A synthetic cannabis-like drug in a pill was safe and effective in treating obstructive sleep apnoea in the first large multi-site study of a drug for apnoea funded by the National Institutes of Health. The study was conducted at Northwestern Medicine and the University of Illinois at Chicago (UIC).
There is currently no drug treatment for sleep apnoea, a sleep breathing disorder affecting about 30m individuals in the US. In sleep apnoea, breathing is interrupted, and these pauses can last from a few seconds to minutes and may occur 30 times or more an hour. Untreated apnoea raises the risk of heart disease, diabetes, sleepiness, cognitive impairment and a motor vehicle accident. Participants in the trial had reduced apnoea and decreased subjective sleepiness.
The common treatment for sleep apnoea is a CPAP (Continuous Positive Airway Pressure) device that delivers air (acting like an air splint) to prevent collapse of the airway and breathing pauses. But adherence to the device can be challenging for many patients, some who simply stop using it.
“There is a tremendous need for effective, new treatments in obstructive sleep apnoea,” said co-lead study author Dr David W Carley, the Katherine M Minnich endowed professor emeritus of bio-behavioural health sciences, medicine and bio-engineering at UIC.
Researchers investigated the effect of dronabinol, a synthetic version of the molecule Delta-9 THC (tetrahydrocannabinol), which is in cannabis, on sleep apnoea in a Phase 2 trial. The trial was the largest and longest randomized, controlled trial to test a drug treatment for sleep apnoea.
Dronabinol was approved by the US Food and Drug Administration more than 25 years ago to treat nausea and vomiting in chemotherapy patients.
The drug treatment was a new approach in that it targeted the brain rather than the physical problem of collapsing airways. This reflects the new belief that sleep apnoea is not just a physical problem but may be caused by multiple factors. One of those is poor regulation of the upper airway muscles by the brain, said co-lead author Dr Phyllis Zee. Zee is the Benjamin and Virginia T Boshes professor of neurology at Northwestern University Feinberg School of Medicine and director of the Northwestern Medicine Sleep Disorders Centre.
“The CPAP device targets the physical problem but not the cause,” Zee said. “The drug targets the brain and nerves that regulate the upper airway muscles. It alters the neurotransmitters from the brain that communicate with the muscles. Better understanding of this will help us develop more effective and personalized treatments for sleep apnoea.”
While CPAP is highly effective, some patients simply refuse to use the machine. Even people who want to use it often only stick with it for about four hours a night, on average, Carley said.
“So the best they can get is a roughly 50% improvement in their apnoea,” Carley said. “When people take a pill to treat apnoea, they are treated for the entire night.”
In the study, 73 adult patients with moderate or severe sleep apnoea were divided into three groups. One group was given a low dose of the drug, a second group received a higher dose and the third, a placebo. Participants took the drug once daily before bed for six weeks.
Six weeks of treatment by the highest dose of dronabinol (10 milligrams) was associated with a lower frequency of apnoeas or hypopneas (overly shallow breathing) during sleep, decreased subjective sleepiness and greater overall treatment satisfaction compared to the placebo group. The severity of their disorder was reduced by 33% compared to complete compliance with the mechanical treatment, although complete compliance for the night is rare.
Can a person simply ingest or smoke marijuana and get the same benefits for sleep apnoea? No, said Zee. “Different types of cannabis have different ingredients,” she noted. “The active ingredient may not be exactly the same as what’s indicated for sleep apnoea.”
“Cannabis contains dozens of active ingredients, but we tested just purified delta-9 THC,” added Carley.
Larger scale clinical trials are needed to clarify the best approach to cannabinoid therapy in obstructive sleep apnoea, the authors said.
UIC has licensed intellectual property related to the experimental drug treatment used in the study to the pharmaceutical company RespireRx.
Researchers have attempted to identify drugs to treat sleep apnoea for nearly 35 years, but to no avail, Carley said. Carley developed the idea that dronabinol might be useful in treating sleep apnoea more than 15 years ago. He and colleagues tested the concept in an animal model of apnoea, publishing their findings in 2002 and launched a subsequent pilot study in humans in 2007. Those encouraging findings from the small-scale pilot study formed the basis for this multi-centre clinical trial led by Carley and Zee.
“By providing a path toward the first viable obstructive sleep apnoea drug, our studies could have a major impact on clinical practice,” he said.
Study Objectives: There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study. Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully-blinded parallel groups, placebo-controlled randomized trial of dronabinol in patients with moderate or severe OSA.
Methods: By random assignment, 73 adults with moderate or severe OSA received either placebo (N=25), 2.5mg dronabinol (N=21) or 10mg dronabinol (N=27) daily, one hour before bedtime for up to 6 weeks.
Results: At baseline, overall apnea/hypopnea index (AHI) was 25.9±11.3, Epworth Sleepiness Scale score (ESS) was 11.45±3.8, maintenance of wakefulness test (MWT) mean latency was 19.2±11.8 min, body mass index (BMI) was 33.4±5.4 kg/m2 and age was 53.6±9.0 years. The number and severity of adverse events, and treatment adherence (0.3±0.6 missed doses/week) were equivalent among all treatment groups. Subjects receiving 10mg/day of dronabinol expressed the highest overall satisfaction with treatment (p=0.04). In comparison to placebo, dronabinol dose-dependently reduced AHI by 10.7±4.4 (p=0.02) and 12.9±4.3 (p=0.003) events/hour at doses of 2.5 and 10 mg/day, respectively. Dronabinol at 10 mg/day reduced ESS score by -3.8±0.8 points from baseline (p<0.0001) and by -2.3±1.2 points in comparison to placebo (p=0.05). MWT sleep latencies, gross sleep architecture and overnight oxygenation parameters were unchanged from baseline in any treatment group.
Conclusions: These findings support the therapeutic potential of cannabinoids in patients with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved subjective sleepiness and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA.
David W Carley, Bharati Prasad, Kathryn J Reid, Roneil Malkani, Hryar Attarian, Sabra M Abbott, Boris Vern, Hui Xie, Chengbo Yuan, Phyllis Zee