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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).

SUBMITTER: Taranto-Montemurro L

PROVIDER: S-EPMC6519859 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe recent discovery that a combination of noradrenergic and antimuscarinic drugs improved upper airway muscle function during sleep and reduced OSA severity has revitalized interest in pharmacologic therapies for OSA.Research questionWould 1 week of reboxetine plus oxybutynin (Reb-Oxy) be effective on OSA severity?Study design and methodsA randomized, placebo-controlled, double-blind, crossover trial was performed comparing 4 mg reboxetine plus 5 mg oxybutynin (Reb-Oxy) vs placebo in patients with OSA. After a baseline in-laboratory polysomnogram (PSG), patients underwent PSGs after 7 nights of Reb-Oxy and 7 nights of placebo to compare apnea-hypopnea index (AHI), which was the primary outcome. Response rate was based on the percentage of subjects with a ≥ 50% reduction in AHI from baseline. Secondary outcomes included Epworth Sleepiness Scale (ESS) score and psychomotor vigilance test (PVT) values. Home oximetry evaluated overnight oxygen desaturation index (ODI) throughout treatment.ResultsSixteen subjects aged 57 [51-61] years (median [interquartile range]) with a BMI of 30 [26-36] kg/m2 completed the study. Reb-Oxy lowered AHI from 49 [35-57] events per hour at baseline to 18 [13-21] events per hour (59% median reduction) compared with 39 [29-48] events per hour (6% median reduction) with placebo (P < .001). Response rate for Reb-Oxy was 81% vs 13% for placebo (P < .001). Although ESS scores were not significantly lowered, PVT median reaction time decreased from 250 [239-312] ms at baseline to 223 [172-244] ms on Reb-Oxy vs 264 [217-284] ms on placebo (P < .001). Home oximetry illustrated acute and sustained improvement in the oxygen desaturation index on Reb-Oxy vs placebo.InterpretationThe administration of Reb-Oxy greatly decreased OSA severity and increased vigilance. These results highlight potential possibilities for pharmacologic treatment of OSA.Clinical trial registrationClinicalTrials.gov; No.: NCT04449133; URL: www.clinicaltrials.gov.

Project description:Introduction: Obstructive sleep apnea (OSA) is a serious condition linked with various metabolic disorders and associated with increased all-cause and cardiovascular mortality. Although the potential mechanisms of pathophysiological processes related to OSA are relatively well known, the data regarding the correlation between obstructive sleep apnea, dyslipidemia, and systemic inflammation are still inconclusive. Methods: The study was conducted as a retrospective cohort study including 328 patients with newly diagnosed obstructive sleep apnea during the period between April 2018, and May 2020, in University Clinical Hospital Center "Bezanijska kosa", Belgrade, Serbia. Polysomnography was performed in all patients according to the protocol. Numerous demographic, antropometric, laboratory, and clinical data were correlated to Apnea-Hypopnea Index (AHI) as a dependent variable, with a particular review on the relation between lipid abnormalities, inflammatory parameters, and obstructive sleep apnea severity. Multivariate logistic regression model was used to assess predictors of severe OSA (AHI ≥30 per hour). Results: A total of 328 patients were included in the study. The mean age of the patients was 54.0 ± 12.5 years and more than two-thirds were male (68.8%). The majority of the patients had an AHI of at least 30 events per hour. Patients with severe OSA were more frequently male, obese, hypertensive and hyperlipidemic, and had increased neck circumference (both male and female patients). One hundred and thirty-two patients had metabolic syndrome. Patients with severe OSA more frequently had metabolic syndrome and significantly higher levels of glucose, creatinine, uric acid, AST, ALT, CK, microalbumine/creatinine ratio, triglyceride, total cholesterol, HDL, total cholеsterol to HDL-C ratio, CRP, and ESR. In the multivariate linear regression model with AHI (≥30 per hour) as a dependent variable, of demographic and clinical data, triglycerides ≥1.7 mmol/L and CRP >5 mg/L were significantly associated with AHI≥30 per hour. Conclusion: The present study on 328 patients with newly diagnosed obstructive sleep apnea revealed significant relation of lipid abnormalities, inflammatory markers, and other clinically important data with obstructive sleep apnea severity. These results can lead to a better understanding of the underlying pathophysiological processes and open the door to a new world of potentially useful therapeutic modalities.

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

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