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Randomized Controlled Trial
. 2016 Apr 1;39(4):757-66.
doi: 10.5665/sleep.5622.

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

Sophie G Carter  1 , Michael S Berger  1 , Jayne C Carberry  1 , Lynne E Bilston  1 , Jane E Butler  1 , Benjamin K Y Tong  1 , Rodrigo T Martins  1 , Lauren P Fisher  1 , David K McKenzie  2 , Ronald R Grunstein  3 , Danny J Eckert  1
Affiliations
Randomized Controlled Trial

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

Sophie G Carter et al. Sleep. .

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.

Keywords: hypnotic; respiratory physiology; sedative; sleep disordered breathing; upper airway physiology.

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Figures

Figure 1
Figure 1
CONSORT diagram indicating the recruitment, randomization, and analysis procedures for this double-blind, placebo-controlled, crossover study. Initially, patients with obstructive sleep apnea with a confirmed diagnosis responded to a research advertisement. Eligible patients (apnea-hypopnea index ≥ 5 events/h of sleep, overnight nadir arterial blood oxygen saturations > 70% who were otherwise healthy) were randomized to the allocation order (placebo first or 7.5 mg of zopiclone first). Participants attended two in-laboratory sleep studies at which time the allocated intervention was administered just prior to sleep during each visit. One of the 14 participants enrolled withdrew on the first night because of discomfort with the study equipment. Another participant discontinued involvement after their first sleep study due to an unrelated medical issue.
Figure 2
Figure 2
Polysomnographic recordings in an individual patient demonstrating how the key upper airway physiology measures were obtained. This example shows an approximately 60-sec epoch of stage N2 sleep on zopiclone in which the 50-y-old male patient (apnea-hypopnea index = 77 events/h sleep; body mass index = 34 kg/m2) experienced an approximately 35-sec respiratory event that ended with an arousal from sleep (gray shaded portion of the electroencephalogram [EEG]). The respiratory arousal threshold is quantified as nadir epiglottic pressure (Pepi) on the effort immediately prior to arousal (in this example approximately −35 cmH2O). Note the increasing effort on Pepi up until arousal despite no airflow during the respiratory event (thick dashed line). The thin dashed line indicates increasing genioglossus muscle activity during the respiratory event. Boxes indicate the first and last efforts used for genioglossus muscle analysis. Nasal flow, nasal airflow measured via mask and pneumotachograph; Processed GG EMG, raw genioglossus EMG rectified and moving time averaged (100 msec); Raw GG EMG, unprocessed raw genioglossus EMG; Peak GG, maximum genioglossus EMG during inspiration; Tonic GG, nadir genioglossus EMG during expiration. Refer to the text for further details.
Figure 3
Figure 3
Respiratory arousal threshold scatter plots representing each individual patient's arousal threshold during nonrapid eye movement sleep (NREM) during the placebo and zopiclone conditions (n = 10 patients with obstructive sleep apnea). Values and error bars presented adjacent to each condition are mean ± standard error of the mean. The asterisk indicates a statistically significant difference versus placebo.
Figure 4
Figure 4
Genioglossus muscle responsiveness scatterplots representing each individual patient's slope of genioglossus muscle responsiveness (as a % of maximal activation) versus negative epiglottic pressure during respiratory events during placebo versus zopiclone (n = 10 patients with obstructive sleep apnea). n = 2 patients had values closer to zero that overlapped indicating poor muscle responsiveness. Values and error bars presented adjacent to each condition are mean ± standard error of the mean. Zopiclone did not impair genioglossus muscle responsiveness. Refer to the text for further details.
Figure 5
Figure 5
Peak genioglossus (GG) muscle activation (as a % of maximal activation) scatterplots representing each individual patient's muscle activation on the effort immediately prior to arousal during placebo versus zopiclone (n = 10 patients with obstructive sleep apnea). Values and error bars presented adjacent to each condition are median and interquartile range. Zopiclone did not impair genioglossus muscle activity immediately prior to arousal. EMG, electromyography. Refer to the text for further details.
Figure 6
Figure 6
Apnea-hypopnea index (AHI) scatterplots representing each individual patient's value during placebo versus zopiclone (n = 12 patients with obstructive sleep apnea). Values and error bars presented adjacent to each condition are mean ± standard error of the mean. Zopiclone did not systematically alter the AHI.
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