The combination of the noradrenergic agent reboxetine plus the anti-muscarinic hyoscine butylbromide reduces OSA severity, according to Australian researchers.
Their preliminary study, published in the Journal of Physiology, provides the promise of a pharmacological approach to OSA – an alternative for patients struggling with adherence to CPAP.
They investigated the repurposing of the drugs in 12 patients with OSA who had in-laboratory, single-night sleep studies before and after either the dual drug therapy or placebo.
Compared to placebo, reboxetine and hyoscine butylbromide reduced the apnoea/hypopnea index (AHI) by 17 events per hour and non-REM AHI by 14 events per hour (P<0.01).
“Both hypopnoea (p=0.03) and apnoea (p<0.01) indices reduced with reboxetine plus hyoscine butylbromide versus placebo,” the study said.
The reduction in AHI was accompanied by an increase in nadir oxygen saturation.
The study found 11 of 12 patients had improvements in OSA severity (AHI and nadir oxygen desaturation) during the drug combination night compared to placebo.
REM sleep reduced with treatment and N2 sleep increased.
“Mechanistically, improvements in breathing and upper airway collapsibility during sleep with reboxetine plus hyoscine butylbromide were driven by increases in the responsiveness of the tonic component of the genioglossus muscle during airway narrowing and stabilisation of respiratory control (i.e. reductions in loop gain and the ventilatory response to arousal),” the investigators said.
“These novel findings further highlight the importance of noradrenergic and muscarinic mechanisms on upper airway control during sleep and the therapeutic potential to target these processes pharmacologically in people with OSA.”
However they noted the drug combination may be most appropriate in those with less severe OSA and pharyngeal collapsibility.
“Pharmacotherapy alone may be less likely to yield major reductions in OSA severity in people with highly collapsible upper airways/impaired pharyngeal anatomy which is a common feature of severe OSA compared to those with less anatomically impaired pharyngeal airways in whom non-anatomical endotypes predominate (e.g. poor muscle responsiveness).”
The findings are consistent with other research showing the combination of atomoxetine and oxybutynin also reduced OSA severity.
CPAP not suitable for all
Senior investigator Professor Danny Eckert, director of the Adelaide Institute for Sleep Health at Flinders University, told the limbic that CPAP therapy helps millions of people with sleep apnoea around the world.
“But half or more of people prescribed CPAP either can’t tolerate it or for various reasons stop using it. Over a million Australians have got this condition so that leaves many people unable to use the main therapy.”
“There are second line therapies like dental splints or mandibular advancement devices and they work well for many patients but it’s a toss of the coin as to whether or not they are going to work, you have to see the dentist, and they are $2,000.”
Professor Eckert said there was a desperate need for some additional treatments, and at the moment there were no drugs to treat sleep apnoea.
“The promising thing is we have now seen this class of medications; at last we are on the right track but these are very early days in the progression of this.”
He said reboxetine was the agent which reduces the REM sleep.
“What that means long term we don’t know but important things happen in REM sleep like memory consolidation and some forms of learning. That being said, sleep apnoea is worse in REM sleep,” he said.
“Ideally in 5-10 years we will have something available, particularly if it is repurposing existing drugs with known safety profiles that makes it a little easier.”
“It’s an encouraging sign and gives us all a bit of hope that we are on the right path. In this study we looked at mechanisms and it reaffirms targeting two of the main causes of sleep apnoea…it all fits.”