The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial

Study Objectives: Recent findings indicate that noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. However, to date, reductions in obstructive sleep apnea (OSA) severity have only been detected when noradrenergic agents are combined with an antimuscarinic. Accordingly, this study aimed to determine if reboxetine alone and combined with oxybutynin reduces OSA severity. The pathophysiological mechanisms underpinning the effects of these agents were also investigated via endotyping analysis.Methods: Sixteen people (6 women) with OSA completed 3 polysomnograms (-1-week washout) according to a double-blind, placebo-controlled, three-way crossover design across 2 sites. Single doses of 4 mg reboxetine, placebo, or 4 mg reboxetine + 5 mg oxybutynin were administered before sleep (order randomized).Results: Reboxetine reduced the apnea-hypopnea index (primary outcome) by 5.4 (95% confidence interval -10.4 to -0.3) events/h, P = .03 (-24 & PLUSMN; 27% in men; -0.7 & PLUSMN; 32% in women). Oxybutynin did not cause additional reductions in apnea-hypopnea index. Reboxetine alone reduced the 4% oxygen desaturation index by (mean & PLUSMN; standard deviation) 5.2 & PLUSMN; 7.2 events/h and reboxetine+oxybutynin by 5.1 & PLUSMN; 10.6 events/h vs placebo, P = .02. Nadir oxygen saturation also increased by 7 & PLUSMN; 11% with reboxetine and 5 & PLUSMN; 9% with reboxetine+oxybutynin vs placebo, P = .01. Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control (loop gain). Larger reductions in apnea-hypopnea index with reboxetine in men were associated with higher baseline loop gain.Conclusions: These findings show the first evidence that reboxetine alone reduces OSA severity. The data provide novel insight into the role of norepinephrine reuptake inhibitors on upper airway stability during sleep and are important to inform future pharmacotherapy development for OSA.Clinical Trial Registration: Registry: Australian New Zealand Clinical Trials Registry; Name: Reboxetine and Combination Therapy with AD128 in Sleep Apnoea Trial: A Double-Blind, 3-Way Cross-Over Study; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374614 & isReview=true; Identifier: ACTRN12620000662965.