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

With this study we demonstrated that the combination of atomoxetine and trazodone reduces the key indexes of OSA severity, namely AHI₄ and HB, and preserves total sleep time. The reduction in AHI₄ on Ato-Trazo may be driven by an increased pharyngeal muscle compensatory activity. Of note, patients on Ato-Lembo did not exhibit any change in OSA severity compared to the placebo night. This study confirms that the combination of a norepinephrine re-uptake inhibitor, atomoxetine, and a serotonergic sedative, trazodone, could be an important approach to OSA treatment, particularly for patients with OSA with disturbed sleep, although this specific phenotype was not studied in this protocol. 

Ato-Trazo increased the estimated muscle compensation vs placebo by approximately 25% of Veupnea his is an important mechanism by which the upper airway can reopen during an event and favor stable breathing and sleep continuity. Ato-Oxy was previously shown to increase genioglossus activity, and it is likely that atomoxetine was responsible for most of the upper airway muscle dilating activity of that combination. The effect of atomoxetine in Ato-Trazo and Ato-Oxy might be similar, which would explain the increase in pharyngeal muscle compensation seen in this study. However, trazodone likely has an important role as well. Indeed, Ato-Oxy and atomoxetine alone reduced arousal threshold, which by contrast was unchanged vs placebo after Ato-Trazo administration. The positive effect of trazodone on arousal threshold in patients with OSA is well known and might have offset atom-oxetine’s awaking properties. With a longer time before arousal, pharyngeal muscles can be more successfully recruited and restore normal airflow after an event^. This mechanism also likely explains why trazodone increased muscle upper airway activity in animal model and improved OSA severity in previous human trials. This synergistic effect was not observed when lemborexant was used as the hypnotic. Reasons for this are unclear. However, several factors could be at play. Orexin receptor antagonists are a relatively new drug class (lemborexant was approved by the US Food and Drug Administration at the end of 201 and their effect on upper airway muscle is still unclear. That being said, orexin projections to the hypoglossal motor nucleus have been describe although their influence on genioglossal muscle activity was not investigated. Additionally, suvorexant, another orexin receptor agonist, was reported to increase the AHI over multiple days of treatment although the mechanism is unclear. Thus, the absence of an effect of lemborexant on OSA severity might then be linked to some myorelaxant properties, although this certainly needs further investigation.

 

https://jcsm.aasm.org/doi/full/10.5664/jcsm.10464