Summary: Reboxetine, a selective norepinephrine reuptake inhibitor normally prescribed for depression, can reduce sleep apnea symptom severity.
Source: Flinders University
Targeting a condition suffered by nearly a billion people worldwide, a new study from Flinders University has shown a drug previously used to treat depression can reduce obstructive sleep apnoea (OSA) severity.
While not yet identifying a cure, the authors say the study opens up further avenues for the development of future drug treatments targeted at the huge number of people unable to tolerate current sleep apnoea therapies, such as continuous positive airway pressure (CPAP) machines.
“Obstructive sleep apnoea can be a debilitating disease, causing poor quality sleep at night and sleepiness during the day,” says study lead author Dr Thomas Altree from FHRMI: Sleep Health (formerly the Adelaide Institute for Sleep Health).
“It affects millions of Australians and causes major impacts on health and productivity.
“Recent research found a combination of the medicines reboxetine and oxybutynin, which were both previously used for unrelated conditions, could be an effective treatment for obstructive sleep apnoea but can cause side effects.
“We wanted to see if reboxetine on its own could be effective and assess exactly how it changes breathing during sleep.”
The team ran a double blind, placebo controlled, randomised, multicentre cross-over trial with collaborators at the Woolcock Institute in Sydney (following a gold standard for drug trials) with 16 people who had OSA. They tested single doses of reboxetine compared to a combination of reboxetine and oxybutynin or placebo.
“Our results showed that reboxetine on its own can reduce sleep apnoea severity,” says Dr Altree.
“We found the drug reduced the number of sleep apnoea events per hour and also improved oxygen levels, while the addition of oxybutynin didn’t cause additional improvements.
“We also used a state-of-the-art computing method to determine how the drug stabilises breathing during sleep, which allows us to identify which patients might benefit most from the drug in the future.”
The team’s findings present the first evidence that reboxetine alone reduces OSA severity, and provides further insight into the role of norepinephrine reuptake inhibitors on upper airway stability during sleep.
“The current gold-standard treatment of sleep apnoea is with a CPAP device during sleep. But this one-size-fits-all approach doesn’t address the fact that there are different causes for sleep apnoea. In addition, many people can’t tolerate CPAP in the long term,” says Dr Altree.
“It’s therefore important we discover other avenues to assist people, and this study provides an important step for future drug development.”
Funding: The study was supported by an investigator-initiated research grant from Apnimed.
The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnoea severity: a double blind, placebo controlled, randomized, cross-over trial
Recent findings indicate that noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. However, to date, reductions in obstructive sleep apnea (OSA) severity have only been detected when noradrenergic agents are combined with an antimuscarinic. Accordingly, this study aimed to determine if reboxetine alone and combined with oxybutynin reduces OSA severity. The pathophysiological mechanisms underpinning the effects of these agents were also investigated via endotyping analysis.
16 people (6 women) with OSA completed three polysomnograms (∼1-week washout) according to a double-blind, placebo-controlled, three-way crossover design across two sites. Single doses of 4 mg reboxetine, placebo, or 4 mg reboxetine+5 mg oxybutynin were administered before sleep (order randomized).
Reboxetine reduced the apnea-hypopnea index (AHI-primary outcome) by 5.4 [95% CI -10.4 to -0.3] events/h, P=0.03 (-24 ± 27% in men; -0.7 ± 32% in women). Oxybutynin did not cause additional reductions in AHI. Reboxetine alone reduced the 4% oxygen desaturation index by (mean ± SD) 5.2 ± 7.2 events/h and reboxetine+oxybutynin by 5.1 ± 10.6 events/h versus placebo, P=0.02. Nadir oxygen saturation also increased by 7 ± 11% with reboxetine and 5 ± 9% with reboxetine+oxybutynin versus placebo, P=0.01. Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control (loop gain). Larger reductions in AHI with reboxetine in men were associated with higher baseline loop gain.
These findings show the first evidence that reboxetine alone reduces OSA severity. The data provide novel insight into the role of norepinephrine reuptake inhibitors on upper airway stability during sleep and are important to inform future pharmacotherapy development for OSA.