The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial

Abstract

Rationale: There is currently no effective pharmacological treatment for obstructive sleep apnea (OSA). Recent investigations indicate that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep. Objectives: We aimed to determine the effects of the combination of a norepinephrine reuptake inhibitor (atomoxetine) and an antimuscarinic (oxybutynin) on OSA severity (apnea-hypopnea index [AHI]; primary outcome) and genioglossus responsiveness (secondary outcome) in people with OSA. Methods: A total of 20 people completed a randomized, placebo-controlled, double-blind, crossover trial comparing 1 night of 80 mg atomoxetine plus 5 mg oxybutynin (ato-oxy) to placebo administered before sleep. The AHI and genioglossus muscle responsiveness to negative esophageal pressure swings were measured via in-laboratory polysomnography. In a subgroup of nine patients, the AHI was also measured when the drugs were administered separately. Measurements and Main Results: The participants' median (interquartile range) age was 53 (46-58) years and body mass index was 34.8 (30.0-40.2) kg/m2. ato-oxy lowered AHI by 63% (34-86%), from 28.5 (10.9-51.6) events/h to 7.5 (2.4-18.6) events/h (P < 0.001). Of the 15/20 patients with OSA on placebo (AHI > 10 events/hr), AHI was lowered by 74% (62-88%) (P < 0.001) and all 15 patients exhibited a ≥50% reduction. Genioglossus responsiveness increased approximately threefold, from 2.2 (1.1-4.7)%/cm H2O on placebo to 6.3 (3.0 to 18.3)%/cm H2O on ato-oxy (P < 0.001). Neither atomoxetine nor oxybutynin reduced the AHI when administered separately. Conclusions: A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on 1 night greatly reduced OSA severity. These findings open new possibilities for the pharmacologic treatment of OSA. Clinical trial registered with www.clinicaltrials.gov (NCT02908529).

Keywords: antimuscarinic; norepinephrine reuptake inhibitors; pharmacologic treatment; upper airway.

Figures

Figure 1.

Consolidated Standards of Reporting Trials diagram of the clinical trial.

Figure 2.

Individual data showing the effect of atomoxetine plus oxybutynin (ato–oxy) on (A) apnea–hypopnea index (AHI) and (B) nadir SaO2. Longer horizontal lines indicate median values, and shorter lines indicate 25th and 75th percentiles. A total of 19/20 subjects had a reduction in obstructive sleep apnea severity. Gray lines indicate patients with an AHI less than 10 on placebo night.

Figure 3.

(A–C) Relationship between apnea–hypopnea index (AHI) reduction and arousal index reduction (A), sleep efficiency increase (B), and sleep quality improvement (C) on atomoxetine plus oxybutynin (ato–oxy) compared with placebo. (D–F) The improvements in arousal index (D), sleep efficiency (E), and subjective sleep quality (F) from placebo to ato–oxy night were all related to the severity of obstructive sleep apnea on placebo night, so that the patients with the highest AHI on placebo had the best improvement in sleep parameters and, on the contrary, those with mild or no obstructive sleep apnea had less or no improvement in objective and subjective sleep quality. TIB = time in bed; VAS = visual analog scale.

Figure 4.

(A) Group data showing the effect of atomoxetine plus oxybutynin (ato–oxy) on genioglossus muscle responsiveness. Muscle responsiveness reflects the change in genioglossus muscle electromyographic activity (% of baseline) per change in esophageal pressure (Pes) swings during spontaneous breathing in non-REM sleep (see example in B for physiological context). Note that the median responsiveness on ato–oxy (slope of solid line) is greater than the responsiveness on placebo (slope of dashed line). Shaded areas represent interquartile range of the slopes. Horizontal error bars illustrate interquartile range of baseline Pes; baseline values (genioglossus electromyographic activity [EMGGG] = 100%) are offset vertically to facilitate visualization of error bars. (B) Example raw data are shown to provide context. Signals illustrate a spontaneous increase in genioglossus muscle activity with increasing Pes swings during sleep. Note the restoration of airflow (Flow) accompanying increasing muscle activity. mta = moving time average.

Figure 5.

Group data showing apnea–hypopnea index (AHI) on placebo, atomoxetine plus oxybutynin (ato–oxy), oxybutynin alone, and atomoxetine alone in nine patients. White lines indicate medians; boxes indicate 25th (bottom) and 75th (top) percentiles. *P = 0.01 versus placebo.