Personalized, physiology-based treatment for obstructive sleep apnea

Author: Ludovico Messineo

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Messineo, Ludovico, 2022 Personalized, physiology-based treatment for obstructive sleep apnea, Flinders University, College of Medicine and Public Health

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Obstructive sleep apnea (OSA) is a multi-factorial disorder with several altered traits that contribute its pathogenesis. These include increased pharyngeal collapsibility, reduced pharyngeal muscle responsiveness, increased loop gain, and reduced respiratory arousal threshold. A reduced arousal threshold (i.e., level of ventilatory drive immediately prior to a respiratory-event-related arousal) is common in OSA with >30% of patients estimated to wake up too easily to progressive pharyngeal narrowing. This promotes increased risk of apnea/hypopnea cycling. A recent clinical trial performed in OSA and healthy participants sleeping on continuous positive airway pressure (CPAP) demonstrated that zolpidem, a “z-drug” class hypnotic, increased the arousal threshold and improved pharyngeal muscle responsiveness. Hence, zolpidem may be an ideal agent to stabilize sleep and breathing for certain OSA patients.

Accordingly, I ran two double-blind, randomized, crossover trials with zolpidem during my candidature.

In the first detailed physiology study, I demonstrated that a standard dose (10mg) of zolpidem increased the arousal threshold and improved sleep efficiency in 19 OSA patients off-CPAP but did not change OSA severity or upper airway muscle responsiveness. Explanations include an insufficient increase of the arousal threshold to consistently stabilize breathing during sleep. Zolpidem did not lead to deterioration of next-day perceived sleepiness or objective alertness. Overall, these results demonstrate that zolpidem is safe in certain OSA patients and may be useful for those with reduced sleep efficiency, such as patients with comorbid insomnia.

In the second study, I investigated the effects of the addition of zolpidem 10mg in 12 OSA patients undergoing simultaneous acute administration of atomoxetine and oxybutynin (Ato-Oxy), two drugs recently shown to greatly reduce OSA severity. I demonstrated that, vs. Ato-Oxy alone, the triple combination increased the arousal threshold and sleep efficiency. The magnitude of the increase was similar to that obtained with zolpidem alone vs. placebo. However, this magnitude of the increase in arousal threshold was insufficient to systematically change OSA severity. Importantly, certain components of next-day alertness (assessed via a driving-simulation test) were impaired with the triple combination.

In the attempt to find new strategies to activate pharyngeal muscles during sleep, in my third study I tested the effects of betahistine, a histaminergic drug, in combination with oxybutynin on OSA severity, in a double-blind, placebo-controlled, crossover trial. Despite no overall effect on AHI, this drug combination increased loop gain. This finding provides new insight into the role of histaminergic processes on respiratory control and opens new potential lines of intervention for disorders characterized by reduced chemosensitivity.

Finally, I ran a detailed physiological study to assess common drive withdrawal to both pump and pharyngeal muscles or a preferential loss of upper airway function during REM sleep and the potential role of these mechanisms on REM OSA. Contrary to common knowledge, I demonstrated that REM-related vulnerability to pharyngeal obstruction importantly relies on withdrawal of common ventilatory drive rather than preferential loss of ventilation or genioglossus activity in REM vs. non-REM. This is clinically important, as REM-related loss of general respiratory drive may be a key target for OSA therapy.

Keywords: Sleep apne pharmacotherapy, sleep apnea physiology, endotypes

Subject: Medical Science thesis

Thesis type: Doctor of Philosophy
Completed: 2022
School: College of Medicine and Public Health
Supervisor: Danny Eckert