Dose-response meta-analysis of dual orexin receptor antagonists on sleep parameters and implications for orexin-mediated arousal.
TL;DR
DORAs produce dose-related improvements in insomnia sleep-related outcomes, with most effects plateauing within therapeutic ranges, consistent with a pharmacodynamic ceiling whereby sufficient attenuation of orexin-mediated arousal is achieved within approved dose ranges, limiting the value of further dose escalation.
Abstract
Objective
The dose-response profiles of dual orexin receptor antagonists (DORAs) remain incompletely characterized, despite their wide usage in insomnia disorder. We aimed to define relationships between dose, sleep parameters and sleep-architecture outcomes for daridorexant, lemborexant, and suvorexant.
Methods
We searched PubMed, EMBASE, CENTRAL, and ClinicalTrials.gov until 06/14/2026, for randomized placebo-controlled trials of daridorexant, lemborexant, and suvorexant in adults with insomnia disorder. Placebo-adjusted mean differences at first post-baseline and repeated-use assessments were modelled using one-stage random-effects dose-response meta-analysis with natural splines. EMAX models were applied when spline models were implausible.
Results
Twenty-one studies were included in the analyses. All three DORAs showed dose-related improvements in sleep-continuity outcomes, including total sleep time, wake after sleep onset, sleep efficiency, and sleep-onset measures. Curves frequently showed saturating or plateau-like patterns within or near approved dose ranges, suggesting limited incremental benefit at supratherapeutic doses. Some effects were larger at first assessment and modestly attenuated after repeated use, although endpoint effects persisted. Lemborexant showed lower attenuation for selected sleep-continuity outcomes. Sleep-architecture analyses suggested broad preservation of physiological sleep organization, with modest drug-specific changes in N1, N2, slow-wave sleep (SWS), REM sleep, and REM latency.
Conclusion
DORAs produce dose-related improvements in insomnia sleep-related outcomes, with most effects plateauing within therapeutic ranges. This pattern is consistent with a pharmacodynamic ceiling whereby sufficient attenuation of orexin-mediated arousal is achieved within approved dose ranges, limiting the value of further dose escalation. These findings do not support supratherapeutic dosing and suggest that clinical response may be better judged after repeated administration.