Reboxetine Plus Oxybutynin for OSA Treatment: A 1-Week, Randomized, Placebo-Controlled, Double-Blind Crossover Trial

Abstract

Background: The 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 question: Would 1 week of reboxetine plus oxybutynin (Reb-Oxy) be effective on OSA severity?

Study design and methods: A 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.

Results: Sixteen 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.

Interpretation: The administration of Reb-Oxy greatly decreased OSA severity and increased vigilance. These results highlight potential possibilities for pharmacologic treatment of OSA.

Clinical trial registration: ClinicalTrials.gov; No.: NCT04449133; URL: www.clinicaltrials.gov.

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

Graphical abstract

Figure 1

Consolidated Standards of Reporting Trials diagram of the clinical trial. PSG = polysomnogram; Reb-Oxy = reboxetine plus oxybutynin.

Figure 2

Individual data showing the effect of Reb-Oxy on total AHI (A) and during NREM (B) or REM (C) sleep stages. Longer horizontal lines indicate median values, and shorter lines indicate 25th and 75th percentiles. D, Group data showing percentage of AHI changes from baseline on placebo and on Reb-Oxy. AHI = apnea-hypopnea index; NREM = non-rapid eye movement; Reb-Oxy = reboxetine plus oxybutynin; REM = rapid eye movement.

Figure 3

A-C, Effect of Reb-Oxy on desaturation index. A, Hypoxic burden as individual data. Longer horizontal lines indicate median values, and shorter lines indicate 25th and 75th percentiles. B, Group data showing percentage of hypoxic burden changes from baseline on placebo and on Reb-Oxy. C, Analysis of repeated measures of ODI 4% obtained during at-home pulse oximetry during placebo (red squares) and during Reb-Oxy (blue dots) weeks. Data were compared by using a mixed effect model including treatment, time, and time × treatment interaction as fixed effects and subjects as a random effect. Only treatment effect was significantly associated with ODI 4% (dependent variable). P values for day-by-day multiple comparisons between placebo and Reb-Oxy arms are adjusted by using the Šidák method. AHI = apnea-hypopnea index; NREM = non-rapid eye movement; ODI = oxygen desaturation index; Reb-Oxy = reboxetine plus oxybutynin.

Figure 4

Effect of Reb-Oxy on PVT reaction time. Longer horizontal lines indicate median values, and shorter lines indicate 25th and 75th percentiles. PVT = psychomotor vigilance test; Reb-Oxy = reboxetine plus oxybutynin.