The Combination of Betahistine and Oxybutynin Increases Respiratory Control Sensitivity (Loop Gain) in People with Obstructive Sleep Apnea: A Randomized, Placebo-Controlled Trial

Abstract

Rationale: There are widespread histaminergic projections throughout the brain, including hypoglossal nuclei, that modulate pharyngeal muscle tone and respiratory control. Hence, histaminergic stimulation pharmacologically may increase pharyngeal muscle tone and stabilize respiratory control (loop gain) to reduce obstructive sleep apnea (OSA) severity. Antimuscarinics also increase REM pharyngeal muscle tone in rats. Thus, a combination of histaminergic and anti-muscarinic drugs may be a novel target for OSA pharmacotherapy. However, this has not been investigated. Accordingly, we aimed to test the effects of betahistine (Beta), an H3-autoreceptor antagonist which thereby increases histamine levels, in combination with the antimuscarinic oxybutynin (Oxy), on OSA severity, OSA endotypes, polysomnography parameters and next-day sleepiness and alertness. Methods: Thirteen adults with OSA received either Beta-Oxy (96–5mg) or placebo according to a randomized, crossover, double-blind design, prior to polysomnography. Participants completed the Karolinska Sleep Scale and Leeds Sleep Evaluation Questionnaire and a driving simulation task to quantify next-day sleepiness and alertness. OSA endotypes were estimated through validated algorithms using polysomnography. Results: Compared to placebo, Beta-Oxy increased respiratory control sensitivity (loop gain) (0.52[0.24] vs 0.60[0.34], median [IQR], P = 0.021) without systematically changing OSA severity (34.4±17.2 vs 40.3±27.3 events/h, mean±SD, P = 0.124), sleep efficiency, arousal index or markers of hypoxemia. Beta-Oxy was well tolerated and did not worsen next-day sleepiness/alertness. Conclusion: Rather than stabilize breathing during sleep, Beta-Oxy increases loop gain, which is likely to be deleterious for most people with OSA. However, in certain conditions characterized by blunted respiratory control (eg, obesity hypoventilation syndrome), interventions to increase loop gain may be beneficial.