Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway

Abstract

Study objectives: Pharmacotherapy for obstructive sleep apnea (OSA) regained consideration after the discovery that atomoxetine and oxybutynin greatly reduced OSA severity. However, atomoxetine and oxybutynin reduced the arousal threshold and may therefore be poorly tolerated in patients with OSA and disturbed sleep. As a result, we tested the combination of atomoxetine plus 2 hypnotics in patients with OSA. The effects of atomoxetine plus: (1) trazodone (Ato-Trazo) and (2) lemborexant vs placebo on apnea-hypopnea index, hypoxic burden, arousal threshold, and total sleep time were assessed. Drug safety was also ascertained, together with the effect of the combinations on other OSA traits, self-reported sleep quality, and next-day alertness.

Methods: Following a baseline study, 15 patients with mild-to-severe OSA with moderate upper airway collapsibility were administered Ato-Trazo, atomoxetine and lemborexant, and matching placebo according to a double-blind, randomized, crossover design. Apnea-hypopnea index and other objective outcomes were calculated from 3 clinical, in-laboratory polysomnograms.

Results: Ato-Trazo significantly reduced apnea-hypopnea index from a median [interquartile range] of 18.2 [11.8 to 31.3] on placebo to 7.4 [5.4 to 16.1] events/h, P = .024, and hypoxic burden from 46.3 [25.1 to 88.3] on placebo to 18.7 [14.9 to 43.5], P = .003. This effect was likely driven by an increase in polysomnography-estimated pharyngeal muscle activity during the events (P = .029). Atomoxetine and lemborexant had smaller statistically insignificant effects. Contrary to atomoxetine and oxybutynin, Ato-Trazo and atomoxetine and lemborexant did not reduce the arousal threshold. Both combinations had no effect on total sleep time but worsened self-reported sleep quality.

Conclusions: Ato-Trazo has the potential to become a useful drug combination, however, longer trials are needed to determine the best dosage and the subgroup of patients who may benefit most from this combination.

Clinical trial registration: Registry: ClinicalTrials.gov; Name: Crossover Trial of AD182 and AD504 in Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT04645524; Identifier: NCT04645524.

Citation: Corser B, Eves E, Warren-McCormick J, Rucosky G. Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. J Clin Sleep Med. 2023;19(6):1035-1042.

Keywords: arousal threshold; atomoxetine; hypoxic burden; obstructive sleep apnea; pharmacotherapy; pharyngeal airway; sleep apnea endotype; trazodone.