Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: a randomized trial

Ludovico Messineo, Sophie G. Carter, Luigi Taranto-Montemurro, Alan Chiang, Andrew Vakulin, Robert J. Adams, Jayne C. Carberry, Danny J. Eckert

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Background and objective: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). Methods: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. Results: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (−26.6 ± 14.5 vs. −33.8 ± 20.3 cm H2O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. Conclusion: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

Original languageEnglish
Pages (from-to)878-886
Number of pages9
Issue number9
Publication statusPublished or Issued - 23 Jun 2021


  • Ato-Oxy
  • anti-muscarinic
  • noradrenergic
  • obstructive sleep apnoea
  • pharmacotherapy
  • respiratory arousal threshold
  • sleep quality
  • zolpidem

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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