Reboxetine Reduces Respiratory Events, Improves Obstructive Sleep Apnea Severity

Thomas Altree, MBBS, FRACP

Findings from a small-scale study of patients with obstructive sleep apnea (OSA) showed that treatment with single doses of 4 mg reboxetine, a selective noradrenaline reuptake inhibitor (NaRI), modestly reduces the frequency of respiratory events and improves overnight oxygenation and snoring. The addition of oxybutynin, a medication typically used to treat overreactive bladder, had mild sedative effects but did not produce additive benefit in reducing OSA severity on a single night despite modest improvements in pharyngeal muscle compensation.

Led by Thomas Altree, MBBS, FRACP, respiratory and sleep medicine physician, Breath SA, this study showed for the first time that reboxetine reduces OSA severity, and provided new insight on the importance of noradrenergic mechanisms in OSA. In total, 16 individuals with OSA between 18 and 65 years old completed 3 visits where they received oral reboxetine alone (4 mg) or reboxetine (4 mg) with oxybutynin (5 mg) or placebo immediately before bedtime. Bedtime was kept constant between study visits and participants were given an 8-hour sleep opportunity on each occasion.

The predefined primary end point was the apnea-hypopnea index (AHI) using 3% desaturation criteria (AHI3). On average, the 16 participants who completed all 3 nights were middle-aged, overweight to obese, had subclinical insomnia, did not have significant daytime sleepiness, and had moderate to severe OSA. Throughout the study, there were no observed serious adverse events (AEs), and all AEs observed from either reboxetine or oxybutynin were expected and had no impact on sleep efficiency.

At the conclusion of the analysis, reboxetine alone reduced the AHI3 by 5.4 events/h (95% CI, –10.4 to –0.3; P = .03) in comparison with placebo, whereas the combination of reboxetine and oxybutynin was not significantly different (4.2 events/h; 95% CI, –9.6 to 1.1; P = .11). There was an overall treatment effect for AHI using the 4% desaturation criteria (AHI4)(ANOVA, P = .002), with reductions observed in both reboxetine alone and combination groups relative to placebo.

Compared with placebo, the reboxetine group alone and combination group demonstrated nadir oxygen saturation increased of 7% (±11) and 5% (±9), respectively. Both groups reduced 4% oxygen desaturation index (ANOVA, P = .049), reduced hypoxic burden (ANOVA, P = .049), and improved the 3% ODI and snoring index relative to placebo.

On sleep parameters, there were no between-group differences in percent of sleep time spent supine, sleep efficiency, wake after sleep onset, arousal index, non-REM AHI, supine AHI, and obstructive apnea index. The treatment arms showed reduced in the proportion of REM sleep and increased stage N2 sleep, with no changes in stages N1 or N3 sleep vs placebo. Morning heart rate was increased in both the reboxetine and reboxetine plus oxybutynin groups; however, there were no changes in morning systolic or diastolic blood pressure, and no participants experienced palpitations during the study.

Reboxetine alone and in combination with oxybutynin improved pharyngeal collapsibility at the lowest decile of respiratory drive compared to placebo (V̇ passive_min: median, 7.7% [IQR 4.4 to 10.7] and 6.4% [IQR 2.7 to 6.4] respectively, both P<0.001). Both treatment groups also showed reductions in loop gain and the ventilatory response to arousal in comparison with placebo. Upper airway muscle compensation was increased in the reboxetine plus oxybutynin group, but not reboxetine alone.

"The reasons for reduced perceived sleep quality with the drug conditions versus placebo in the current single night study are likely driven by the excitatory noradrenergic properties of reboxetine as reflected by a shift towards lighter stages of sleep and potentially its mild side effects,” Altree et al wrote. "While any reductions in perceived sleep quality are not favorable, the magnitude was mild. Indeed, overall objective sleep efficiency, next day perceived sleepiness and driving simulator performance were not different between conditions."

REFERENCES
1. Altree TJ, Aishah A, Loffler KA, Grunstein RR, Eckert DJ. The norepinephrine reuptake inhibitor reboxetine along reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial. J Clin Sleep Med. Published online January 1, 2023. doi:10.5664/jcsm.10256