O001 Reboxetine reduces obstructive sleep apnea severity: a randomized trial

Abstract

Abstract Introduction Noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. Selective norepinephrine reuptake inhibitors (SNRIs) such as reboxetine combined with an antimuscarinic reduce obstructive sleep apnea (OSA) severity. The effects of reboxetine alone on OSA severity are unknown. Methods Double-blind, placebo-controlled, three-way crossover trial in 16 people with OSA. Each participant completed three overnight polysomnograms (~1-week washout). Single doses of reboxetine 4mg, placebo, or reboxetine+oxybutynin 5mg were administered before sleep (randomized order). The primary outcome was apnea-hypopnea index (AHI). Secondary outcomes included other polysomnography parameters, next day sleepiness and alertness. Endotyping analysis was performed to determine the medications’ effects on OSA pathophysiological mechanisms. Results Reboxetine reduced the AHI by 5.4 [95% CI -10.4 to -0.3] events/h, P=0.03 (men: -24±27%; women: -0.7±32%). The addition of oxybutynin did not further reduce AHI. Reboxetine alone and reboxetine+oxybutynin reduced overnight hypoxemia versus placebo (e.g. 4% oxygen desaturation index 10.4±12.8 vs. 10.6±12.8 vs. 15.7±14.7 events/h, P=0.02). Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control stability. Men had higher baseline loop gain. Larger reductions in AHI with reboxetine occurred in those with high loop gain. Neither drug intervention changed next day sleepiness or alertness. Discussion A single 4mg dose of reboxetine modestly reduces OSA severity without further improvement with the addition of an antimuscarinic. Reboxetine increases breathing stability via improvements in pharyngeal collapsibility and respiratory control. These findings provide new insight into the role of SNRIs on upper airway stability during sleep and have important implications for pharmacotherapy development for OSA.