Postherpetic neuralgia (PHN) is clinically significant pain presenting 30~180 days after the onset of the skin rash of herpes zoster (HZ)12345. The reported risk of developing PHN varied from 5% to >30%, depending on the study design, age distribution of the study population, and definition. More than 30% of patients with PHN experienced persistent pain for >1 year6. In elderly patients, the prevention of PHN has major implications on the patients' daily activity and quality of life.

Antiviral agents used at the time of the rash and active interventional pain management procedures (IPs) for early pain control have been proposed as methods to prevent the development of PHN37. A recent meta-analysis showed high-quality evidence that oral acyclovir does not reduce the incidence of PHN significantly. In addition, this study demonstrated insufficient evidence to determine the effect of other antiviral treatments such as famciclovir7. Although several IPs, such as epidural sympathetic block to reduce the acute HZ-related pain, have been indicated to have some level of effectiveness in the prevention of PHN, there is no conclusive evidence at present. Dermatologists are the ideal sentinels for the early management of HZ and the prevention of PHN. Therefore, dermatologists should be aware of the effects of early IPs in the prevention of PHN. The aim of this study was to evaluate the evidences about the efficacy of IPs during the acute phase of HZ (within 14 days after the onset of the rash) on the prevention of PHN in elderly patients, through a systematic review with a meta-analysis of randomized controlled trials (RCTs).

The databases that we used included PubMed, SCOPUS, and the references of retrieved articles from inception to August 31, 2013. In this study, combinations of the following keywords were used for the literature search: "analgesia", "electrical nerve stimulation", "epidural", "herpes zoster", "herpes zoster-related pain", "injection", "intervention", "interventional pain management", "nerve block", "pain", "paravertebral", "postherpetic neuralgia", "shingles related pain", and "sympathetic", with no limits on the study date or language. We focused on RCTs that analyzed the association between the IPs during the acute phase of HZ and PHN occurrence. The studied population consisted of elderly patients (≥50 years old) with the acute phase of HZ. The evaluated intervention was various types of IPs. The outcome was PHN development (≥3 months) in the elderly. All of the selected studies must have included the use of a visual analogue scale (VAS) for pain assessment. Two evaluators independently evaluated all the reports retrieved from the databases. We estimated the pooled odds ratios (ORs) and 95% confidence intervals (CIs) by using Comprehensive Meta Analysis (version 2.0; Biostat Inc., Englewood, NJ, USA). As shown in Fig. 1, 2,670 articles were obtained after the initial search of the databases and relevant bibliographies. After excluding 710 duplicate articles and 1,935 articles that did not meet the selection criteria, we reviewed the full text of the 25 articles. Among these, only five RCTs were included in the final analysis12345.

The final analysis from five RCTs included 1,405 total subjects, 708 of whom received IPs with or without standard antiviral medication such as acyclovir or famciclovir and 697 received standard antiviral therapy only. The types of IPs were as follows: epidural and paravertebral block, stellate ganglion block, and percutaneous electrical nerve stimulation (Table 1). The funnel plot of this meta-analysis showed asymmetry; however, the distribution was regular. Therefore, we analyzed the data by using a random-effects model. The results of meta-analysis showed that IPs with or without antiviral therapy during acute HZ had a preventive effect on the development of PHN over antiviral therapy at 3 months (OR 3.28, 95% CI 1.20~8.96; p=0.02) and 6 months (OR 3.86, 95% CI 1.25~11.89; p=0.02) (Fig. 2). Further subgroup analyses according to the type of prevention and sexual differences showed no effect on the prevention of PHN.

The mechanism of PHN remains unclear; however, ganglionitis and neuritis of the affected nerve result in sympathetic stimulation, which leads to decreased intraneural blood flow, resulting in nerve ischemia and finally in irreversible nerve damage8. Early IPs that reduce repetitive painful stimuli and prevent vasoconstriction during the acute phase of HZ may attenuate central sensitization, prevent nerve scarring, and substantially account for the prevention of PHN.

This study has some limitations. Funnel plot analysis, the value of which was limited by the small number of studies, showed a slight asymmetry that could be due to publication bias. This means that smaller studies showing low effects on the prevention of PHN could have not been published. In addition, we pooled studies in which PHN was treated by using different IPs, such as epidural and paravertebral block, stellate ganglion block, and percutaneous electrical nerve stimulation. This could be viewed as a source of heterogeneity. These factors could have led to some overestimation of IPs.

Although the sample size is relatively small to be conclusive, the present meta-analysis showed that by preventing PHN, IPs can be effective during acute HZ in elderly patients. However, more data from RCTs will be needed to confirm these results. In the treatment of HZ, dermatologists have a tendency to hesitate about providing early, active management of HZ-related pain. Active management of acute HZ-related pain through an early multidisciplinary approach with pain management specialists may be helpful in preventing PHN development.