The quest for sleep apnoea drugs

Many patients are desperate for pharmacotherapy, begging clinicians for an alternative to CPAP.

---

Nearly one billion people globally and over one million Australian adults are estimated to have obstructive sleep apnoea (OSA).¹ 

The first-line therapy continuous positive airway pressure (CPAP) was invented in Australia² and is highly effective in resolving the repetitive upper airway narrowing and closure that characterises sleep apnoea and reducing daytime sleepiness. 

However, the diagnosis and treatment process can be time consuming and frustrating for many patients, the vast majority of whom (about 90% or more) are prescribed CPAP therapy.^3,4  Indeed, 50% or more of all patients prescribed CPAP therapy for their OSA are either unable to tolerate the therapy or stop using it for other reasons.^5,6 

Alternative therapies such as mandibular advancement splints fitted by a dentist and upper airway surgery can yield equivalent health benefits compared with CPAP for many patients.^7,8 

However, about 50% of patients either do not respond or have an incomplete response to mandibular advancement therapy or upper airway surgery.^7,9 Predicting which patients will respond to these therapies remains a major clinical challenge. Lifestyle and diet and weight loss strategies can also reduce sleep apnoea severity in obese individuals but practically, can be very difficult to achieve and maintain.¹⁰ 

Modafinil is used internationally to improve daytime alertness in patients who are on CPAP therapy but have residual sleepiness.¹¹ However, there are currently no approved pharmacotherapies to treat OSA. 

Conceptually, this should simply be a matter of identifying the neurotransmitters involved in pharyngeal muscle atonia during sleep and targeting these with medications to reverse this effect. 

However, despite considerable research efforts over more than 40 years this has proved challenging. Initially, based on animal studies serotonin was believed to be very important.¹² However, unfortunately, this did not translate to human studies.^12,13  

More recently, the noradrenergic and muscarinic systems have been identified in animal studies as important mediators of pharyngeal muscle atonia during sleep.¹⁴ The current study,¹⁵ along with other recent findings in people with¹⁶ and without sleep apnoea¹⁷ indicate that these initial findings based on animal studies do indeed translate to humans. As such they show considerable promise for the development of pharmacotherapy for OSA.¹²

There is no doubt that there is a huge desire from people who suffer from OSA for a medication-based solution to their condition. For example, one of our OSA pharmacotherapy research studies was briefly featured in a television news piece where we highlighted that we required six more volunteers to complete our study. The response was overwhelming with more than 2,500 calls in the first day alone! 

Some of the written responses that I have received highlight the heartbreaking struggles that many patients face and their desire for effective alternate treatment solutions beyond the status quo. For example. One patient stated: “I am desperate to take part in your study, as even though I have a machine and am using it, I am not getting the required sleep. In fact, no one that wears a mask, regardless of how much oxygen they get, is ever going to get the required hours of sleep as the masks are always moving, leaking and you can feel the mask on your face, and as we slowly approach warmer weather, it is only going to get worse. So please I beg of you, end this miserable cycle”.

Another said: “I have been using the CPAP machine for nearly two years and I hate the damn thing. I was just reading the article about the two different types of medications that might help and I was after more information regarding this and would I be eligible to at least give it a go.” 

While we are only at the beginning of this discovery journey, and much more needs to be done to carefully investigate long term safety and efficacy profiles, the current and other recent study findings provide hope that we are on the right path to developing a medication-based therapy for this common and often debilitating chronic health condition for which current treatment approaches are failing too many patients. 

Professor Danny Eckert is a respiratory and sleep researcher and the director of the Adelaide Institute for Sleep Health at Flinders University in South Australia

References

1. Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med 2019; 7(8): 687-98.
2. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; 1(8225): 862-5.
3. Gray EL, McKenzie DK, Eckert DJ. Obstructive Sleep Apnea Without Obesity is Common and Difficult to Treat: Evidence for a Distinct Pathophysiological Phenotype. J Clin Sleep Med 2017; 13(1): 81–8.
4. Carberry JC, Amatoury J, Eckert DJ. Personalized Management Approach for OSA. Chest 2018; 153(3): 744-55.
5. McEvoy RD, Antic NA, Heeley E, et al. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med 2016; 375(10): 919-31.
6. Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc 2008; 5(2): 173-8.
7. MacKay S, Carney AS, Catcheside PG, et al. Effect of Multilevel Upper Airway Surgery vs Medical Management on the Apnea-Hypopnea Index and Patient-Reported Daytime Sleepiness Among Patients With Moderate or Severe Obstructive Sleep Apnea: The SAMS Randomized Clinical Trial. Jama 2020; 324(12): 1168-79.
8. Phillips CL, Grunstein RR, Darendeliler MA, et al. Health Outcomes of Continuous Positive Airway Pressure versus Oral Appliance Treatment for Obstructive Sleep Apnea. Am J Respir Crit Care Med 2013; 187(8): 879-87.
9. Sutherland K, Vanderveken OM, Tsuda H, et al. Oral appliance treatment for obstructive sleep apnea: an update. J Clin Sleep Med 2014; 10(2): 215-27.
10. Gottlieb DJ, Punjabi NM. Diagnosis and Management of Obstructive Sleep Apnea: A Review. Jama 2020; 323(14): 1389-400.
11. Chapman JL, Vakulin A, Hedner J, Yee BJ, Marshall NS. Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis. Eur Respir J 2016; 47(5): 1420-8.
12. Aishah A, Eckert DJ. Phenotypic approach to pharmacotherapy in the management of obstructive sleep apnoea. Curr Opin Pulm Med 2019; 25(6): 594-601.
13. Marshall NS, Yee BJ, Desai AV, et al. Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. Sleep 2008; 31(6): 824-31.
14. Horner RL, Grace KP, Wellman A. A resource of potential drug targets and strategic decision-making for obstructive sleep apnoea pharmacotherapy. Respirology 2017; 22(5): 861-73.
15. Lim R, Messineo L, Grunstein RR, Carberry JC, Eckert DJ. The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double-blind, placebo-controlled, randomised crossover trial. J Physiol 2021.
16. Taranto-Montemurro L, Messineo L, Sands SA, et al. The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial. Am J Respir Crit Care Med 2019; 199(10): 1267-76.
17. Lim R, Carberry JC, Wellman A, Grunstein R, Eckert DJ. Reboxetine and hyoscine butylbromide improve upper airway function during nonrapid eye movement and suppress rapid eye movement sleep in healthy individuals. Sleep 2019; 42(4): pii: zsy261.