Venlafaxine for the Prevention of Postherpetic Neuralgia in Patients with Acute Herpes Zoster: Protocol for a Randomized Controlled Trial.

BACKGROUND: Postherpetic neuralgia (PHN) affects approximately 30% of individuals with herpes zoster (HZ), with approximately 80% of cases occurring in individuals aged 50 years or older. PHN represents a major clinical challenge due to its chronicity and impact on quality of life. Current treatments for acute HZ pain have limited efficacy in preventing PHN, highlighting the need for effective preventive strategies targeting early pathophysiological mechanisms. STUDY DESIGN: Multicenter, prospective, randomized, open-label, blinded-endpoint controlled trial. METHODS AND ANALYSIS: A total of 832 patients with acute HZ within 30 days of rash onset and moderate to severe pain (NRS ≥4) will be randomly assigned (1:1) to receive either conventional therapy alone or venlafaxine plus conventional therapy. Venlafaxine will be initiated at 75 mg once daily and titrated based on pain response and tolerability. If pain persists, the dose will be increased to 150 mg once daily during the second week and subsequently to a maximum of 225 mg once daily. Treatment will continue until pain resolves or until 90 days after rash onset. After assessment of the primary endpoint at day 90, participants who develop PHN will receive guideline-based treatment according to their clinical condition. All participants will receive standardized analgesic management following the World Health Organization pain ladder. The study duration will be 52 weeks. The primary outcome is the incidence of PHN at 90 days after rash onset, defined as clinically meaningful persistent pain in the affected dermatome with an average NRS score ≥3. Secondary outcomes include pain intensity, proportion of patients achieving pain reductions, analgesic consumption, Herpes Zoster Severity of Illness Index, 12‑item Short‑Form Health Survey, Medical Outcomes Study Sleep Scale, Neuropathic Pain Scale, and adverse events. Participants and treating physicians will be aware of the assigned treatment, whereas outcome assessors will remain blinded to group allocation. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (KY2025-369-02). The trial will be conducted in accordance with the Declaration of Helsinki, and written informed consent will be obtained from all participants prior to enrollment. The findings will be disseminated through publication in peer-reviewed journals and presentation at scientific conferences. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT07361796. Registered on January 2026 (https://clinicaltrials.gov/study/NCT07361796?term=NCT07361796).