTs start from a grading of high, and may be downgraded if they have study limitations, consistency of effect, imprecision, indirectness or publication bias. The reasons for upgrading from downgraded RCTs are: a large effect size, a dose-response gradient or when all plausible confounding tend to underestimate the size of the effect (GRADE working group 2004; Schünemann 2011a; Schünemann 2011b).

Search methods for identification of studies

We searched for all RCTs of antiviral treatment for preventing PHN after an acute herpes zoster infection, irrespective of any language restrictions.

Electronic searches

On 26 April 2013, we updated searches in the Cochrane Neuromuscular Disease Group Specialized Register (26 April 2013), (CENTRAL) (2013, Issue 3 in The Cochrane Library), MEDLINE (January 1966 to April 2013), EMBASE (January 1980 to April 2013), LILACS (January 1982 to April 2013), and the Chinese Biomedical Retrieval System (January 1978 to April 2013). We searched ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp/en/) for ongoing trials.

We also searched DARE (Database of Abstracts of Reviews of Effects), HTA (Health Technology Assessment Database) and NHSEED (NHS Economic Evaluation Database) (all 2013, Issue 1 in The Cochrane Library) for information to include in the Discussion.

The detailed search strategies are in the appendices: Appendix 1 (CENTRAL), Appendix 2 (MEDLINE), Appendix 3 (EMBASE), Appendix 4 (LILACS), and Appendix 5 (the Chinese Biomedical Retrieval System).

Searching other resources

We checked the references of published studies to identify additional trials. We also reviewed the bibliographies of the trials identified, and contacted the authors and known experts in the field to identify additional published or unpublished data.

Data collection and analysis

Selection of studies

Two review authors scrutinised the titles and abstracts identified from the searches. They independently screened the full text of all potentially relevant studies. The review authors decided which trials fitted the inclusion criteria and resolved disagreements about inclusion criteria by discussion. A third review author (L He) was invited to arbitrate if there was a failure in resolving disagreement.

Data extraction and management

Two review authors (Q Li, N Chen) independently extracted the methodological details and data from publications using a data extraction form. Data for extraction included study name, design, study population size, duration, number of dropouts, participant withdrawals, participants analysed in the different treatment groups, inclusion and exclusion criteria, intervention (route and dosage) and outcomes. One author (N Chen) entered data into the Cochrane statistical software, Review Manager 5 (RevMan) (RevMan 2012), and a second (Q Li) checked the data entry.

Assessment of risk of bias in included studies

We assessed the risk of bias in each trial, and the assessment took into account the security of randomisation, allocation concealment, blinding of participants, personnel and outcome assessment, completeness of outcome data, selective reporting and any other potential bias. Two authors (N Chen, Q Li) independently assessed these items and assessed trials for each domain as 'low', 'unclear' or 'high' risk of bias, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

Measures of treatment effect

We undertook the task of analysing the data using RevMan 5 and reported them according to Cochrane Collaboration guidelines. We calculated a treatment effect using a fixed-effect model across trials with RevMan 5. We expressed results as risk ratios (RRs) with 95% confidence intervals (CIs), risk differences with 95% CIs for dichotomous outcomes and as mean differences for continuous outcomes. If studies used differing follow-up periods, we rescaled the results or expressed them as effects/unit time to allow for this. If the difference in effect with the standard error was available, but the standard deviations of the individual study groups were not, we used the RevMan generic inverse variance facility to pool studies.

Unit of analysis issues

It is not possible to conduct cluster-randomised trials or cross-over trials to evaluate the effectiveness of antiviral treatment for PHN. To avoid unit-of-analysis errors, we defined several different outcomes based on different periods of follow-up and performed separate analyses. In studies that compared more than two intervention groups, we selected the relevant pair of intervention groups to include in the analyses.

Dealing with missing data

We analysed data on an intention-to-treat basis, so that all participants with available data would be included in the analysis in the group to which they were allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants were not analysed in the group to which they were randomised, and there was sufficient information in the trial report, we attempted to restore them to the correct group. We obtained missing data from the study authors whenever possible.

Assessment of heterogeneity

We assessed heterogeneity amongst trials by using the Chi2 test with a 10% level of statistical significance (P < 0.1) and I2 greater than 50% (Higgins 2002; Higgins 2003). If significant heterogeneity was present, we planned to check the data again and find out the causes of heterogeneity and then undertake sensitivity analyses. If there was still unexplained heterogeneity, we combined the study results using a random-effects model. For trials that were clinically heterogeneous or present insufficient information for pooling, we performed a descriptive analysis (Higgins 2011b).

Assessment of reporting biases

There are insufficient studies to use a funnel plot to investigate the possibility of publication bias. If there are sufficient studies in future updates we will assess publication bias as described in our protocol (Li 2007).

Data synthesis

We used RevMan to perform meta-analyses of the studies that reported on the efficacy of antiviral treatment for preventing PHN and displayed the results as a forest plot. We only included trials that provided a measure of effect size. We also undertook descriptive analyses of other included trials.

Subgroup analysis and investigation of heterogeneity

We carried out the following subgroup analyses.

  1. Treatment started sooner (24 hours or less), or later (more than 24 hours), after herpes zoster onset.

  2. Younger (adults 49 years of age or less) and older (adults 50 years or more).

Sensitivity analysis

We also undertook a sensitivity analysis on the basis of risk of bias by repeating the calculation after omitting the trials which had a high or unclear risk of bias in some domains.

We reported any differences between the review methods and those described in the protocol (Li 2007) in Differences between protocol and review.

Results

Description of studies

Results of the search

The updated searches in 2013 retrieved a large number of references: 151 from the Cochrane Neuromuscular Disease Group Specialized Register, 219 from CENTRAL, 333 from MEDLINE, 525 from EMBASE, 4 from LILACS and 458 from the Chinese Biomedical Retrieval System. There were also 10 references from DARE, 1 from HTA and 9 from NHSEED. In this update, we did not find any newly published studies that appeared to meet the inclusion criteria. As a result, there were still 21 potentially eligible trials identified by scrutinising the titles and abstracts. We excluded 15 trials after we screened their full text. Six trials fulfilled the inclusion criteria (Huff 1988; Wood 1988; Morton 1989; Harding 1991; Tyring 1995; Whitley 1996). Our searches of trials registries did not identify any ongoing trials.

Included studies

We found many studies of antiviral treatment for acute zoster, but only a few studies addressed relevant end points, such as the incidence and duration of PHN or the associated pain after the acute phase. Among the studies, six trials with a total of 1211 participants were suitable for inclusion.

