Finally… A Sleep Apnea Pill

By Alex Dimitriu MD

Finding an effective pharmacologic approach to alleviating obstructive sleep apnea (OSA) could revolutionize treatment of this complex, underdiagnosed, and life-threatening sleep disorder. Results of a study – the MARIPOSA trial — published in the October 2023 issue of the American Journal of Respiratory and Critical Care Medicine indicate a combination of two medications, oxybutynin, and atomoxetine, has been shown “clinically meaningful” in improving OSA.

The double-blind investigation involved more than 200 patients, including 176 who actually completed the four-week protocol. The drugs reportedly act together to increase what one physician describes as “the activity of the dilator muscles in the upper airways.” They do so by “activating the genioglossus muscle [a muscle of the tongue] with a synergic effect on the upper respiratory tract during sleep.”

Study authors report patients receiving the drug combination experienced significantly less sleep disturbance due to disruptions in their breathing and a higher quality of sleep. But neither medication taken alone proved effective and, in some cases, slightly worsened a person’s sleep disturbance score or lowered sleep quality, the scientists state. With CPAP compliance rates at about 50%, any alternative to improving airflow during sleep is a welcome addition to the field.

But No Pill Yet for the Problem

No FDA-approved pharmaceutical treatment option currently exists for treatment of OSA, an issue that continues to spur ongoing drug investigations. The MARIPOSA trial is only the latest of a series of OSA-related pharmacologic studies published during the past several years. Some scientists have likened the hunt for an effective OSA drug to a “search for the Holy Grail.”

One report — in a 2022 issue of the Journal of Clinical Sleep Medicine — suggests reboxetine, a drug formerly used to treat depression, shows positive action in reducing the severity of OSA. The National Sleep Foundation indicates that, in July 2023, the FDA approved further testing of an investigational sleep apnea drug, IHL-42X, in phase II and phase III patient trials. Advanced by Icannex Healthcare, IHL-42X contains dronabinol and acetazolamide. Dronabinol is a synthetic cannabinoid with effects similar to compounds in the marijuana plant. Preliminary research shows IHL-42X can cut sleep apnea patients’ episodes of disruptive breathing by more than half, according to the Sleep Foundation.

Also being tested for potential efficacy in decreasing the severity of OSA is a combination of AD109 and AD504, under development by the pharmaceutical firm Apnimed.

All About Obstructive Sleep Apnea

OSA is characterized by the narrowing and obstruction of the upper airway during sleep, causing a person to stop breathing repeatedly. The term “apnea” or “apnoea” applies to the cessation of breathing for 10 seconds or longer. Symptoms include excessive snoring, awakening from sleep gasping, daytime sleepiness and fatigue, morning headaches and sore throat, and problems focusing. If untreated, the disorder increases a person’s risk for stroke, cardiovascular disease, heart failure, pulmonary arterial hypertension, and development of neurobehavioral issues like mood changes and depression. The disease also may eventually lead to poor dietary habits, lack of exercise, altered insulin resistance, and systemic inflammation.

Obesity, older age, genes, alcohol use, smoking, and anatomical issues like a deviated septum, mandibular hypoplasia, or enlarged tongue or tonsils are all factors that can promote occurrence of OSA. The disease tends to be more prevalent in men, and, according to health professionals, affects between 9 percent and 38 percent of adults in the United States and nearly a billion people worldwide.

Less Sleep Quality Most Concerning

Perhaps, one of the most disconcerting aspects of the disorder is its association with a decline in sleep duration, sleep hygiene, and overall quality.

A study just published in December 2023 by JAMA Network Open indicates OSA patients with “shorter objective sleep duration had higher risk for all-cause mortality independent of AHI [apnea-hypopnea index] compared with those sleeping at least seven hours.” The research involved 2,574 OSA patients, representing men and women from a variety of races. AHI measures the average number of apnea (breathing stops) or hypopneas (incidents of abnormally shallow breathing) a person experiences in an hour. In other words, according to the researchers, lack of sufficient sleep plays a much greater role in an OSA patient’s morbidity and mortality than simply the number of times the person experiences a breathing episode during sleep.

OSA’s negative impact on sleep architecture and hygiene is a prime impetus for doctors’ efforts to find effective medications.

Current OSA Treatment Options

Until now, treatment for OSA has been limited to use of electrical devices that exert continuous positive airway pressure (CPAP machines), which an estimated half of OSA patients have difficulty tolerating; custom-fitted oral appliances to push the jaw forward and alleviate airway obstruction; lifestyle changes and correction of underlying medical conditions like obesity and atrial fibrillation; positional therapy for keeping patients sleeping in their side; and surgical procedures to eliminate anatomical defects like enlarged tonsils and create more breathing space in the oropharynx. The oropharynx is that part of the throat connecting the mouth and the upper portion of the airway.

Experts warn of the long-term consequences of uncontrolled OSA. In fact, some speculate that sleep apnea may have been the ultimate cause of the 2016 death of Supreme Court Justice Antonin Scalia. But who should be screened for the disorder? Many OSA patients are either asymptomatic or report only vague symptoms like daytime fatigue that is unaccompanied by any other obvious signs.

Authors of a 2022 article on the website of the National Center for Biotechnology Information indicate universal OSA screening for asymptomatic individuals is not recommended. However, they advise people who experience excessive daytime sleepiness or are told by a bed partner that they snore loudly, choke or gasp during sleep, or seem to stop breathing multiple times should contact a physician.

A Few Tips

Although not all factors that increase the potential for developing OSA can be eliminated or controlled, people may reduce their risks. Among important steps to take:

• Get enough sleep – sleep apnea is worse when you are sleep deprived or exhausted. Stick to regular timing, and a cool, dark and quiet bedroom.
• Increase physical activity, especially if much of the time is spent sitting in an office or at home in front of a computer.
• Undergo treatment for hypertension, chronic nasal congestion and upper respiratory infections, and other conditions that contribute to OSA.
• Achieve a weight and body mass index appropriate to age and height.
• Reduce consumption of alcohol, particularly just before bedtime, and
• Eliminate smoking as part of an overall healthy lifestyle.
• Be careful driving and avoid doing so if you have any tendency to doze off. Speak with your doctor immediately if you have trouble staying awake during the day.

When it comes to our health, American philosopher and historian Will Durant, perhaps, said it best: We are what we repeatedly do. Excellence [good health] then, is not an act, but a habit.”