Dronabinol, a synthetic form of the cannabis compound tetrahydrocannabinol (THC), shows efficacy in the treatment of obstructive sleep apnea (OSA), possibly representing a first pharmacologic approach to the tough-to-treat but potentially serious condition.
“These findings support the therapeutic potential of cannabinoids in patients with obstructive sleep apnea,” the authors, led by Phyllis Zee, MD, the Benjamin and Virginia T. Boshes Professor of Neurology at Northwestern University Feinberg School of Medicine and director of the Northwestern Medicine Sleep Disorders Center, Chicago, Illinois, write.
“In comparison to placebo, dronabinol was associated with lower apnea/hypopnea index (AHI), improved subjective sleepiness and greater overall treatment satisfaction,” they add.
The study was published online in Sleep.
Promising Findings
With no approved pharmacotherapies available for sleep apnea, the current first-line treatment is use of a continuous positive airway pressure (CPAP) device to keep the airways open during sleep. Although effective, the device can be cumbersome to wear to bed, and long-term adherence is low.
Dronabinol, a synthetic formulation of the molecule delta-9 THC and a nonselective cannabinoid type 1 and type 2 receptor agonist, was first approved in 1985 by the US Food and Drug Administration (FDA) for the treatment of nausea and vomiting associated with chemotherapy. It is also indicated for appetite stimulation in AIDS-related wasting syndrome.
In previous animal studies and a small pilot study in 17 humans, the current study investigators found that dronabinol also showed some signs of reducing spontaneous sleep apneas.
To expand on that research, the researchers conducted a multisite, phase 2 study, Pharmacotherapy of Apnea by Cannabimimetic Enhancement (PACE), which included 73 adult patients with moderate or severe sleep apnea.
Participants were randomly assigned to treatment with 2.5 mg of dronabinol (n = 21), 10 mg dronabinol (n = 27), or placebo (n = 25), 1 hour before bedtime, for up to 6 weeks.
Patients had a mean baseline body mass index (BMI) of 33.4 kg/m2 and a mean age of 53.6 years. The mean overall baseline AHI was 25.9 and the mean Epworth Sleepiness Scale (ESS) score was 11.5.
The primary endpoint was change from baseline in AHI after 6 weeks of treatment. After adjustment for a variety of factors, including age, race, ethnicity, and baseline AHI, the investigators found significant improvements in the 2.5-mg group, with a reduction of 10.5 events per hour (P = .02), and the 10-mg group, with a reduction of 12.9 events per hour (P = .004), in rapid eye movement (REM) as well as non-REM sleep.
No significant changes were seen in the placebo group, and differences in improvement between the 2.5- and 10-mg groups were not statistically significant.
The 10-mg group also showed a significant reduction in the secondary primary endpoint of subjective daytime sleepiness, assessed by the ESS, with a reduction of 3.8 points from baseline (P < .0001), and a reduction of 2.3 points compared with placebo (P = .05). The reduction in the ESS score in the 2.5-mg and placebo groups from baseline was not statistically significant.
Patients receiving 10-mg also expressed that highest overall satisfaction with their treatment, as assessed on the Treatment Satisfaction Questionnaire for Medication (P = .04).
There were no changes in objective measures of the maintenance of wakefulness test (MWT), including sleep latencies, gross sleep architecture, and overnight oxygenation measures, in any of the groups.
No Psychoactive Effects Observed
During the study, 7 patients discontinued because of adverse events, and an additional 10 elected to discontinue for other reasons. However, there were no significant differences in dropout rates by study group, BMI, baseline AHI, or other factors. In addition, rates of adverse events were similar between those who did and did not complete the study. Men were more likely to discontinue than women (P = .07).
Whereas most patients (88%) experienced one or more adverse events during the study, most events were mild; there were no significant differences between the groups in terms of the number or severity of events.
There was one serious adverse event of diarrhea and vomiting that required admission to hospital for hydration and monitoring. The patient was released after 24 hours and went on to complete the study; the adverse event was determined to be possibly related to the study medication.
Treatment adherence did not significantly differ among the study groups, with nearly two thirds of patients taking all scheduled doses.
With dronabinol’s indication for appetite stimulation in HIV-infected patients, weight gain was a concern, but weight change did not differ among groups. The fact that improvement was seen in non-REM as well as REM sleep was a notable finding, the authors note.
“Most patients with obstructive sleep apnea experience a significant number of disordered breathing events during both non-REM and REM sleep, [therefore], for any therapeutic intervention to be generally effective, it should be able to control disordered breathing throughout all stages of sleep,” the authors write.
“Here, we observed significant dronabinol-related decreases of disordered breathing events during both non-REM and REM sleep.”
THC is the principal component of cannabis linked to the psychotropic effects associated with its use. However, no such psychoactive effects were observed in the study, senior author Dr Zee told Medscape Medical News. “In our study, the treatment did not seem to have this effect,” she said.
