Dual Orexin Receptor Antagonists for Delirium: A Scoping Review and Feasibility Trial of Daridorexant

No medication is currently approved either for the prevention or treatment of delirium despite its tremendous clinical impact. Sleep-wake disturbances offer a promising target for delirium therapeutics, with a growing body of literature suggesting a potential role of dual orexin receptor antagonists (DORAs).

This report provides a scoping review of the literature on DORAs for delirium and the results of a feasibility trial of daridorexant to prevent delirium after heart surgery.

We conducted a scoping review according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) for Scoping Reviews guidelines for peer-reviewed reports of DORAs for delirium. Next, we report sample characteristics and results for the feasibility aims from our single-site, double-blind, randomized placebo-controlled feasibility trial of daridorexant 50 mg given the first three nights after heart surgery to prevent delirium.

Our scoping review includes 30 reports: 4 case reports/series, 1 clinical effectiveness project, 22 retrospective cohort studies, and 3 clinical trials. This literature is authored almost exclusively by teams from Japan. Most publications are on suvorexant. Although published data suggest a potential role for DORAs to prevent delirium, they remain inconclusive. We demonstrate the feasibility of our study (n = 11). In this preliminary trial, daridorexant-arm subjects had a numerically lower mean delirium symptom burden on postoperative days 1-3.

The evidence in support of DORAs for delirium calls for adequately powered efficacy trials. We also emphasize the importance of considering the pharmacokinetics of DORAs for delirium to maximize potential benefit and minimize the risk of next-morning sedation.