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

Study objectives: Pharmacotherapy for obstructive sleep apnea (OSA) regained consideration after the discovery that atomoxetine and oxybutynin (Ato-Oxy) greatly reduced OSA severity. However, Ato-Oxy 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 two hypnotics in patients with OSA. The effects of atomoxetine plus: 1) trazodone (Ato-Trazo), and 2) lemborexant (Ato-Lembo) versus placebo on AHI, hypoxic burden (HB), arousal threshold and total sleep time (TST) were assessed. Drug safety was also ascertained, together with the effect of the combinations on other OSA traits, subjective sleep quality, and next-day alertness.

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

Results: Ato-Trazo significantly reduced AHI from a median [IQR] of 18.2 [11.8 to 31.3] on placebo to 7.4 [5.4 to 16.1] events/h, p=0.024 and HB from 46.3 [25.1 to 88.3] on placebo to 18.7 [14.9 to 43.5], p=0.003. This effect was likely driven by an increase in polysomnography-estimated pharyngeal muscle activity during the events (P=0.029). Ato-Lembo had smaller statistically insignificant effects. Contrary to Ato-Oxy, Ato-Trazo and Ato-Lembo did not reduce the arousal threshold. Both combinations had no effect on TST, but worsened subjective 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.

Comments：

In this study, the combination of atomoxetine plus trazodone (Ato-Trazo) was found to significantly reduce obstructive sleep apnea (OSA) severity, as measured by the apnea-hypopnea index (AHI) and hypoxic burden (HB), without reducing the arousal threshold. In contrast, the combination of atomoxetine plus lemborexant (Ato-Lembo) had smaller and statistically insignificant effects. Both combinations had no effect on total sleep time (TST) but worsened subjective sleep quality. The increase in pharyngeal muscle activity during events may be responsible for the Ato-Trazo effect. The safety of both combinations was established, and longer trials are needed to determine the best dosage and the subgroup of patients who may benefit most from this combination.

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