Effects of Ramelteon on the Prevention of Postoperative Delirium in Older Patients Undergoing Orthopedic Surgery: The RECOVER Randomized Controlled Trial

Objectives: Postoperative delirium, associated with negative consequences including longer hospital stays and worse cognitive and physical outcomes, is frequently accompanied by sleep-wake disturbance. Our objective was to evaluate the efficacy and short-term safety of ramelteon, a melatonin receptor agonist, for the prevention of postoperative delirium in older patients undergoing orthopedic surgery. Design: A quadruple-masked randomized placebo-controlled trial (Clinical Trials.gov NCT02324153) conducted from March 2017 to June 2019. Setting: Tertiary academic medical center. Participants: Patients aged 65 years or older, undergoing elective primary or revision hip or knee replacement. Intervention: Ramelteon (8 mg) or placebo Measurements: Eighty participants were randomized to an oral gel cap of ramelteon or placebo for 3 consecutive nights starting the night before surgery. Trained research staff conducted delirium assessments for 3 consecutive days starting on postoperative day (POD) 0, after recovery from anesthesia, and on to POD2. A delirium diagnosis was based upon DSM-5 criteria determined by expert panel consensus. Results: Of 80 participants, five withdrew consent (one placebo, four ramelteon) and four were excluded (four ramelteon) after randomization. Delirium incidence during the 2 days following surgery was 7% (5 of 71) with no difference between the ramelteon versus placebo: 9% (3 of 33) and 5% (2 of 38), respectively. The adjusted odds ratio for postoperative delirium as a function of assignment to the ramelteon treatment arm was 1.28 (95% confidence interval: 0.21–7.93; z-value 0.27; p-value = 0.79). Adverse events were similar between the two groups. Conclusion: In older patients undergoing elective primary or revision hip or knee replacement, ramelteon was not efficacious in preventing postoperative delirium.