The reports of all included studies explicitly stated Inclusion and exclusion criteria. All the studies recruited adults with the characteristic rash of herpes zoster that had been present for 72 hours or less. One study was limited to people over 50 years of age (Whitley 1996), while another study involved people over 60 years of age (Wood 1988); the other trials only required adults to be older than 16 to 20 years. Sample sizes differed between trials, ranging from 46 to 419 participants (three studies had more than 100 participants (Wood 1988; Tyring 1995; Whitley 1996)). Each trial reported the demographic characteristics of participants, including gender distribution, mean age and mean duration of rash before enrolment; they recorded no significant differences. Altogether, 580 males and 614 females were included in our review (discrepancies in the number of participants were due to occasional missing items of data in some trials). More than 831 (69%) participants were 50 years of age or older. The locations of rashes were reported in several trials (Wood 1988; Morton 1989; Tyring 1995), and one trial enrolled people with acute herpes zoster ophthalmicus only (Harding 1991). Common exclusion criteria across the trials included: immunosuppression; pregnant or nursing women; hepatic or renal dysfunction; systemic glucocorticosteroid therapy or any antiviral therapy; people who required immunosuppressive therapy; cancer; and the presence of crusts on herpetic lesions at enrolment. No trial evaluating the efficacy of antiviral treatment for people who were immunocompromised met the inclusion criteria for our review.

Oral aciclovir was the most commonly used antiviral treatment for herpes zoster, and five of the six studies evaluated its effect, with treatment commencing within 72 hours of the zoster rash. These five studies used oral aciclovir at a dose of 800 mg five times daily: two studies administered the antiviral for seven days (Wood 1988; Morton 1989), two studies administered the antiviral for 10 days (Huff 1988; Harding 1991), and the remaining study administered the antiviral for 21 days (Whitley 1996). Huff 1988 additionally studied a 400 mg dosage five times per day for 10 days. Whitley 1996 randomised participants to aciclovir, prednisone, both aciclovir and prednisone, or neither aciclovir or prednisone, for 21 days.

In the sixth included trial (Tyring 1995), participants were assigned to one of the following regimens: famciclovir 500 mg, famciclovir 750 mg or matched placebos, identical in taste and appearance three times daily for seven days from within 72 hours of onset of the rash. All aciclovir trials followed the participants for six months or longer after enrolment, while in the famciclovir study participants were followed for five months after the lesions healed. Follow-up included the following approaches: participants returned to see the physician at a prescribed time or as often as clinically necessary (Harding 1991; Tyring 1995); investigators contacted participants by telephone (Huff 1988); or a research nurse or assistant assessed the participants at home (Wood 1988; Morton 1989). The remaining trial did not describe the method of follow-up (Whitley 1996). The six trials reported loss to follow-up and withdrawal, but one trial did not refer to the reasons for loss to follow-up or withdrawal (Huff 1988). Only two trials stated that an intention-to-treat analysis was performed (Tyring 1995; Whitley 1996), which was not described in the other trials.

The outcome measures differed between the trials. All the included trials reported the presence or duration of PHN, which was defined with different cut-off times and intensities of pain. Severity of pain was referred to as a separate outcome in several trials, but measured in different ways: specifically, Harding 1991 used a VAS set vertically at 100 mm, and compared pain scores directly between groups, while Wood 1988 recorded pain by asking participants to mark a linear scale ranging from 'none' to 'very severe', and for analysis, translated the mark on this linear scales to a score of zero to three by quartering. In the other trials, the intensity of pain was only evaluated as 'absent', 'slight', 'moderate', or 'severe', and was often recorded in the acute phase only. Quality of life was measured in Whitley 1996 and included the times to cessation of acute neuritis, return to uninterrupted sleep, and return to 100% usual activity, but it was only evaluated during the first month after disease onset. None of the trials reported quality of life measured with the SF-36 after six months. All included trials reported adverse events during treatment, or within two weeks of stopping treatment. Adverse events were categorised as 'serious' or 'not serious'.

Excluded studies

The main reasons for exclusion of the 15 potentially relevant studies were as follows: the follow-up was too short or irregular to obtain data for evaluation of PHN (Galbraith 1983; Wassilew 1987); the control group was not treated with a placebo but another agent (Benoldi 1991); there was no comparison with a placebo, or no treatment group (Hoang-Xuan 1992; Wood 1994); the length of time from onset of herpes zoster to treatment was over 72 hours (Esmann 1982; McGill 1983; Cobo 1986; Payne 1989); topical antiviral treatment was used (Mandal 1988); and examination of the methods showed the study to be neither an RCT nor a quasi-RCT (Mondelli 1996); only an abstract was available, with insufficient data to assess eligibility (Dekonenko 1998); no report was available (in spite of attempts to obtain further details) (Dekonenko 1999); and one study did not specify a limit for the course of the disease in the inclusion criteria (we have as yet received no reply to an email to the author requesting detailed information) (Varotti 2001). See Characteristics of excluded studies.

Risk of bias in included studies

Most of the included studies were randomised, double-blind, placebo-controlled parallel trials. Two of the studies were performed in a single centre (Morton 1989; Harding 1991) and the other studies were performed in multiple centres (see Characteristics of included studies). According to the summary assessment of the risk of bias for each important outcome (Higgins 2011a), we rated one of the trials as at a low risk of bias (Wood 1988), rated five of the trials as at an unclear risk of bias (Huff 1988; Morton 1989; Harding 1991; Tyring 1995; Whitley 1996), and none were at a high risk of bias. The 'Risk of bias' figure summarises the review authors' judgements about each 'Risk of bias' item (Figure 1).

Figure 1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Green = low risk of bias; yellow = unclear risk of bias, red = high risk of bias (not shown).

Allocation

Trial reports of all the included studies stated that they were RCTs. Four of the studies reported the method of randomisation (Huff 1988; Wood 1988; Morton 1989; Whitley 1996). The Huff, Whitley and Wood studies used a computer-generated randomisation code to randomly assign participants to the treatment groups (Huff 1988; Wood 1988; Whitley 1996). In Morton 1989, the laboratories of the centre conducting the trial provided each course of study medication in a numbered and randomised bottle. Harding 1991 and Tyring 1995 did not describe the method of randomisation. In two studies, allocation concealment was probably done: in Wood 1988, participants and investigators enrolling participants could not foresee assignment because the allocation was done by the study centre, and in Morton 1989, the centre conducting the trial randomised sequentially-numbered bottles containing trial treatment courses. However, it was unclear from the reports if there was adequate allocation concealment in the other included studies. Therefore, risk of selection bias due to generation of a randomised sequence or its concealment prior to assignment was unclear in those four trials (Huff 1988; Harding 1991; Tyring 1995; Whitley 1996).

Blinding

All of the six included trials were double blind, using placebo in the control group. Most of the trials used matching placebo identical to the active drug, but only described blinding in broad terms, such as 'double blind,' which made it impossible to know exactly who was blinded (Higgins 2011a). Only two trials reported blinding in detail: Whitley 1996 stated, "all research personnel remained blinded to drug assignment until the study was completed and the database was locked", and Morton 1989 specified that "the investigators, research nurse, general practitioners, and patients were all fully blinded to treatment status". Further all the outcomes, including persistence and severity of pain and adverse events, were participant-reported, so the risk of bias from knowledge of the allocated interventions by participants and personnel during the study or by outcome assessors was low in those two trials, but there was insufficient information for the other four trials (Huff 1988; Harding 1991; Tyring 1995; Wood 1988) to make an assessment.

