One step closer to pharmacotherapy for sleep apnoea

Abstract

It is estimated that almost 1 billion people have sleep apnoea (Benjafield et al. 2019). Hypopnoeas (inadequate ventilation) and apnoeas (cessation of ventilation) disrupt pulmonary gas exchange and sleep architecture. Obstructive sleep apnoea syndrome (OSAS) drives multi-system morbidity and if untreated causes premature death. Continuous positive airway pressure is the first line treatment for people with OSAS. Although effective for many, adherence to therapy is generally low. There is a recognised requirement to develop alternative therapeutic strategies for OSAS, particularly given that there are various disease endotypes, revealing the multifactorial basis for the manifestation of disordered breathing during sleep. Pharmacotherapy is an attractive proposition for OSAS, but to date, notwithstanding many valiant efforts, there is no ‘magic pill’. Basic research in animals and human participants has contributed to a wealth of understanding of the physiological mechanisms controlling pharyngeal airway calibre across the sleep–wake cycle. There has been keen interest in delineating the pathways and processes underpinning the reduction or loss of pharyngeal muscle tone during sleep that provides the substrate for airway narrowing, which in some people provokes recurrent occlusions of the upper airway, the hallmark feature of OSAS. Sleep-related withdrawal of excitatory facilitation of cranial motor outflow contributes to upper airway hypotonia. Whereas serotonin has achieved much attention in the past, there is at current interest in the facilitatory role of noradrenaline. In addition, a pivotal finding was the observation in rats that sleep-related atonia of the genioglossus (principal airway dilator muscle) arises due to cholinergic inhibition of hypoglossal motor neurons innervating the tongue (Grace et al. 2013). These and other studies have translated to interventional trials in human participants. Notably, combined noradrenergic receptor agonism and muscarinic receptor antagonism was recently shown to improve upper airway function during sleep in healthy participants (Lim et al. 2019), paving the way for clinical trials in people with OSAS. In this issue of The Journal of Physiology, Lim et al. (2021) extend their recent work to consider the efficacy of a combined drug therapy on sleep and upper airway function in people with severe OSAS. In a double-blind, placebo-controlled, randomised cross-over study of 12 participants, a single dose immediately prior to sleep of a noradrenergic agent (reboxetine) combined with an anti-muscarinic (hyoscine buytlbromide) decreased the apnoea–hypopnoea index and the magnitude of the resultant episodic hypoxia associated with these events. The drug combination increased tonic genioglossus muscle responsiveness and decreased airway collapsibility, loop gain (a phenomenon causing ventilatory instability) and the ventilatory response to arousal, without influencing the arousal threshold (propensity for awakening due to airway narrowing). Total sleep efficiency was equivalent between placebo and drug conditions, but in the latter, there was a notable reduction in rapid eye movement (REM) sleep in favour of increased non-REM (N2) stage sleep. OSAS severity tends to be greatest in REM sleep, but importantly, the authors emphasize that the reduction in OSAS severity following drug treatment was not exclusively due to REM suppression, since the apnoea–hypopnoea index was reduced during NREM sleep consistent with the overall effect. The study represents an important advance in the search for the optimal pharmacotherapy for OSAS. A comparison of the findings with recent intervention studies in the field suggests a dominant effect of different noradrenergic agents, but interestingly efficacy in reducing sleep apnoea severity is dependent upon co-administration with anti-muscarinic agents. Whether this represents additive or synergistic effects amongst other complex interactions remain to be determined. One might also consider that selective sub-type receptor agents could improve efficacy, but interestingly it appears that non-selective antimuscarinic blockade is the superior strategy (Aishah et al. 2021). The authors acknowledge several issues that remain outstanding before this matter is put to bed. The current trial was in a small sample of people with severe OSAS, mostly men. It is necessary to widen the demographic, and encouragingly, as discussed by Lim et al. (2021), pharmacotherapy may prove most effective for specific OSAS endotypes in the mild-to-moderate severity banding and perhaps especially women. There is need for continued vigilance in the assessment of drug-induced effects on sleep architecture and daytime behaviours. Moreover, it is critically essential to determine the temporal efficacy of pharmacotherapeutic strategies. Once refined, large scale clinical trials to thoroughly interrogate pharmacotherapy alone and in combination with other strategies will be required. Thus, it appears that pharmacotherapy for OSAS, once the holy grail of the field, is front and centre as a priority area with tangible strategies. The search is on for the ‘perfect’ cocktail for OSAS. Sláinte!