A Month of Nightly Atomoxetine-Oxybutynin Treatment for OSA Is Safe, Effective

Various dose combinations of atomoxetine and oxybutynin (ato-oxy) administered nightly before sleep for 1 month are safe and relatively well-tolerated in patients with obstructive sleep apnea (OSA), with high dose ato-oxy showing greatest efficacy for OSA, according to study findings published in the Annals of the American Thoracic Society.

The efficacy and tolerability of ato-oxy among patients with OSA for more than a single night has not previously been assessed, according to the study authors. They therefore sought to determine the safety, tolerability, and potential efficacy of different doses of nightly ato-oxy for 1 month in patients with OSA.

Participants with OSA were recruited from 2 sites in Australia and were randomly assigned into 1 of these dosing groups: (1) 80/5-mg ato-oxy; (2) 40/5-mg ato-oxy; (3) 40/2.5-mg ato-oxy; or (4) placebo. The patients were instructed to take the medication for 30 nights before sleep and underwent in-laboratory polysomnography (PSG) studies at baseline, night 1, and night 30.

Primary safety endpoints included prostate function based on the International Prostate Symptom Score in men and blood pressure. Next-morning sleepiness, alertness, and memory following each PSG visit were evaluated with use of questionnaires, memory/reaction, and driving simulator tasks. Among the efficacy measures, sleep staging, cortical arousals, and respiratory events were assessed, and apnea-hypopnea index 3% and 4% oxygen desaturations (AHI₃ and AHI₄) were quantified.

A total of 39 participants (mean [SD] age, 51 [11] years; 29 male) were included in the study; the 80/5-mg ato-oxy, 40/2.5-mg ato-oxy, and placebo groups each had 10 patients, and the 40/5-mg ato-oxy group had 9 patients.

Dry mouth was the most common side effect of medication and increased dose dependently with oxybutynin in the drug treatment groups (reported by 78% of participants in the 80/5-mg and 40/5-mg ato-oxy groups, 20% in the 40/2.5-mg ato-oxy group, and 10% in the placebo group).

Evening blood pressure was not different among the ato-oxy treatment groups vs the placebo group, although by night 30 a non-dose-dependent increase was observed in heart rate from mean baseline of 8 [10] beats/min in the 80/5-mg ato-oxy group and 9 [14] beats/min in the 40/2.5-mg ato-oxy group. Heart rate during sleep was higher in all 3 drug arms compared with the placebo group on night 30.

No differences were found for evening memory task accuracy among the treatment groups for the 2-N-back working memory task assessment and the digit substitution test (DSST). Participants’ reaction time was faster by about 100 milliseconds at night 30 vs night 1 for the 40/2.5-mg ato-oxy group compared with placebo during the DSST. No changes occurred in subjective evening or morning alertness or in the effect of sleepiness on daily activities across treatment groups.

AHI₄ at night 1 decreased in the 80/5-mg ato-oxy dose group vs placebo (change from baseline: -12 [7] vs 3 [8] events/hour, P <.01) and by night 30 (-8 [16] vs 1 [5] events/hour, P =.09). Compared with placebo, hypoxic burden decreased on night 1 (-45 [37] vs 7 [43] %min/hour, P <.01) but not on night 30 (-24 [57] vs -3 [15] %min/hour, P =.16).

No significant differences occurred in AHI₃ from baseline to night 1 (-7 [6] vs -1 [12] events/hour, P =.18) or night 30 (-10 [13] vs 1 [11], P =.27) compared with placebo. The obstructive apnea index score was reduced overall (-7 [7] vs 1 [4], P =.01) and during non-REM sleep (-6 [5] vs 1 [4], P =.02).

Among noted limitations, plasma concentration of the combined agents was not quantified. In addition, no adjustments were made to differentiate between potential poor drug metabolizers and interaction effects with other medications that could affect drug bioavailability and elimination. Also, the study had a relatively small sample size for each dose, and the placebo group was overall healthier compared with the drug combination groups.

“Overall, 1 month of various dose combinations of nightly atomoxetine and oxybutynin are safe and generally well tolerated in people with OSA,” stated the researchers, adding that “hypoxic burden decreased by ~50% with 80/5mg ato-oxy from baseline.” Accordingly, researchers noted that “The high-dose 80/5mg ato-oxy combination appears to be the most promising combination to further investigate for OSA pharmacotherapy.”

Disclosure: This study was supported by a research grant from Apnimed. One of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.