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Am J Respir Crit Care Med. 2019 May 15;199(10):1267-1276. doi: 10.1164/rccm.201808-1493OC.

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

Author information

1
1 Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham & Women's Hospital & Harvard Medical School, Boston, Massachusetts.
2
2 Respiratory Medicine and Sleep Laboratory, Department of Internal Medicine, Spedali Civili di Brescia, University of Brescia, Brescia, Italy.
3
3 Sleep Laboratory, Pulmonary Division, Heart Institute (InCor), Hospital das Clinicas, Facultade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.
4
4 Sleep and Circadian Medicine Laboratory, Department of Physiology, and.
5
5 School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Victoria, Australia; and.
6
6 Neuroscience Research Australia and the University of New South Wales, Randwick, New South Wales, Australia.

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

PMID:
30395486
PMCID:
PMC6519859
[Available on 2020-05-15]
DOI:
10.1164/rccm.201808-1493OC

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