Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold

Abstract

Recent insights into sleep apnoea pathogenesis reveal that a low respiratory arousal threshold (awaken easily) is important for many patients. As most patients experience stable breathing periods mediated by upper-airway dilator muscle activation via accumulation of respiratory stimuli, premature awakening may prevent respiratory stimuli build up as well as the resulting stabilization of sleep and breathing. The aim of the present physiological study was to determine the effects of a non-benzodiazepine sedative, eszopiclone, on the arousal threshold and the AHI (apnoea/hypopnoea index) in obstructive sleep apnoea patients. We hypothesized that eszopiclone would increase the arousal threshold and lower the AHI in patients with a low arousal threshold (0 to -15 cm H(2)O). Following a baseline overnight polysomnogram with an epiglottic pressure catheter to quantify the arousal threshold, 17 obstructive sleep apnoea patients, without major hypoxaemia [nadir SaO(2) (arterial blood oxygen saturation) >70%], returned on two additional nights and received 3 mg of eszopiclone or placebo immediately prior to each study. Compared with placebo, eszopiclone significantly increased the arousal threshold [-14.0 (-19.9 to -10.9) compared with -18.0 (-22.2 to -15.1) cm H(2)O; P<0.01], and sleep duration, improved sleep quality and lowered the AHI without respiratory event prolongation or worsening hypoxaemia. Among the eight patients identified as having a low arousal threshold, reductions in the AHI occurred invariably and were most pronounced (25±6 compared with 14±4 events/h of sleep; P<0.01). In conclusion, eszopiclone increases the arousal threshold and lowers the AHI in obstructive sleep apnoea patients that do not have marked overnight hypoxaemia. The greatest reductions in the AHI occurred in those with a low arousal threshold. The results of this single night physiological study suggest that certain sedatives may be of therapeutic benefit for a definable subgroup of patients. However, additional treatment strategies are probably required to achieve elimination of apnoea.

Figure 1. A PSG example of the procedure used to quantify the respiratory arousal threshold

PSG tracings are from a baseline study in a 55-year-old female patient with moderately severe obstructive sleep apnoea (AHI = 23 events/h of sleep). EEG, C3–A2; nasal flow, nasal airflow (arbitrary units); Pepi, pressure at the level of the epiglottis. Results presented show an approx. 45-s segment during stage 2 sleep in which the patient is experiencing an approx. 30-s respiratory event. Note the increasing breathing efforts (more pronounced negative Pepi) during the period of impaired airflow up until the point of arousal from sleep (grey-shaded portion of the EEG). As indicated, the respiratory arousal threshold is quantified as the nadir epiglottic pressure during the effort immediately prior to arousal from sleep (in this example approx. −20 cmH₂O).

Figure 2. Flow diagram of the enrollment, randomization and analysis procedures

The present study was a double-blind placebo-controlled cross-over study in which an overnight baseline PSG was initially performed to determine eligibility. If deemed eligible, OSA patients were randomized to the allocation order (placebo first or 3 mg of eszopiclone first) and returned for two additional PSG studies at which time the appropriate intervention was administered prior to sleep (visit 1 and visit 2). Refer to the text for further details.

Figure 3. AHI scatter plots representing each individual patient’s AHI during the placebo and eszopiclone condition (n = 17)

Mean ± S.E.M. values are presented adjacent to each condition. *Significant difference compared with placebo.

Figure 4. Stage 2 sleep arousal threshold scatter plots representing each individual patient’s arousal threshold during the placebo and eszopiclone condition (n = 17)

Median (interquartile range) values are presented adjacent to each condition. *Significant difference compared with placebo.

Figure 5. AHI scatter plots during the placebo and eszopiclone condition in (A) the patients with (n = 8) and (B) the patients without (n = 9) a low respiratory arousal threshold (between 0 and −15 cmH₂O)

Mean ± S.E.M. values are presented adjacent to each condition. *Significant difference compared with placebo.