BackgroundPostherpetic neuralgia (PHN) is the most common complication attributed to herpes zoster, which involves the reactivation of residual varicella zoster virus. It has been reported previously that pre-emptive amitriptyline following acute herpes zoster has shown latent positive effects in the prevention of PHN. In this study, by interfering with the same targets, norepinephrine and serotonin, we aim to evaluate whether pre-emptive duloxetine may proactively prevent PHN development.MethodsThis is a nationwide multicentric, randomized, open-label, blinded-endpoint study that will recruit 750 participants from 18 primary centres in China. Patients aged more than 50years who are diagnosed with uncomplicated HZ, present with vesicles within 72h of their emergence, and have an average pain score of at least 40/100mm on a visual analogue scale (VAS, 0mm=no pain, 100mm=worst possible pain, at opposite ends of a 100-mm line) will be recruited for this study. Participants will be randomized into a duloxetine arm and a control arm. Participants allocated to the duloxetine arm will be given antivirals, analgesics and duloxetine, while those allocated to the control arm will receive antivirals and analgesics but no duloxetine. The primary outcome of this study is preventive efficacy against PHN, which will be evaluated based on a 100mm VAS. Any pain scores other than 0mm on the VAS 12weeks after HZ onset will be defined as PHN. The secondary outcomes will consist of the average weekly VAS score, the average weekly consumption of each analgesic, weekly feature of the pain, patients' quality of life based on the 12-item Short-Form Health Survey, Patient Global Impression of Change Scale, sleep quality as evaluated by the Pittsburgh Sleep Quality Index and adverse events during the study period.DiscussionThis study will investigate a prophylactic approach for reducing the prevalence of postherpetic neuralgia with duloxetine and will add significant new knowledge on the preventive effects of duloxetine on PHN.Trial registrationClinicaltrials.gov NCT04313335. Registered on 18 March 2020.