Incomplete outcome data

The included studies all reported the time of follow-up: one study used five months (Tyring 1995), and five studies used six months (Huff 1988; Wood 1988; Morton 1989; Harding 1991; Whitley 1996). Five of the studies reported information about follow-up and dropouts, and clearly described the reasons for dropout; Huff 1988 did not mention the reason for dropout. Harding 1991 considered the presence of bias due to incomplete outcome data since four participants withdrew because of side effects, and the study analysed data on the remaining participants (Harding 1991). One study claimed to have used intention-to-treat analysis (Whitley 1996); however, the other five included studies did not state whether or not the analysis was by intention to treat. Nevertheless, we were able to obtain sufficient information from the trial report to restore dropouts to the correct group and perform an intention-to-treat analysis in our review.

Selective reporting

Since most of the included trials were designed primarily to assess efficacy of antivirals during the acute phase of herpes zoster and all reported negative results or marginal positive results for antiviral treatment for preventing PHN, we considered reporting bias introduced by the investigators to be small.

Other potential sources of bias

Differences in the definition of PHN and end outcome measurements in the included trials made our review of the relevant studies complicated. Although we stated the definition of PHN in our review as 'persistent or recurrent pain at the site of shingles at least 120 days after the onset of the acute rash', we still evaluated all relevant studies which adopted different definitions of PHN to avoid missing potential data. Instead, we have attempted to perform a subcategory analysis of different study data using alternative cut-off times.

We also considered performance bias due to use of other treatment measures. Exclusion criteria usually ruled out people on other relevant treatments from the studies but in some trials, other conventional medications, such as corticosteroids, analgesics, anti-inflammatory drugs, topical preparations and antidepressants, were permitted during treatment and follow-up (Morton 1989; Harding 1991; Whitley 1996). Although study reports stated that there was no significant difference in the use of any additional medications between the treatment and placebo groups, we thought this might have had some degree of impact on the results.

In several trials, the trialists asked participants to contact investigators if PHN developed or to recall their condition over the entire period at one time point of follow-up. Recall bias in reporting of the condition or inaccurate recall of adverse events could have produced error in these trials (Huff 1988; Morton 1989; Wood 1988).

Effects of interventions

See: Summary of findings for the main comparison Oral aciclovir for acute herpes zoster to prevent postherpetic neuralgia (PHN)

Primary outcome measure

The presence of PHN six or four months after the onset of acute herpetic rash
Aciclovir versus placebo

Five trials compared oral aciclovir with placebo, and two of the trials (Wood 1988; Whitley 1996), with a total of 476 participants, provided relevant data on the presence of PHN six months after the onset of the acute rash. Whitley 1996 recruited a total of 100 participants in the oral aciclovir and placebo group and only reported the results with RRs and 95% CIs, without detailed information on the number of participants with PHN during the follow-up period (we contacted the trial author for the primary data but did not receive any reply). Therefore, we conducted the meta-analysis in RevMan 5 with the inverse variance method for the two trials (Wood 1988; Whitley 1996). In the meta-analysis, the incidence of PHN events for the aciclovir group was not significantly different from that for placebo (RR 1.05, 95% CI 0.87 to 1.27, P = 0.62; Analysis 1.1; Figure 2), which indicated that oral aciclovir did not significantly prevent PHN six months after the onset of rash.

Figure 2.

Forest plot of comparison 1: Oral aciclovir versus placebo or no treatment, outcome 1.1 The presence of PHN 6 months after the onset of the acute herpetic rash.

We also conducted a meta-analysis for the presence of PHN using a cut-off time of four months after rash onset, since half of the included trials reported relevant data at this cut-off time point and so met the definition of PHN in the present review (at least 120 days from rash onset) (Desmond 2002). The three trials included a total of 609 participants (Huff 1988; Wood 1988; Harding 1991). The incidence of PHN was slightly, but not significantly, less in the treated than in the placebo group (RR 0.75, 95% CI 0.51 to 1.11, P = 0.15; Analysis 1.2; Figure 3).

Figure 3.

Forest plot of comparison 1 Oral aciclovir versus placebo or no treatment, outcome 1.2 The presence of PHN 4 months after the onset of the acute herpetic rash.

Famciclovir versus placebo

The only trial comparing two dosages of famciclovir with placebo (Tyring 1995), defined PHN as pain after rash healing, and followed participants up five months after rash healing. No detailed data were obtained about the presence of PHN six months after the rash onset. The proportion of participants who had PHN was similar in each of the three treatment groups: 44.2% (61/138 participants) for the 500 mg dose, 50.4% (68/135 participants) for the 750 mg dose, and 38.4% (56/146 participants) for placebo. For the 500 mg and 750 mg doses respectively, RRs of PHN versus placebo were 1.15 (95% CI 0.87 to 1.52) and 1.31 (95% CI 1.01 to 1.71) (Analysis 2.1). The trial indicated that oral famciclovir did not significantly prevent PHN after rash healing, although the article authors reported that famciclovir could promote the resolution of PHN (approximately two-fold faster than placebo).

Secondary outcome measures

Pain severity measured by a validated VAS or numerical descriptive scale after three, six, and 12 months

Most included trials described pain intensity in the acute phase, but not after three months or longer. Only two trials reported the intensity of pain three and six months after using aciclovir for acute herpes zoster (Wood 1988; Harding 1991), but they used different pain evaluation methods, and recorded data in different ways, so we could not combine the data in a meta-analysis.

Harding 1991 (46 participants) reported lower mean pain scores recorded by VAS (0 mm to 100 mm) in the aciclovir than the placebo group, reaching a significant difference between two to six months (0.6 versus 9.7 after three months, P = 0.02; 1.0 versus 9.3 after six months, P = 0.03). In Wood 1988 (376 participants), marks by participants on the linear scale ranging from 'none' to 'very severe', were translated to a score of zero to three. The analyses of mean changes in pain took place only during treatment and showed a significantly greater reduction in the aciclovir group compared with the placebo group. Thereafter, the trialists recorded and compared only the number of participants with each score (already analysed as the primary outcome), and we could not obtain data for changes in individuals.

No data on this outcome were available in the famciclovir trial (Tyring 1995).

Quality of life measured with a validated scale, such as the SF-36, after six months

Only Whitley 1996 (201 participants) addressed any aspect of assessment of quality of life. The investigators did not use a validated scale, but referred to the following: return to 100% usual activity, return to uninterrupted sleep, and cessation of use of analgesic agents. There were, however, no significant differences in any of these outcomes between the aciclovir plus prednisone placebo and double placebo group (Whitley 1996).

None of the trials reported separate data on quality of life measured with the SF-36 after six months.

No data on this outcome were available in the famciclovir trial (Tyring 1995).

Adverse events during treatment, or within two weeks of stopping treatment

Adverse events included serious and non-serious events, and we analysed them as a whole. Table 1 provides details for individual studies.

