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, placebocontrolled, 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/m 2. 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 H 2 O on placebo to 6.3 (3.0 to 18.3)%/cm H 2 O 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).

Sleep Pharmacotherapy for Common Sleep Disorders in Pregnancy and Lactation

“…115 Nonetheless, a recently completed trial investigating the impact of atomoxetine, a norepinephrine reuptake inhibitor, and oxybutynin, an antimuscarinic drug, on OSA showed dramatic improvements in the apnea-hypopnea index. 116 The relevance of the currently investigated drugs in the pregnant population is unclear because upper airway function, ventilatory control, and arousal physiology may all be different in this population due to the effect of significantly elevated levels of sex hormones 4 and other pregnancy-specific factors. Hence, there is a need to better understand pregnancy-specific physiology of upper airway and ventilatory control prior to attempting the use of pharmacotherapy in this population.…”

Contemporary Concise Review 2019: Sleep and ventilation

“…Further data are clearly required to assess hard outcomes before widespread use of wake‐promoting pharmacotherapy can be strongly advocated. In addition, there are no studies to date comparing the different wake‐promoting agents in sleepy OSA patients.Regarding therapeutic pharmacotherapy for OSA, a recent study showed potential benefits of the combination of atomoxetine, a selective norepinephrine reuptake inhibitor, plus oxybutynin, an anti‐muscarinic, for the treatment of OSA . Based on the premise that norepinephrine drive is central to pharyngeal muscle tone and muscarinic activity to rapid eye movement (REM) sleep‐related pharyngeal tone, the combination of atomoxetine and oxybutynin was hypothesized to cause an increase in genioglossus activity and reduce OSA severity.…”

The Role of Animal Models in Developing Pharmacotherapy for Obstructive Sleep Apnea

“…Taken together with the data from Horner's lab in sleeping rats, the study provides credible evidence that noradrenergic drugs may be useful in OSA. These experiments laid the foundation for a recent human clinical trial utilizing a combination of the noradrenergic agonist, atomoxitine, and a muscarinic blocker, oxybutinine [77]. Nevertheless, both classes of drugs have significant systemic adverse effects on cardiovascular, gastrointestinal, and urogenital systems, limiting their clinical use.…”