Effects of Vornorexant, a Dual Orexin Receptor Antagonist, on Bladder Function in Rats and Nocturnal Voiding Frequency in Patients With Insomnia

OBJECTIVES: Nocturia has been reported to exacerbate sleep disturbances, such as insomnia and poor sleep quality, resulting in increased risks of falls, fractures, and mortality. These consequences significantly impact the physical health and overall prognosis of patients. Dual orexin receptor antagonists, prescribed for the treatment of insomnia, have been shown to reduce nocturnal voiding frequency. However, the mechanisms underlying this effect are not yet fully elucidated. METHODS: Intercontraction intervals and micturition pressure were measured using cystometry following intraduodenal administration of vornorexant to anesthetized rats. Subsequently, urine production was assessed following oral administration of vornorexant in a water-loaded rat model. To evaluate the effect of vornorexant on nocturnal voiding frequency in patients with comorbid insomnia and mild nocturia, a post hoc analysis was conducted using data from a prior clinical study in Japanese patients. Participants were stratified by baseline voiding frequency (0 vs. ≥ 1 voids/night), and nocturnal voiding frequency was summarized. RESULTS: In the anesthetized rats, vornorexant significantly prolonged intercontraction intervals without affecting micturition pressure. In the water-loaded rats, vornorexant did not significantly affect urine volume. In this exploratory post hoc analysis, bedtime vornorexant significantly but modestly reduced nocturnal voiding compared with placebo in patients with ≥ 1 voids/night at baseline. CONCLUSIONS: These findings suggest that vornorexant may improve nocturia in patients with comorbid insomnia and mild nocturia, potentially through the modulation of micturition control pathways. Future clinical studies could explore the potential of improving nocturia through modulation of the micturition control pathway, which may open new possibilities for targeted therapeutic interventions.