Table 1. Adverse events in included studies
Study nameAntiviral agentAdverse events
Harding 1991AciclovirNo serious adverse events developed. 12 of the aciclovir recipients (50%) and 11 of the placebo recipients (50%) reported non-serious adverse events. Nausea and vomiting were most frequent. Other infrequent adverse events included anorexia, malaise, dyspepsia, heartburn and depression, with an even spread between the two groups
Huff 1988AciclovirNo serious adverse events developed. Non-serious adverse events such as nausea, diarrhoea and headache developed in both groups (aciclovir and placebo), without significant differences
Morton 1989AciclovirIn the week of treatment, there was no significant difference between groups in the numbers of events reported, with a mean of 2.7 events per participant on aciclovir and 3.1 on placebo. In the second week there were 1.3 events per participant on aciclovir, just significantly fewer than the 1.7 events per participant on placebo (P = 0.044). There were 2 deaths during the study, 1 in each group. None was proven to be drug related
Tyring 1995FamciclovirNo serious adverse events developed. The most frequently reported non-serious adverse events were headache (23.2% of participants receiving 500 mg of famciclovir, 22.2% of participants receiving 750 mg of famciclovir, and 17.8% of participants receiving placebo, respectively) and nausea (12.3%, 12.6% and 11.6% of participants, respectively)
Whitley 1996AciclovirThe most frequently reported clinical adverse events were gastrointestinal symptoms, especially nausea and vomiting. The rate of adverse events was lower in the placebo group (12%) than in the aciclovir plus prednisone placebo group (27%), without significant difference
Wood 1988AciclovirA large number of adverse events were reported, including depression, headache, anorexia, nausea, tiredness, and vomiting. During treatment, 124 aciclovir recipients reported a total of 302 adverse events, and 129 placebo recipients reported a total of 359 adverse events. The incidence was similar in the two treatment groups. None of the adverse events was considered serious
Oral aciclovir versus placebo

None of the included trials reported any serious adverse effects attributable to the experimental treatment during treatment or within two weeks of stopping treatment. The most commonly reported non-serious adverse events were nausea, vomiting, diarrhoea and headache, which were recorded in most of the included trials. Morton 1989 reported untoward medical events as numbers of mean events per participant, which was just significantly different between the two groups in the week after treatment (1.3 and 1.7 events per participant on aciclovir and placebo respectively, P = 0.044). These data were not suitable for inclusion in the meta-analysis for the incidence of adverse events.

The meta-analysis of four aciclovir trials indicated that the incidence of adverse events for oral aciclovir (178/355 participants (50.1%)) was not significantly different from placebo (174/354 participants (49.2%); RR 1.01, 95% CI 0.88 to 1.15, P = 0.91; Analysis 1.4; Figure 4) (Huff 1988; Wood 1988; Harding 1991; Whitley 1996).

Figure 4.

Forest plot of comparison 1 Oral aciclovir versus placebo or no treatment, outcome 1.4 Adverse events.

Oral famciclovir versus placebo

The trial (419 participants) comparing famciclovir with placebo concluded that famciclovir was well tolerated, with a safety profile similar to that of placebo (Tyring 1995). The most frequently reported adverse events were headaches and nausea. The frequency of adverse events in the famciclovir and placebo groups was similar (see Table 1). Investigators classified adverse events as "related", "possibly related to study medication", "unknown", or as cases in which assessment was missing. The most common events related to study medication were headache (8.0%, 8.1%, and 6.8% of participants receiving 500 mg famciclovir, 750 mg famciclovir and placebo, respectively) and nausea (5.1%, 3.0% and 8.2% of participants, respectively), but without significant differences. There were no reports of any serious adverse events in this trial.

Additional outcome measure not specified in the protocol

The presence of herpetic neuralgia one month after the onset of acute herpetic rash

Four trials recorded relevant data on the presence of herpetic neuralgia one month after the onset of the acute herpetic rash (Huff 1988; Wood 1988; Morton 1989; Harding 1991). A meta-analysis of these trials, with a total of 692 participants, showed a significantly lower incidence of pain in the aciclovir group (153/347 participants (44.1%)) than in the placebo group (184/345 participants (53.3%)) (RR 0.83, 95% CI 0.71 to 0.96, P = 0.01; Analysis 1.3; Figure 5).

Figure 5.

Forest plot of comparison 1 Oral aciclovir versus placebo or no treatment, outcome 1.3 The presence of herpetic neuralgia 1 month after the onset of the acute herpetic rash.

No data on this outcome were reported in the famciclovir trial (Tyring 1995).

Subgroup analyses

Early and late treatment (24 hours or less after onset; more than 24 hours after onset)

Three trials stratified the participants into subgroups by duration of rash before enrolment for comparison of the participant characteristics (Wood 1988; Tyring 1995; Whitley 1996), but the details of the results for each group were not available for this subgroup analysis. This information was not available from the other published reports.

Younger and older adults (younger than 50 years of age; adults 50 years of age or older)
Adults younger than 50 years of age

Two trials provided relevant data on the presence of PHN six months after the onset of the acute rash (Wood 1988; Whitley 1996), but neither of them included participants who were under 50 years of age. The trial authors extracted data on participants under 50 years of age from only one of the included trials (Huff 1988), in which 7 of 44 participants developed herpetic neuralgia one month after rash onset in the oral aciclovir group and 12 of 45 developed PHN in the placebo group. There were no significant differences between the groups (RR 0.60, 95% CI 0.26 to 1.37, P = 0.23; Analysis 3.1).

Adults 50 years of age or older

More than 831 (69%) of all the participants were 50 years of age or older. Two trials only included participants who were either 50 or 60 years of age or older (Wood 1988; Whitley 1996). Another trial recorded the presence of PHN among younger and older participants during the follow-up period (Huff 1988). We performed a meta-analysis of the relevant data and found no significant difference between the aciclovir and control groups for the presence of pain at six months (RR 1.05, 95% CI 0.87 to 1.27, P = 0.62; Analysis 1.1; Figure 2), four months (RR 0.98, 95% CI 0.59 to 1.62, P = 0.93) and one month (RR 0.92, 95% CI 0.79 to 1.08, P = 0.31) after rash onset (Analysis 3.2).

Sensitivity analysis

No significant heterogeneity was present when we conducted a meta-analysis to investigate oral aciclovir for preventing PHN six months after the onset of the acute herpetic rash. To perform a sensitivity analysis, we excluded trials with a high or uncertain risk of bias (Huff 1988; Morton 1989; Harding 1991), which left one trial with a low risk of bias (Wood 1988). Wood 1988 reported the presence of herpetic neuralgia comparing aciclovir with placebo treatment by monthly intervals after the onset of the acute herpetic rash (111/190 versus 110/186 at one month, P = 0.89; 26/190 versus 26/186 at four months, P = 0.93; and 22/190 versus 20/186 at six months, P = 0.80). As a result of the sensitivity analysis, the results of the primary outcome did not change, still without a significant difference between groups (RR 1.08, 95% CI 0.61 to 1.91, P = 0.80, Analysis 4.1; Figure 6). The results for the presence of herpetic neuralgia one month after the onset of the acute herpetic rash changed from a significant difference (RR 0.83, 95% CI 0.71 to 0.96, P = 0.01) to no significant difference (RR 0.99, 95% CI 0.83 to 1.17, P = 0.89).

Figure 6.

Forest plot of comparison 4 Sensitivity analysis, outcome 4.1 The presence of postherpetic neuralgia.

Discussion

Antiviral treatment has been widely used to accelerate the resolution of herpes zoster and its complications. The differing results from relevant trials and reviews of the efficacy of antiviral treatment for preventing PHN prompted the present systematic review of RCTs. We have done our best to collect and extract all possible data to conduct a more complete systematic analysis.

