Drug therapy for obstructive sleep apnoea in adults

Background
Obstructive sleep apnoea (OSA) is caused by collapse of the upper airway. The mainstay of medical treatment is continuous positive airways pressure (CPAP), delivered through a mask during sleep, aiming to keep the airway opened. Drug therapy has been proposed for individuals with mild OSA and those intolerant of CPAP.

Review question
We wanted to look at the evidence from randomised controlled trials which compared drug therapy with placebo for sleep apnoea.

What we did
We searched and reviewed all randomised placebo controlled trials of drugs to treat OSA in adult patients. Most of the trials had methodological flaws or were for only one or two nights, which is hardly long enough to find out whether the treatments are effective or acceptable to the people taking them.

Results
Of 25 drugs tested, 10 had some impact on the severity of OSA (as measured by the apnoea hypopnoea index or AHI) and four altered symptoms of sleepiness, although in most people changes were only modest.

Eszopiclone, acetazolamide, naltrexone, physiostigmine and nasal lubricant (phosphocholinamine) were trialled for one to two nights only and the long-term effects are therefore unknown. A topical nasal steroid was well tolerated and reduced the severity of sleep apnoea and improved subjective daytime alertness in a specific subgroup of people with both OSA and rhinitis. Acetazolamide reduced the number of respiratory events per hour of sleep but did not reduce daytime sleepiness and was poorly tolerated long term. Paroxetine had only a small effect on the severity of OSA and while it was tolerated there was no useful effect on daytime symptoms. In contrast, participants reported a symptomatic benefit from protriptyline but there was no improvement in OSA, suggesting a different mechanism for their improved sense of well-being. The antidepressant mirtazapine improved the severity of sleep apnoea in older trials, however two more recent, larger trials failed to demonstrated the same results; moreover, participants experienced side effects of sleepiness and weight gain. Donepezil, well established in the treatment of Alzheimer's disease, improved oxygen saturation and the severity of OSA in patients with and without dementia. In people with no dementia it was shown to reduce sleepiness but the study was small and neither the AHI nor ESS were normalised. Further trials are needed to confirm these results. Eszopliclone reduced the severity of OSA in selected patients nonetheless larger scale trials are needed to verify the results.

Bottom line
Some of the drugs may be helpful, however their tolerability needs to be considered in long-term trials.

Authors' conclusions: 

There is insufficient evidence to recommend the use of drug therapy in the treatment of OSA. Small studies have reported positive effects of certain agents on short-term outcomes. Certain agents have been shown to reduce the AHI in largely unselected populations with OSA by between 24% and 45%. For donepezil and fluticasone, studies of longer duration with a larger population and better matching of groups are required to establish whether the change in AHI and impact on daytime symptoms are reproducible. Individual patients had more complete responses to particular drugs. It is possible that better matching of drugs to patients according to the dominant mechanism of their OSA will lead to better results and this also needs further study.

Read the full abstract...
Background: 

The treatment of choice for moderate to severe obstructive sleep apnoea (OSA) is continuous positive airways pressure (CPAP) applied via a mask during sleep. However, this is not tolerated by all individuals and its role in mild OSA is not proven. Drug therapy has been proposed as an alternative to CPAP in some patients with mild to moderate sleep apnoea and could be of value in patients intolerant of CPAP. A number of mechanisms have been proposed by which drugs could reduce the severity of OSA. These include an increase in tone in the upper airway dilator muscles, an increase in ventilatory drive, a reduction in the proportion of rapid eye movement (REM) sleep, an increase in cholinergic tone during sleep, an increase in arousal threshold, a reduction in airway resistance and a reduction in surface tension in the upper airway.

Objectives: 

To determine the efficacy of drug therapies in the specific treatment of sleep apnoea.

Search strategy: 

We searched the Cochrane Airways Group Specialised Register of trials. Searches were current as of July 2012.

Selection criteria: 

Randomised, placebo controlled trials involving adult patients with confirmed OSA. We excluded trials if continuous positive airways pressure, mandibular devices or oxygen therapy were used. We excluded studies investigating treatment of associated conditions such as excessive sleepiness, hypertension, gastro-oesophageal reflux disease and obesity.

Data collection and analysis: 

We used standard methodological procedures recommended by The Cochrane Collaboration.

Main results: 

Thirty trials of 25 drugs, involving 516 participants, contributed data to the review. Drugs had several different proposed modes of action and the results were grouped accordingly in the review. Each of the studies stated that the participants had OSA but diagnostic criteria were not always explicit and it was possible that some patients with central apnoeas may have been recruited.

Acetazolamide, eszopiclone, naltrexone, nasal lubricant (phosphocholinamine) and physiostigmine were administered for one to two nights only. Donepezil in patients with and without Alzheimer's disease, fluticasone in patients with allergic rhinitis, combinations of ondansetrone and fluoxetine and paroxetine were trials of one to three months duration, however most of the studies were small and had methodological limitations. The overall quality of the available evidence was low.

The primary outcomes for the systematic review were the apnoea hypopnoea index (AHI) and the level of sleepiness associated with OSA, estimated by the Epworth Sleepiness Scale (ESS). AHI was reported in 25 studies and of these 10 showed statistically significant reductions in AHI.

Fluticasone in patients with allergic rhinitis was well tolerated and reduced the severity of sleep apnoea compared with placebo (AHI 23.3 versus 30.3; P < 0.05) and improved subjective daytime alertness. Excessive sleepiness was reported to be altered in four studies, however the only clinically and statistically significant change in ESS of -2.9 (SD 2.9; P = 0.04) along with a small but statistically significant reduction in AHI of -9.4 (SD 17.2; P = 0.03) was seen in patients without Alzheimer's disease receiving donepezil for one month. In 23 patients with mild to moderate Alzheimer's disease donepezil led to a significant reduction in AHI (donepezil 20 (SD 15) to 9.9 (SD 11.5) versus placebo 23.2 (SD 26.4) to 22.9 (SD 28.8); P = 0.035) after three months of treatment but no reduction in sleepiness was reported. High dose combined treatment with ondansetron 24 mg and fluoxetine 10 mg showed a 40.5% decrease in AHI from the baseline at treatment day 28. Paroxetine was shown to reduce AHI compared to placebo (-6.10 events/hour; 95% CI -11.00 to -1.20) but failed to improve daytime symptoms.

Promising results from the preliminary mirtazapine study failed to be reproduced in the two more recent multicentre trials and, moreover, the use of mirtazapine was associated with significant weight gain and sleepiness. Few data were presented on the long-term tolerability of any of the compounds used.

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