The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose escalating, open-label trial.

STUDY OBJECTIVES: The potential sedative effect of dronabinol and the high expression of cannabinoid receptors on the hypoglossal motor nuclei makes this agent a good candidate for obstructive sleep apnea (OSA) pharmacotherapy, to be tested with atomoxetine, a noradrenergic reuptake inhibitor that reduced OSA severity in combination with oxybutynin. Here we tested the effect of atomoxetine 80 mg plus dronabinol (Ato-Dro) at two different doses (5 and 10 mg) vs. baseline and atomoxetine alone in a two-center, open-label, dose-escalating trial. The primary outcome was the effect of Ato-Dro vs. baseline on OSA severity (apnea-hypopnea index, AHI4 ). Safety of the combination and subjective outcomes were also assessed.

METHODS: 15 OSA patients received progressively increasing Ato-Dro doses (dose escalation was performed every week, starting from Ato-Dro 40-2.5 mg, then 80-5 mg and finally 80-10 mg). A clinical, in-lab polysomnography was performed at baseline, on Ato-Dro 80-5 and Ato-Dro 80-10 mg.

RESULTS: Ato-Dro 80-10 mg did not significantly reduce AHI4 and hypoxic burden and yielded limited clinical benefit vs. baseline and atomoxetine alone. However, Ato-Dro 80-5 mg did improve OSA severity (ΔAHI=8.3[0.3, 16.3] events/h; mean[CI]; Δhypoxic burden=37.7[12.5, 62.7] %min/hr) and multiple subjective outcomes vs. baseline and/or atomoxetine alone. Ato-Dro administration was characterized by several potentially harmful side effects and treatment discontinuation in 1/3 of cases.

CONCLUSIONS: Ato-Dro 80-5 mg might be useful to reduce OSA severity and led to subjective improvement in those who could tolerate the combination. However, given the numerous side effects and the exploratory nature of this open-label study, our results warrant further validation in larger trials.

CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Identifier: NCT05101122; Title: Study for Efficacy and Dose Escalation of AD313 + Atomoxetine (SEED) (SEED); URL: https://clinicaltrials.gov/ct2/show/NCT05101122.