Summary of main results

We included six randomised controlled trials that addressed relevant endpoints for treatment of PHN, five of which compared oral aciclovir with a control treatment (Huff 1988; Wood 1988; Morton 1989; Harding 1991; Whitley 1996), and the sixth oral famciclovir (Tyring 1995). Despite different designs, methods, duration of follow-up, and efficacy end points, sufficient similarities (such as reports of the presence of PHN, duration of rash before treatment initiation (less than 72 hours), and treatment regimen) meta-analysis was possible. Based on a limited number of studies, the result indicated that antiviral treatment did not have a significant effect on the incidence of PHN after four or six months compared to placebo (three studies after four months (Huff 1988; Harding 1991; Wood 1994), and two studies after six months (Wood 1994; Whitley 1996)). Summary of findings for the main comparison shows the main findings, including key information concerning the quality of evidence, the magnitude of effect of oral aciclovir and the sum of data on the main outcomes. The incidence of PHN, reported in some natural history studies, was 10% to 50%, according to different definitions of PHN and different possible risk factors for its development such as age, prodromal pain, ophthalmic zoster and immunocompromised state (Griffin 1998; Stankus 2000). In trials included in this review, the incidence of PHN in placebo groups was 11% to 60%, which might be considered as the natural incidence of PHN. The incidence in treatment groups was similar at 12% to 58%.

Although studies defined PHN in several ways, opinion supports the definition of pain lasting at least 120 days from rash onset (Desmond 2002), and in this way we partitioned pain lasting 30 to 120 days after rash onset as subacute herpetic neuralgia. As an additional outcome measure, we extracted all data about herpetic neuralgia from one month after the onset of the rash. The meta-analysis showed a slight but significant reduction in the incidence of pain in the aciclovir group compared with the placebo group (RR 0.83, 95% CI 0.71 to 0.96). This finding is consistent with the benefit reported in some controlled trials from antiviral treatment for acute herpes zoster (Cobo 1986; McKendrick 1986; Wassilew 1987).

Compared to the incidence of PHN, which was the main focus in this review, measures of severity of pain and quality of life can help assess the efficacy of treatment for preventing PHN. However, only a few trials addressed these measures. One trial reported significantly lower mean VAS pain scores in the aciclovir than in the placebo group at two to six months (Harding 1991). Whitley 1996 concluded that no significant difference existed in any aspect of quality of life between the aciclovir plus prednisone-placebo and the double placebo group, as evaluated by the times to return to uninterrupted sleep, 100% usual activity and total cessation of the use of analgesic agents, but without any validated scale. Similar information was not obtainable from the other trials.

There were no serious adverse effects attributable to the experimental therapy reported during treatment, or within two weeks of stopping treatment. Adverse effects were not significantly more common amongst the antiviral than the control participants.

Additionally, we analysed important demographic prognostic variables that might have had an impact on the results in subgroups. Although we obtained insufficient information to undertake the subgroup analysis for a different duration of rash before treatment initiation (24 hours or less versus longer than 24 hours), we did an evaluation of the efficacy of oral aciclovir according to the age of participants, and it did not show a significant benefit either in those older or younger than 50 years of age.

Overall completeness and applicability of evidence

Most of the included trials addressed relevant endpoints for PHN and adverse effects, but data regarding the severity of pain and quality of life were limited. The types of participants allowed us to draw conclusions only for people who are immunocompetent. Our analysis does not include people who were immunocompromised, which is a population at high risk for herpes zoster and PHN, because we did not find any eligible trials evaluating the efficacy of antiviral treatment in this group. Because of insufficient data, we did not assess the effects of antiviral treatment starting sooner rather than later after the onset of herpes zoster.

We included none of the intravenous antiviral treatment trials because follow-ups were limited to assessment of efficacy during the acute phase, so the trials did not address the incidence of PHN.

Thus, the results of our review were limited to oral antiviral agents (aciclovir and famciclovir) and immunocompetent people with herpes zoster. These results do not provide evidence of efficacy on outcomes such as pain severity and quality of life.

In the opinion of the authors, since antiviral treatment is still widely used for acute and subacute herpes zoster, it is important to inform patients that PHN might still develop despite antiviral treatment in the early phase, because the relationship between acute inflammation, pain and PHN is not simple or clear.

Quality of the evidence

All six included trials were randomised, controlled parallel studies. However, we rated only one trial as good quality, because of its design and efforts to avoid selection, performance, detection, attrition, reporting and other bias. We rated the others as fair, since they had an unclear risk of bias for one or more key domains, commonly for allocation concealment, blinding of participants and personnel, or incomplete outcome data. Hence, the identified evidence did not permit a totally robust conclusion to be reached on the efficacy of antiviral treatment for preventing PHN.

Potential biases in the review process

Different definitions of PHN and different time points for measures between trials hampered the extraction of data. Although we tried to collect all relevant data at several cut-off times, the possibility of missing data remained. For example, Tyring 1995 defined PHN as pain after rash healing, and followed participants up monthly for five months thereafter. We have contacted the author for the primary data but have not yet received a reply.

We have done our best to search the pertinent literature, including published and unpublished studies, without any language restrictions, and we contacted the investigators to obtain additional information as required. As there were too few studies, we did not use a funnel plot to investigate the possibility of publication bias, but used a descriptive analysis to evaluate the possible reporting bias. There is still a need, however, to take publication bias into account because most of the included studies were published in English, and trial authors did not provide enough useful information in response to enquiries. To reduce the risk of attrition bias, the meta-analyses were of the intention-to-treat population.

Agreements and disagreements with other studies or reviews

There have been several reviews and meta-analyses for treatment or prevention of PHN, largely based on the same trials that we included in our review, but their results were different.

Crooks and colleagues published an overview of clinical trials with aciclovir for zoster-associated chronic pain (Crooks 1991). They conducted a pooled analysis of four trials of recommended doses of oral aciclovir versus placebo (Huff 1988; Wood 1988; Morton 1989; Harding 1991), and calculated that the incidence of PHN at six months was reduced by 42% in the participants treated with aciclovir. However, we could not substantiate from the original trials the incidence rates reported in the Crooks 1991 review.

A meta-analysis of the same four trials performed by Wood and colleagues indicated a significant reduction of at least 50% in the prevalence of PHN at three and six months among aciclovir recipients (Wood 1996). However, the meta-analysis seemed not to include Wood 1988.

The most recent systematic review reviewed several approaches including antiviral treatment for preventing or shortening PHN (which was defined as any pain after healing of cutaneous zoster) (Alper 2000). Alper and co-workers also included the four above-mentioned placebo-controlled trials of oral aciclovir (Alper 2000), providing marginal evidence for a reduction in the incidence of PHN at one to three months; and one trial of oral famciclovir (Tyring 1995), concluding that it significantly reduced the duration, but not the incidence of PHN. The conclusions are partly in agreement with our review. However, Alper 2000 only performed a descriptive analysis without a meta-analysis.

A review of famciclovir for herpes zoster included the only famciclovir trial in the present review, besides three comparative trials of famciclovir and aciclovir (Anonymous 1998). It suggested a slight benefit of famciclovir for reducing the incidence of post-zoster pain, and showed no statistically significant difference between famciclovir and aciclovir in terms of efficacy or tolerability.

