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

Introduction 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. Methods 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. Results 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. Conclusions Viloxazine-trazodone reduced OSA severity. Potential deleterious effects of viloxazine on sleep quality appeared partly attenuated by trazodone. Trial registration number NCT05793684.