The Effect of Donepezil on Arousal Threshold and Apnea-Hypopnea Index. A Randomized, Double-Blind, Cross-Over Study

Abstract

Rationale: Obstructive sleep apnea (OSA) has multiple pathophysiological causes. A low respiratory arousal threshold (ArTh) and a high loop gain (unstable ventilatory control) can contribute to recurrent respiratory events in patients with OSA. Prior studies have shown that donepezil, an acetylcholinesterase inhibitor, might improve OSA, but the mechanism is unknown.

Objectives: To determine whether a single dose of donepezil lowers the apnea-hypopnea index by modulating the ArTh or loop gain.

Methods: In this randomized, double-blind, crossover trial, 41 subjects with OSA underwent two polysomnograms with ArTh and loop gain evaluated, during which 10 mg of donepezil or placebo was administered.

Measurements and main results: Compared with placebo, sleep efficiency (77.2 vs. 71.9%; P = 0.015) and total sleep time decreased with donepezil (372 vs. 351 min; P = 0.004). No differences were found in apnea-hypopnea index (51.8 vs. 50.0 events/h; P = 0.576) or nadir oxygen saturation as determined by pulse oximetry (80.3 vs. 81.1%; P = 0.241) between placebo and donepezil, respectively. ArTh was not significantly changed (-18.9 vs. -18.0 cm H2O; P = 0.394) with donepezil. As a whole group, loop gain (ventilatory response to a 1-cycle/min disturbance) did not change significantly (P = 0.089).

Conclusions: A single dose of donepezil did not appear to affect the overall severity of OSA in this patient group, and no consistent effects on ArTh or loop gain were observed. Donepezil may have minor effects on sleep architecture. Clinical trial registered with www.clinicaltrials.gov (NCT02264353).

Keywords: arousal threshold; donepezil; loop gain; obstructive sleep apnea; treatment.

Figures

Figure 1.

Sleep apnea severity as measured by apnea–hypopnea index (AHI, events/h) under each condition.

Figure 2.

Arousal threshold (cm H2O) under placebo and donepezil conditions.

Figure 3.

Loop gain (the ventilatory response to a 1-cycle/min disturbance) under the placebo and donepezil conditions for each patient.

Figure 4.

Change in apnea–hypopnea index (AHI) under the placebo and donepezil conditions and the change in respiratory arousal threshold (ArTh). There was no significant association between changes in AHI and change in ArTh (r = 0.331, P = 0.143).

Figure 5.

Change in apnea–hypopnea index (AHI) under placebo and donepezil conditions and the change in loop gain (the ventilatory response to a 1-cycle/min disturbance, LG1). There was a positive association between the change in AHI and the change in LG1 (r = 0.325, P = 0.038).