Authors' conclusions

Implications for practice

There is high quality evidence that oral aciclovir does not significantly reduce the incidence of postherpetic neuralgia, defined as pain lasting 120 days or longer from rash onset. There was some evidence for a reduction in the incidence of pain in the short term, that is four weeks after the onset of rash. There was insufficient evidence to support the use of other antiviral agents for preventing PHN.

Implications for research

Further trials of aciclovir would be inappropriate, but well-designed, randomised controlled trials of famciclovir or other new antiviral agents, comparing them to aciclovir and with a greater number of participants, are needed to evaluate the efficacy of these antiviral agents in preventing postherpetic neuralgia. Future investigators should pay more attention to the severity of pain and quality of life, and should consider different subgroups, such as the immunocompromised. The effects of antiviral treatment started sooner rather than later after herpes zoster onset should be stratified for assessment. Moreover, the quality of reporting should be improved, so that more useful data can be obtained.

Acknowledgements

The authors are grateful for the assistance of Professor Richard Hughes, Kate Jewitt, Ruth Brassington, Janice Fernandes and Angela Gunn of the Cochrane Neuromuscular Disease Group. Angela Gunn performed searches of CENTRAL, MEDLINE, EMBASE, LILACS, DARE, HTA and NHSEED.

The editorial base of the Cochrane Neuromuscular Disease Group receives support from the MRC Centre for Neuromuscular Diseases.

Data and analyses

Download statistical data

Comparison 1. Oral aciclovir versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Presence of PHN 6 months after the onset of the acute herpetic rash2 Risk Ratio (Fixed, 95% CI)1.05 [0.87, 1.27]
2 Presence of PHN 4 months after the onset of the acute herpetic rash3609Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.51, 1.11]
3 Presence of PHN 1 month after the onset of the acute herpetic rash4692Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.71, 0.96]
4 Adverse events4709Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.88, 1.15]
Analysis 1.1.

Comparison 1 Oral aciclovir versus placebo or no treatment, Outcome 1 Presence of PHN 6 months after the onset of the acute herpetic rash.

Analysis 1.2.

Comparison 1 Oral aciclovir versus placebo or no treatment, Outcome 2 Presence of PHN 4 months after the onset of the acute herpetic rash.

Analysis 1.3.

Comparison 1 Oral aciclovir versus placebo or no treatment, Outcome 3 Presence of PHN 1 month after the onset of the acute herpetic rash.

Analysis 1.4.

Comparison 1 Oral aciclovir versus placebo or no treatment, Outcome 4 Adverse events.

Comparison 2. Oral famciclovir versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Presence of PHN1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 500 mg famciclovir1284Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.87, 1.52]
1.2 750 mg famciclovir1281Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.01, 1.71]
Analysis 2.1.

Comparison 2 Oral famciclovir versus placebo or no treatment, Outcome 1 Presence of PHN.

Comparison 3. Subgroup analysis (the presence of PHN)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Adults 49 years of age or less1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 The presence of herpetic neuralgia 1 month after the onset of the acute herpetic rash189Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.26, 1.37]
2 Adults aged 50 years or more2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 The presence of PHN 4 months after the onset of the acute herpetic rash1376Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.59, 1.62]
2.2 The presence of herpetic neuralgia 1 month after the onset of the acute herpetic rash2475Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.79, 1.08]
Analysis 3.1.

Comparison 3 Subgroup analysis (the presence of PHN), Outcome 1 Adults 49 years of age or less.

Analysis 3.2.

Comparison 3 Subgroup analysis (the presence of PHN), Outcome 2 Adults aged 50 years or more.

Comparison 4. Sensitivity analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Presence of PHN1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 The presence of herpetic neuralgia 1 month after the onset of the acute herpetic rash1376Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.83, 1.17]
1.2 The presence of PHN 4 months after the onset of the acute herpetic rash1376Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.59, 1.62]
1.3 The presence of PHN 6 months after the onset of the acute herpetic rash1376Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.61, 1.91]
Analysis 4.1.

Comparison 4 Sensitivity analysis, Outcome 1 Presence of PHN.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Herpes Zoster explode all trees
#2 "herpes zoster" or shingles
#3 MeSH descriptor Neuralgia, Postherpetic, this term only
#4 "postherpetic neuralgia" or "post herpetic neuralgia"
#5 phn
#6 (#1 OR #2 OR #3 OR #4 OR #5)
#7 MeSH descriptor Antiviral Agents explode all trees
#8 "antiviral agents"
#9 MeSH descriptor Acyclovir explode all trees
#10 acyclovir or aciclovir or valacyclovir or valaciclovir or valtrex or famciclovir or famvir or penciclovir or gamciclovir or brivudin
#11 (#7 OR #8 OR #9 OR #10)
#12 (#6 AND #11)

Appendix 2. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to April Week 3 2013>
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (346797)
2 controlled clinical trial.pt. (85759)
3 randomized.ab. (249438)
4 placebo.ab. (137469)
5 clinical trials as topic.sh. (164083)
6 randomly.ab. (178468)
7 trial.ti. (106903)
8 or/1-7 (800563)
9 exp animals/ not humans.sh. (3804093)
10 8 not 9 (736627)
11 exp herpes zoster/ (9224)
12 herpes zoster.tw. (5953)
13 shingle$.mp. (758)
14 exp neuralgia, postherpetic/ (534)
15 (postherpetic neuralgia or post-herpetic neuralgia).tw. (1641)
16 (postherpetic pain or post-herpetic pain).tw. (67)
17 PHN.tw. (997)
18 or/11-17 (11903)
19 exp antiviral agents/ (269906)
20 antivir$ agent$.tw. (4850)
21 exp acyclovir/ (11822)
22 (acyclovir or aciclovir or valacyclovir or valaciclovir).tw. (6935)
23 (valtrex or famciclovir or famvir or penciclovir or ganciclovir or brivudin).tw. (5857)
24 exp ganciclovir/ (5142)
25 or/19-24 (273352)
26 10 and 18 and 25 (339)
27 remove duplicates from 26 (333)

Appendix 3. EMBASE (OvidSP) search strategy

Database: Embase <1980 to 2013 Week 16>
Search Strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (36683)
2 double-blind procedure.sh. (114133)
3 single-blind procedure.sh. (17264)
4 randomized controlled trial.sh. (340667)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (947074)
6 trial.ti. (143750)
7 or/1-6 (1079185)
8 (animal/ or nonhuman/ or animal experiment/) and human/ (1253779)
9 animal/ or nonanimal/ or animal experiment/ (3377180)
10 9 not 8 (2794226)
11 7 not 10 (989841)
12 limit 11 to embase (774165)
13 exp herpes zoster/ (16232)
14 herpes zoster.tw. (7797)
15 shingle$.mp. (1163)
16 exp postherpetic neuralgia/ (3592)
17 (postherpetic neuralgia or post-herpetic neuralgia).tw. (2641)
18 (postherpetic pain or post-herpetic pain).tw. (100)
19 PHN.tw. (1424)
20 or/13-19 (20481)
21 exp antivirus agent/ (589070)
22 exp aciclovir/ (28798)
23 valaciclovir/ (5126)
24 famciclovir/ (3257)
25 exp ganciclovir/ (18457)
26 (antivir$ agent$ or acyclovir or aciclovir or valacyclovir or valaciclovir).tw. (15755)
27 (famciclovir or famvir or valtrex or penciclovir or ganciclovir or brivudin).tw. (8073)
28 or/21-27 (591294)
29 12 and 20 and 28 (527)
30 remove duplicates from 29 (525)

