Effect of viloxazine and trazodone in obstructive sleep apnoea: a randomised, placebo-controlled, cross-over study

Combination of the noradrenergic atomoxetine with either the antimuscarinic aroxybutynin or trazodone has been shown to improve obstructive sleep apnoea (OSA) severity. However, atomoxetine may contribute to apnoea-cycling and reduced drug tolerability due to wake-promoting, especially in a subgroup (poor cytochrome 2D6 metabolisers leading to higher blood concentration of medication). We investigated the effect of a potentially more manageable noradrenergic, viloxazine, with and without trazodone, on OSA severity.

In this double-blind, placebo-controlled, cross-over study, 24 patients with OSA (18-75 years) were analysed and randomised to 500 mg viloxazine, 500/75 mg viloxazine-trazodone (vilo-trazo) or placebo; taken before bed for 2 weeks with 1-week washout between treatments. In-laboratory polysomnography was performed at the end of each cross-over period. Mixed-model analyses compared the effect of vilo-trazo versus placebo on AHI₄ (apnoea-hypopnoea index with 4% desaturations; primary outcome) and hypoxic burden (secondary outcome). Additional outcomes examined the effects of vilo-trazo versus viloxazine on total sleep time (TST) and wake-after-sleep-onset (WASO). Safety endpoints (patient-reported outcomes, heart rate and adverse events) were also assessed.

Vilo-trazo reduced AHI₄ (mean difference (95% CI): 10.5 (6.6, 13.6) events/hour, p<0.001) and hypoxic burden (16.7 (9.6, 21.8) %min/hr, p<0.001) versus placebo. Compared with viloxazine, TST tended to be longer on vilo-trazo (22.3 (-1.4, 46.0) min, p<0.065), while WASO was unchanged. TST and WASO remained significantly reduced on vilo-trazo versus placebo. Both interventions worsened patient-reported outcomes, although to a lesser extent on vilo-trazo, and increased heart rate versus placebo. Commonly reported adverse events were insomnia, constipation, headache and xerostomia.

Viloxazine-trazodone reduced OSA severity. Potential deleterious effects of viloxazine on sleep quality appeared partly attenuated by trazodone.

NCT05793684.