Melatonin for preventing postoperative delirium in elderly patients: A multicenter randomized placebo-controlled pilot study

BACKGROUND: Postoperative delirium (POD) in older adults is associated with high risk of morbidity and mortality. With limited treatment options, prevention is essential. Melatonin has been suggested to prevent delirium through regulating the sleep-wake cycle and serotonin metabolism, which has been shown to be disrupted in patients with POD. However, the evidence regarding the use of melatonin for POD prevention is limited and inconclusive. METHODS: Our multicenter, 2-arm, parallel-group, feasibility randomized controlled trial evaluated the effect of melatonin on POD incidence after noncardiac surgery in patients >65 years (n = 120). Patients were randomized to 3 mg oral melatonin or placebo once preoperatively and for 7 days postoperatively. Patients were assessed twice daily for delirium and followed at 3 months postoperatively. Feasibility outcomes were recruitment rate, medication adherence, and proportion completing 3-month follow-up. Clinical outcomes were delirium incidence, sleep quality, institutional discharge, and cognitive status at 3 months. RESULTS: Between September 2021 and June 2023, 85 patients were randomized (~1 patient/wk); of these, 92.9% adhered to study medications and 87.1% completed the 3-month follow-up. POD occurred in 9 patients with no statistical difference between the groups (melatonin group, n = 7; placebo group, n = 2; adjusted odds ratio: 1.12; 95% confidence interval: 0.006-150.1). There were no differences in any other clinical outcomes. Pandemic-related challenges, including interruption of surgeries and restrictions on research procedures impacted feasibility and the study was terminated early due to futility. CONCLUSIONS: Based on our observations, a sample size of >1000 patients is required for a definitive trial to evaluate the role of melatonin in reducing the incidence of POD. Design changes need to be considered to address feasibility challenges and ongoing post-pandemic modifications to patient care.