Comparison of efficacy and safety of non-oral therapeutic interventions for zoster-associated pain: a systematic review and network meta-analysis.

Background: Zoster-associated pain (ZAP) encompasses acute, subacute, and postherpetic neuralgia stages. It often results in persistent sensory abnormalities and substantial impairment of quality of life. Although oral pharmacotherapy remains the first-line and foundational approach, its effectiveness may be limited in some patients; accordingly, non-oral interventions are investigated as complementary or escalated strategies. However, high-quality evidence investigating the relative efficacy and safety of these interventions remains scarce. Objective: This study intended to systematically evaluate the efficacy and safety of a variety of non-oral therapeutic interventions for ZAP, thereby providing evidence to inform clinical decision-making. Methods: Web of Science, Cochrane Library, Embase, and PubMed were searched to identify eligible randomized controlled trials (RCTs). Data from the included studies were extracted, and the risk of bias was examined via the Cochrane Risk of Bias Tool 2.0. A Bayesian network meta-analysis (NMA) was carried out to compare different interventions, and surface under the cumulative ranking curve (SUCRA) probabilities were utilized to rank relative treatment effects. STATA 18 and R version 4.4.2 were employed to conduct statistical analyses. Results: Fifty-three RCTs involving 4,973 patients were included. The NMA showed that chemical selective neurolysis provided the greatest pain relief compared with other treatments (standardized mean difference [SMD]: 4.34; 95% credible interval [CrI]: 2.18 to 6.49). The analysis showed no statistically significant increase in the incidence of adverse events (AEs) (risk ratio: 32.05; 95% CrI: 0.57 to 3,326.64), though the extremely wide CrI indicated substantial uncertainty in this risk estimate. There were no serious complications. Minimally invasive central nervous system neuromodulation combined with topical and peripheral chemical interventions demonstrated the most favorable overall benefits in both pain relief (SMD = 3.41, 95% CrI: 1.08 to 5.73) and sleep improvement (SMD = 3.71, 95% CrI: 1.86 to 5.77). This was followed by minimally invasive peripheral nerve modulation combined with systemic pharmacological analgesia. Regarding safety, no statistically significant differences in AE incidence were found among interventions. However, SUCRA rankings suggested that oral medication and minimally invasive central nervous system neuromodulation had the most favorable safety profiles. Conclusion: Combination therapies utilizing minimally invasive neuromodulation show favorable potential in managing ZAP. While chemical selective neurolysis may benefit refractory cases, its use necessitates careful ethical and safety evaluation. Due to the low overall certainty of the evidence, these findings should be interpreted with caution, underscoring the critical need for rigorous future research to confirm long-term outcomes. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD420251059913.