Appendix 4. LILACS search strategy

(MH:C02.256.466.423$ or shingles or "postherpetic neuralgia" or "post-herpetic neuralgia" or "neuralgia postherpetica" or "neuralgia post-herpetica" or "neuralgia pos-herpetica" or "neuralgia posherpetica" or phn) and (MH:D27.505.954.122.388$ or antivirales or antivirais or acyclovir or aciclovir or valacyclovir or valaciclovir or valtrex or famciclovir or famvir or penciclovir or ganciclovir) and ((PT:"Randomized Controlled Trial" or "Randomized Controlled trial" or "Ensayo Clínico Controlado Aleatorio" or "Ensaio Clínico Controlado Aleatório" or PT:"Controlled Clinical Trial" or "Ensayo Clínico Controlado" or "Ensaio Clínico Controlado" or "Random allocation" or "Distribución Aleatoria" or "Distribuição Aleatória" or randon$ or Randomized or randomly or "double blind" or "duplo-cego" or "duplo-cego" or "single blind" or "simples-cego" or "simples cego" or placebo$ or trial or groups) AND NOT (B01.050$ AND NOT (humans or humanos or humanos)))

Appendix 5. Chinese Biomedical Retrieval System Database search strategy

(All of the search terms were translated to Chinese terms when we conducted the searches)

1. herpes zoster
2. postherpetic neuralgia
3. PHN
4. shingle
5. 1-4/or
6. herpes
7. neuralgia
8. 6 and 7
9. 5 or 8
10. antiviral agents
11. acyclovir
12. aciclovir
13. valacyclovir
14. valaciclovir
15. valtrex
16. famciclovir
17. famvir
18. penciclovir

19. gamciclovir

20. brivudin

21. 10-20/or
22. random
23. control24. clinical trial
25. placebo
26. 22-25/or
27. 9 and 21 and 26

What's new

DateEventDescription
26 April 2013New search has been performedWe updated the searches. We updated the 'Risk of bias' tables, added a 'Summary of findings' table and revised the review. Published notes are included.
17 April 2013New citation required but conclusions have not changedThere were no new trials for inclusion.

Contributions of authors

Ning Chen and Muke Zhou identified the studies and revised the updated version in 2013. Qifu Li and Ning Chen assessed the risk of bias and extracted data. Li He, the contact (corresponding) author, developed the proposal, offered expert advice, reviewed the protocol, and she is responsible for developing and updating the review. Jie Yang, Dong Zhou and Muke Zhou helped to perform the bibliographic searches.

Declarations of interest

None known

Sources of support

Internal sources

  • Department of Neurology, West China Hospital, China.

External sources

  • No sources of support supplied

Differences between protocol and review

An additional outcome measure, the presence of herpetic neuralgia one month after the rash onset, which was not specified in the protocol, was reported in the review. The authors changed the inclusion criteria to exclude quasi-RCTs, because RCTs are thought to be the only way to prevent systematic differences of baseline characteristics between intervention groups, according to the latest Cochrane Handbook for Systematic Reviews of Interventions. However, no quasi-RCTs were found.

We assessed the methodological quality of included studies using the Cochrane 'Risk of bias' tool (Higgins 2011a). In this update we added a 'Summary of findings' table.

Notes

New evidence on this topic is slow to emerge. The next scheduled update of this review will be four years from the date of search rather than the usual two years. However, if we become aware of new data before the update is due, we will plan an earlier update.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Harding 1991

MethodsA randomised, double-masked (blinded), placebo-controlled, single-centre trial (methods not described)
Participants

46 people with acute herpes zoster ophthalmicus

People with rash of more than 72 hours duration or with intraocular complication on entry were excluded

Interventions46 participants were started on 800 mg oral aciclovir 5 times per day (n = 24) or matched placebo (n = 22) for 10 days. Matched placebo was identical in appearance to the active drug
OutcomesPrimary outcome: mean pain scores and proportion of participants with pain scores greater than 0 during the study period
NotesConducted in the Accident and Emergency department at St Paul's Eye Hospital, Liverpool
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method of randomisation was not described
Allocation concealment (selection bias)Unclear riskThe method of allocation concealment was not described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskProbably done because the report stated, "double-masked study" and "matched placebo was identical to the active drug"
Blinding of outcome assessment (detection bias)
All outcomes
Low riskA double-blind study, and all the outcomes were reported by participants
Incomplete outcome data (attrition bias)
All outcomes
Low risk4 participants were withdrawn because of nausea and vomiting. Follow-up was incomplete in 3 participants in the aciclovir group. Intention-to-treat analysis was not performed
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported
Other biasUnclear riskTopical steroids were given to 6 participants; 1 in the aciclovir group and 5 in the placebo group

Huff 1988

MethodsMulticentre, randomised placebo-controlled, double-blind study
Participants187 adults (108 men and 79 women) with localised rashes of herpes zoster that had been present for 3 days or less. 98 of the participants were 50 years old or older. Exclusion criteria were: 1. age less than 18 years; 2. pregnant or nursing women; 3. immunosuppressed; 4. hepatic or renal dysfunction; 5. receipt of systemic glucocorticosteroid therapy or any antiviral therapy within the preceding 10 days
Interventions2 doses of aciclovir were studied in this trial (the total number of participants was 252), but the study does not state the incidence of PHN following the low dose (400 mg, 5 times per day), so we only included the high dose and placebo groups. 187 participants received oral aciclovir (800 mg 5 times per day for 10 days) (n = 93) or matching placebo (n = 94)
OutcomesPrimary outcome: the presence of PHN during 6 months post-treatment
NotesConducted in 6 university medical centres in the USA
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed a computer-generated randomisation code
Allocation concealment (selection bias)Unclear riskThe method of allocation concealment was not described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskProbably done, because participants were assigned in a double-blind manner and matched medications were identical capsules
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind design, and all outcomes were reported by participants themselves
Incomplete outcome data (attrition bias)
All outcomes
Low risk36 participants (19%) were lost to follow-up: 23% (21/93) of the aciclovir recipients and 16% (15/94) of the placebo recipients. Intention-to-treat analysis was not performed
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported
Other biasLow riskNo other potential bias was found

