Comparison of next-morning residual effects by bedtime administration of vornorexant and zopiclone in healthy older participants: postural stability, neuropsychological functions, and subjective sleepiness in a randomized clinical study

Rationale Vornorexant is a novel dual orexin receptor antagonist for insomnia treatment with the shortest half-life in its class. Objective This study aimed to compare the next-morning residual effects of vornorexant and zopiclone following bedtime administration in healthy older adults. Methods In this randomized, double-blind, placebo- and active-controlled, four-way crossover study, 16 healthy participants aged ≥65 years received single bedtime doses of vornorexant (5 and 10 mg), placebo, or zopiclone (positive control) administered during hospitalization. Pharmacodynamic endpoints were assessed 8 h after administration. Results The primary endpoint, area of body sway with eyes open (calculated using the root mean square of the center of pressure), was significantly smaller in the vornorexant 5 mg and 10 mg groups compared to zopiclone (p=0.001 and 0.003, respectively), but not significantly different from placebo (p=0.289 and 0.547, respectively). Similarly, significant impairments in word recall and psychomotor vigilance task performance were observed in the zopiclone group compared to the vornorexant groups, while no such effects were seen between the vornorexant and placebo groups. No significant difference was observed in the digit symbol substitution test between groups. Somnolence was observed in one, three, and two cases treated with vornorexant 5 mg, vornorexant 10 mg, and zopiclone, respectively. Conclusions Our findings indicated that vornorexant 5 mg and 10 mg did not exhibit next-morning residual effects at 8 h from bedtime administration. Clinical trial registration ClinicalTrial.gov ( https://clinicaltrials.gov/ ): NCT05819710, registered on April 6, 2023. jRCT ( https://jrct.mhlw.go.jp/ ): jRCT2071230009, registered on April 17, 2023