Potential Mechanism
The mechanisms of dronabinol that are speculated to play a role in treatment of obstructive sleep apnea include signals to regions of the brain involved in respiratory regulation.
“Based on a series of animal investigations, we proposed that drugs which dampen afferent vagal feedback to the medulla may be effective in stabilizing respiratory pattern generation and increasing activation of upper airway dilating muscles during sleep,” the authors write.
Dr Zee added that larger studies will be necessary to shed more light on dronabinol’s specific clinical applications in sleep apnea.
“Due to the phase 2 study, it would be premature to comment on how the compound will be used in clinical settings. Larger studies that can be generalized to the obstructive sleep apnea population are needed. It could conceivably be used in patients who fail CPAP, [and] other approved therapies, such as oral appliances or as adjunctive therapy,” she said.
While the current study focuses on dronabinol, the University of Illinois at Chicago is in an intellectual property licensing agreement with the pharmaceutical company RespireRx that also covers other cannabinoid drugs for the treatment of sleep-related breathing disorders, according to the study’s co-lead author David W. Carley, PhD, the Katherine M. Minnich Endowed Professor Emeritus of Biobehavioral Health Sciences, Medicine and Bioengineering at the University of Illinois at Chicago.
“For example, other formulations may target specific cannabinoid receptors or selectively target receptors in the peripheral versus central nervous system,” Dr Carley told Medscape Medical News.
Dr Carley holds patents on some of the drugs for sleep apnea indications.
He noted that the next steps in terms of dronabinol will likely be to determine parameters necessary from the FDA on possibly moving ahead with a pivotal phase 3 trial.
“Broadly speaking, we need more tools in the apnea treatment toolbox,” he said.
“No current treatment is sufficient for all patients. There are at least one million individuals in the US with diagnosed obstructive sleep apnea who have refused, failed or abandoned all available treatments, [and for this] reason, new drug treatments would have a great clinical impact.”
Potentially Beneficial Drug
While agreeing that further research is needed, sleep specialist James A. Rowley, MD, said the study is important in shedding light on a potentially beneficial therapy.
“There really is no pharmacological therapy for obstructive sleep apnea,” Dr Rowley, who is interim chief of the Division of Pulmonary, Critical Care & Sleep Medicine and medical director of the Detroit Receiving Hospital Sleep Disorders Center at Wayne State University, Detroit, Michigan, told Medscape Medical News.
“Most studies that have looked at various agents, often serotonergic agents, have been small studies that do not show any significant improvements in the severity of obstructive sleep apnea, as measured by the AHI.”
“Hence, this study marks an advancement in the pharmacologic therapy of obstructive sleep apnea. However, it is only a phase 2 study, so will need replication in a larger, phase 3 study, before dronabinol can be considered for obstructive sleep apnea therapy.”
While improvement seen in the endpoint of the AHI with dronabinol is not as significant as is reported with CPAP, the improvement in sleepiness observed in the study is more impressive, Dr Rowley said.
“The change in AHI is less than what would be expected with CPAP, which generally gets the AHI to less than 5 events per hour, and the number of responders would also be less than with CPAP. However, the change in Epworth score is similar to many studies of CPAP,” he added.
Dr Rowley noted that the lack of improvement seen in the objective MWT measures with dronabinol was not necessarily surprising.
“It does not concern me that there was no significant change in the MWT as other studies of CPAP using the MWT have also been negative,” he said.
Dronabinol’s role as a synthetic form of THC, on the other hand, is more of a concern, he said.
“Until we have a phase 3 study, it would concern me that the drug is a synthetic THC. [We] clearly would need to find out more about its side effects [and] whether it affects driving ability, et cetera.”
Dr Rowley added that a likely reason for the lack of research on pharmacologic approaches for sleep apnea is that a multitude of brain centers and neurotransmitters are involved in the control of breathing and control of upper airway muscles.
“Thus, finding a single pharmacologic agent can be difficult. Also, most patients present for diagnosis of obstructive sleep apnea after years of actually having it; hence, it is unclear if there have been long-term changes in brain neurochemistry that are not easily fixed by one medication,” he said.
The research was supported by a grant from the National Institutes of Health. University of Illinois at Chicago has licensed intellectual property related to dronabinol to the pharmaceutical company RespireRx. Dr Carley is the inventor of intellectual property assigned to the University of Illinois at Chicago, including US patent 7,705,039; US patent 8,207; US patent application 20130281523; and US patent application 20120231083. He holds shares of common stock in RespireRx Pharmaceuticals. He has not been paid by, nor does he advise, RespireRx Pharmaceuticals. Dr Zee and Dr Rowley have disclosed no relevant financial relationships.
Sleep. Published online November 7, 2017. Abstract
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