A systematic review and meta-analysis of risk factors for postherpetic neuralgia

Abstract

Patients with herpes zoster can develop persistent pain after rash healing, a complication known as postherpetic neuralgia. By preventing zoster through vaccination, the risk of this common complication is reduced. We searched MEDLINE and Embase for studies assessing risk factors for postherpetic neuralgia, with a view to informing vaccination policy. Nineteen prospective studies were identified. Meta-analysis showed significant increases in the risk of postherpetic neuralgia with clinical features of acute zoster including prodromal pain (summary rate ratio 2.29, 95% confidence interval: 1.42-3.69), severe acute pain (2.23, 1.71-2.92), severe rash (2.63, 1.89-3.66), and ophthalmic involvement (2.51, 1.29-4.86). Older age was significantly associated with postherpetic neuralgia; for individual studies, relative risk estimates per 10-year increase ranged from 1.22 to 3.11. Evidence for differences by gender was conflicting, with considerable between-study heterogeneity. A proportion of studies reported an increased risk of postherpetic neuralgia with severe immunosuppression (studies, n = 3/5) and diabetes mellitus (n = 1/4). Systemic lupus erythematosus, recent trauma, and personality disorder symptoms were associated with postherpetic neuralgia in single studies. No evidence of higher postherpetic neuralgia risk was found with depression (n = 4) or cancer (n = 5). Our review confirms a number of clinical features of acute zoster are risk factors for postherpetic neuralgia. It has also identified a range of possible vaccine-targetable risk factors for postherpetic neuralgia; yet aside from age-associated risks, evidence regarding risk factors to inform zoster vaccination policy is currently limited.

Figure 1

Flow diagram describing study selection.

Figure 2

Summary of associations between postherpetic neuralgia and clinical features of acute zoster. ¹Composite score ranges from 0-100 numerical pain ratings and McGill Pain Questionnaire Present Pain ²Intensity ratings of average and worst shingles pain. ²Intensity of pain using the Short Italian questionnaire, from 0-10. ³³Temperature differences are between normal and affected skin. ⁴Percentage of body surface area thermal asymmetry (≥3 vs <3%). †Risk factors too varied to combine in meta-analyses. •Not included in summary RR (either because study has already contributed to meta-analysis, or exposure definition is not in-keeping with other studies). *Studies reporting RR (rather than OR) are not included in meta-analysis. CI, confidence interval; DN4, Neuropathic pain questionnaire with 4 questions; NPSI, Neuropathic pain symptom inventory score; OR, odds ratio; RR, rate ratio; SF-12, short-form 12; VAS, visual analogue scale ranging from 0 (non pain) to 100 (worst pain ever experienced); VZV, varicella zoster virus; ZBPI, Zoster brief pain inventory interference score.

Figure 3

Summary of associations between postherpetic neuralgia and vaccine-targetable risk factors from identified studies. *Only 10/20 studies reported age such that the effect estimate could be converted into 10-year increases. Of the remaining 10 studies; 8 reported an increased risk of PHN with greater age, 1 showed no effect all, and 1 did not report an age-effect. **Studies reporting RRs rather than ORs not included in meta-analysis as RR can underestimate OR when outcome becomes common. ***Effect estimate from study may be erroneous therefore the study is not included in the meta-analysis: Parruti 2010 CIs are too narrow, and Opstelten 2002 confidence also too narrow. ¹Using high-dose oral corticosteroids or other immunosuppressive drugs, having invasive cancer or HIV/AIDS. ²Undefined, however included HIV or currently being treated for cancer. ³Connective tissue disease, HIV infection or organ allograft. ⁴Better health: measured using continuous physical component summary score (higher scorer score reflects worse health). ⁵Poorer health: measured using continuous variable of total number of medical conditions. †Risk factors too varied to combine in meta-analyses. ‡The large study by Jih et al. (N = 34,280) dominated the pooled relative risk contributing to 99·1% of the model. Other risk factors investigated as predictors of PHN, but not included in the final model, included; surgical intervention, hepatitis-C virus infection, hypertension, neurological disorders, allergy, family history of CHD, angina, chronic obstructive pulmonary disorder, education, alcohol abuse, familial status, years of education and race. APOE, alipoprotien E; CI, confidence interval; OR, odds ratio; RA, rheumatoid arthritis; RR, rate ratio; SLE, systemic lupus erythematosus.

Figure 4

Assessment of publication bias for gender as a risk factor for postherpetic neuralgia. Funnel plot of the log odds ratio plotted against the standard error of the log odds ratio for seven studies reporting the effect of female gender on PHN risk (dotted line represents pseudo 95% confidence limits).