Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea

Abstract

STUDY OBJECTIVES: To determine the effects of the nonbenzodiazepine sedative zopiclone on the threshold to arousal with increasing respiratory effort and genioglossus muscle activity and to examine potential physiological factors mediating disparate effects of zopiclone on obstructive sleep apnea (OSA) severity between patients. METHODS: Twelve patients with OSA (apnea-hypopnea index = 41 +/- 8 events/h) were studied during 2 single night sleep studies conducted approximately 1 w apart after receiving 7.5 mg of zopiclone or placebo according to a double-blind, placebo-controlled, randomized, crossover design. The respiratory arousal threshold (epiglottic pressure immediately prior to arousal during naturally occurring respiratory events), genioglossus activity and its responsiveness to pharyngeal pressure during respiratory events, and markers of OSA severity were compared between conditions. Genioglossus movement patterns and upper airway anatomy were also assessed via magnetic resonance imaging in a subset of participants (n = 7) during wakefulness. RESULTS: Zopiclone increased the respiratory arousal threshold versus placebo (-31.8 +/- 5.6 versus -26.4 +/- 4.6 cmH2O, P = 0.02) without impairing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure during respiratory events (-0.56 +/- 0.2 versus -0.44 +/- 0.1 %max/-cmH2O, P = 0.48). There was substantial interindividual variability in the changes in OSA severity with zopiclone explained, at least in part, by differences in pathophysiological characteristics including body mass index, arousal threshold, and genioglossus movement patterns. CONCLUSIONS: In a group of patients with predominantly severe OSA, zopiclone increased the arousal threshold without reducing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure. These properties may be beneficial in some patients with OSA with certain pathophysiological characteristics but may worsen hypoxemia in others. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, trial ID: ACTRN12614000364673.