The effect of Dual Orexin Receptor Antagonists on sleep: a systematic review and pairwise meta-analysis

Evidence supporting pharmacological treatment of insomnia remains limited. Dual orexin receptor antagonists (DORAs), a novel drug class, show therapeutic promise. This systematic review and meta-analysis evaluates DORAs' efficacy, safety, and tolerability across all eligible populations, regardless of diagnosis. We systematically searched MEDLINE, Embase, PsycINFO, Cochrane CENTRAL, WHO ICTRP, ClinicalTrials.gov through January 2026 for randomised controlled trials comparing DORAs with placebo. We included studies across all patient populations. Analyses employed random-effects models, calculating risk ratios (RR) for dichotomous outcomes, weighted mean differences (MD) for continuous outcomes, and standardised mean differences (SMD) when scales varied. Primary outcomes included subjective total sleep time, sleep quality, treatment-emergent somnolence and insomnia. Subgroup and sensitivity analyses explored heterogeneity and result robustness. 77 trials (16,416 participants) were included. DORAs improved subjective total sleep time (MD = 18.91 min , 95 % CI: 15.87 to 21.95). Sleep quality was not improved (SMD = 0.19, 95 % CI: 0.02 to 0.39). DORAs increased the risk of somnolence (RR = 2.91, 95 % CI: 2.31 to 3.67), while no difference was found for insomnia (RR = 0.97, 95 % CI: 0.60 to 1.57). Effects were consistent across treatment durations. DORAs appear largely efficacious, safe and tolerable. Clinical interpretation should be done with caution, in conditions other than insomnia, as data for these diagnoses were scarce.