en Anesthesiology Review Background: Melatonin has attracted interest as a perioperative adjunct because of its potential antinociceptive, anxiolytic, sleep-regulating, and anti-inflammatory effects. Acute analgesia and prevention of persistent postsurgical pain represent distinct therapeutic objectives.<br> <br> Objective: To critically examine the mechanisms and clinical evidence supporting perioperative melatonin, emphasizing the distinction between early symptom relief and durable prevention.<br> <br> Methods: A focused narrative synthesis was conducted using targeted retrieval of PubMed records, accessible publisher reports, and relevant reference lists. Experimental investigations, selected randomized clinical trials, and systematic reviews were examined. Evidence was organized by mechanism, surgical setting, regimen, and follow-up duration. No new meta-analysis or formal certainty assessment was performed.<br> <br> Results: Experimental evidence supports biological plausibility, while clinical findings vary across procedures. Evidence syntheses suggest possible early pain reduction, but heterogeneity, methodological limitations, and uncertain opioid-sparing effects restrict confidence. A 2022 randomized lumbar disc surgery trial reported lower postoperative pain after preoperative oral melatonin, without establishing a clear dose-response relationship or long-term prevention. Neutral clinical studies and recovery-related trade-offs qualify favorable findings. Limited longer-term observations do not establish a reproducible preventive effect on clinically defined persistent postsurgical pain.<br> <br> Conclusion: Melatonin remains a candidate adjunct for acute postoperative analgesia. The evidence evaluated does not support routine administration specifically to prevent persistent postsurgical pain. Procedure-specific trials should assess pain, rescue analgesia, function, and safety, with prespecified follow-up beyond three months for preventive claims. Melatonin, Postoperative pain, Chronic postsurgical pain, Analgesia, Sleep, Randomized controlled trial 45 53 http://tbsrj.mazums.ac.ir/browse.php?a_code=A-10-3644-1&slc_lang=en&sid=1 Mehdi Hojjati Msp556291@gmail.com 100319475328460032174 100319475328460032174 No Department of Burn Surgery, Faculty of Medicine, University of Mazandaran, Sari, Iran. Samira Sobhani ssobhani@mazums.ac.ir 100319475328460032175 100319475328460032175 Yes Department of Anesthesiology, Faculty of Medicine, University of Mazandaran, Sari, Iran.