Morton 1989

MethodsSingle-centre double-blind, randomised, placebo-controlled trial
Participants83 immunocompetent people with herpes zoster rash were enrolled in the study by 30 Auckland general practitioners. Exclusion criteria included: presentation more than 72 hours after onset of rash; presence of known renal insufficiency; and pregnancy. There was no significant difference in age, sex distribution, or rash descriptors between the 2 groups
InterventionsParticipants received either oral aciclovir, 800 mg five times daily for seven days (n = 40), or identical placebo (n = 43)
OutcomesPrimary outcome: prevalence of pain and clinically-defined PHN 1 month after the onset of the acute herpetic rash
NotesConducted by the Wellcome Research Laboratories, Beckenham, UK
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed numbered bottles that were generated and randomised by the centre
Allocation concealment (selection bias)Low riskEach course provided in a bottle numbered and randomised by the Wellcome Research Laboratories, Beckenham, UK
Blinding of participants and personnel (performance bias)
All outcomes
Low riskInvestigators, research nurse, general practitioners and participants were all fully blinded to treatment status
Blinding of outcome assessment (detection bias)
All outcomes
Low riskParticipants were blinded to treatment status, and they reported their outcomes
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll enrolled participants completed the initial phase; 1 participant died in each group and 1 withdrew during follow-up. Intention-to-treat analysis was not performed
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported
Other biasUnclear riskUse of other treatments such as oral prednisone, antidepressants, anxiolytics and nonsteroidal anti-inflammatory drugs was permitted, which might have produced potentially-significant baseline differences between groups

Tyring 1995

MethodsA randomised, double-blind, placebo-controlled, multicentre trial (methods not described)
Participants419 immunocompetent adults with uncomplicated herpes zoster. Exclusion criteria included: zoster rash that had been present for more than 72 hours; complications of herpes zoster; presence of crusts at the enrolment; other serious underlying disease; pregnancy or lactation
InterventionsParticipants were assigned to 3 groups: famciclovir, 500 mg (n = 138); famciclovir, 750 mg (n = 135); or placebo (n = 146), three times daily for 7 days
OutcomesPrimary outcome: the presence of PHN during 5 months' follow-up after the lesions had healed
NotesConducted in 36 centres in the USA, Canada, and Australia
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe method of sequence generation was not described
Allocation concealment (selection bias)Unclear riskThe method of allocation concealment was not described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe study was stated to be 'double-blind', but the method was not described
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe study was double-blind, and outcomes were reported by participants
Incomplete outcome data (attrition bias)
All outcomes
Low riskNone was lost to follow-up for presence of PHN. Intention-to-treat and efficacy-evaluable analyses were both performed
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported
Other biasLow riskNo other potential bias was found

Whitley 1996

MethodsMulticentre randomised, double-blind, placebo-controlled, parallel study with a 2 x 2 factorial design
Participants208 immunocompetent participants older than 50 years of age who had localised herpes zoster that developed less than 72 hours before study enrolment. 201 participants were included in the analysis. The following groups were excluded: people who required immunosuppressive therapy; those with cancer; women capable of conceiving and bearing a child; people with a history of hypertension (diastolic pressure > 100 mmHg) or who were receiving antihypertensive therapy; people with osteoporosis or insulin-dependent diabetes mellitus; those who had received other antiviral drugs or immunoglobulin products within the four weeks before the study began; and people with a history of glycosuria or hyperglycaemia
Interventions

Oral aciclovir (800 mg, 5 times daily) or a matched placebo for 21 days. Prednisone or a matched placebo was given orally 60 mg/day for days one to seven, 30 mg/day for days 8 to 14, and 15 mg/day for days 15 to 21. Matched medications were identical in taste and appearance. The 4 treatment regimens were aciclovir plus prednisone, aciclovir plus prednisone placebo, prednisone plus aciclovir placebo, and placebos for both aciclovir and prednisone

Numbers of participants:

  • 51 aciclovir plus prednisone (24 males and 27 females, mean age 63)

  • 48 aciclovir plus prednisone placebo (21 males and 27 females, mean age 62)

  • 50 prednisone plus aciclovir placebo (26 males and 24 females, mean age 60)

  • 52 aciclovir and prednisone placebo (25 males and 27 females, mean age 61)

OutcomesPrimary outcome:
6-month evaluation of pain (time to cessation of zoster-associated pain)
Secondary outcomes:
1. 1-month evaluation of quality of life
2. Adverse events
NotesConducted in 15 university hospitals or affiliated clinics in USA
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed a computer-generated randomisation code
Allocation concealment (selection bias)Unclear riskThe method of allocation concealment was not described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll research personnel and participants remained blinded to drug assignment until the study was completed, and the database was locked. All matched medications were identical in taste and appearance
Blinding of outcome assessment (detection bias)
All outcomes
Low riskParticipants were blinded to treatment measures, and they reported outcomes after therapy
Incomplete outcome data (attrition bias)
All outcomes
Low riskOne participant died and 32 (16%) were lost to follow-up (equally distributed among the treatment groups, and an intention-to-treat analysis was performed
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported
Other biasUnclear riskUse of analgesic agents was permitted during the treatment and follow-up

Wood 1988

MethodsMulticentre randomised, double-blind, placebo-controlled trial
ParticipantsA total of 376 immunocompetent participants presenting with a herpes zoster rash of less than 72 hours in duration were enrolled. The study excluded people who had received specific antiviral therapy for the present infection, if they had renal insufficiency or if they were unable to comply with the protocol
InterventionsParticipants were allocated to receive either aciclovir (n = 190), 800 mg as 2 x 400 mg tablets, or matching placebo (n = 186) approximately 4-hourly, omitting the dose in the middle of the night (i.e. 5 times per day), for 7 days
Outcomes

Primary outcome: Pain severity measured by a pain scores at monthly intervals during the 6-month follow-up after the end of therapy

Second outcome: Adverse events

NotesConducted at three centres in the United Kingdom
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed a computer-generated randomisation code
Allocation concealment (selection bias)Low riskThe computer-generated randomisation code was stratified by study centre to allocate participants to either group
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants were assigned in a double-blind manner and matched medications were identical
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind and outcomes were reported by participants
Incomplete outcome data (attrition bias)
All outcomes
Low risk12 (3.2%) of the enrolled participants withdrew and minor protocol violations occurred in 15 participants but the latter were included in the analyses. Details of missing data and reasons were reported in each group. The report does not state whether the analysis was on an intention-to-treat basis
Selective reporting (reporting bias)Low riskOutcomes listed in the methods section were all reported
Other biasLow riskNo other potential bias was found

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Benoldi 1991The control group was treated with carbamazepine
Cobo 1986Participants were included within 7 days of the onset of herpes zoster. Definition of PHN was unclear
Dekonenko 1998Only an abstract with insufficient data available to assess eligibility
Dekonenko 1999No abstract available
Esmann 1982People with a zoster eruption of less than 96 hours were included
Galbraith 1983The follow-up was only 28 days and the definition of PHN was unclear
Hoang-Xuan 1992Antiviral treatment was not compared with a control (placebo or no treatment)
Mandal 1988Used topical aciclovir cream
McGill 1983Included participants who presented less than 96 hours after the onset of the rash
Mondelli 1996Methods indicate that the study was not an RCT or a quasi-RCT
Payne 1989Included participants were within 96 hours of the onset of pain or eruption
van der Broek 1984The follow-up was only 10 days after termination of treatment
Varotti 2001This study did not specify a limit for the course of the disease in the inclusion criteria for the participants (we have sent an email to the author requesting detailed information, but have not yet received a reply)
Wassilew 1987The definition of PHN was unclear and the follow-up was irregular, so that data on the incidence of PHN were not available
Wood 1994Antiviral treatment was not compared with a control (placebo or no treatment)

Ancillary