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

Carter, Sophie G.; Berger, Michael S.; Carberry, Jayne C.; Bilston, Lynne E.; Butler, Jane E.; Tong, B; Martins, Rodrigo Tomazini; Fisher, Lauren P.; McKenzie, David K.; Grunstein, Ronald R.

doi:10.5665/sleep.5622

Cited by 84 publications

(79 citation statements)

References 33 publications

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“…22 Nonmyorelaxant sedatives increase the threshold for arousal and reduce OSA severity in patients who have a low arousal threshold. 21,22,40,41 The current findings indicating that as many as 9 of 10 nonobese patients with OSA have a low threshold supports a study on the effects of sleep-promoting agents in nonobese patients with OSA.…”

Section: Nonanatomical Contributions To Osa Pathogenesis In Nonobese supporting

confidence: 77%

Obstructive Sleep Apnea without Obesity Is Common and Difficult to Treat: Evidence for a Distinct Pathophysiological Phenotype

Gray

McKenzie

Eckert

2017

Journal of Clinical Sleep Medicine

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116

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Study Objectives: To determine the proportion and physiological characteristics of nonobese patients with obstructive sleep apnea (OSA) and their response to prescribed therapy. Methods: Data from 163 consecutive in-laboratory diagnostic sleep studies for participants referred to an academic teaching-hospital sleep clinic for suspected OSA were assessed. Sleep and anthropometric parameters at baseline and follow-up (up to 22 mo) were examined and compared between obese and nonobese patients with a diagnosis of OSA (apnea-hypopnea index > 5 events/h sleep). A key nonanatomical contributor to OSA pathogenesis, the respiratory arousal threshold, was compared between groups. Results: Twenty-five percent of the participants with a diagnosis of OSA had a body mass index (BMI) within the normal range (BMI < 25 kg/m 2 ) and 54% had a BMI < 30 kg/m 2 (nonobese). Of the patients prescribed continuous positive airway pressure (CPAP), more nonobese patients reported not using their CPAP machine at all at follow-up (36% vs. 13%, p = 0.03). Objective CPAP compliance was also lower in the nonobese patients with OSA (5.1 ± 0.4 vs. 6.4 ± 0.4 h/night, p < 0.03). A higher proportion of the nonobese patients had a low respiratory arousal threshold compared to obese OSA patients (86% vs. 60%, p < 0.001). Conclusions: A substantial proportion of patients with OSA are not obese. These patients are challenging to treat with existing therapies as they are less adherent and compliant with CPAP therapy. Nonanatomical contributors to OSA, such a low threshold for arousal, are likely to be particularly important in OSA pathogenesis in nonobese patients with OSA. These findings have important implications for the pathogenesis of OSA in nonobese patients and potential therapeutic targets for this group of patients. Keywords: arousal threshold, continuous positive airway pressure therapy, nonobese, sleep apnea pathogenesis, upper airway Citation: Gray EL, McKenzie DK, Eckert DJ. Obstructive sleep apnea without obesity is common and difficult to treat: evidence for a distinct pathophysiological phenotype. J Clin Sleep Med. 2017;13(1):81-88.

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Section: Nonanatomical Contributions To Osa Pathogenesis In Nonobese supporting

confidence: 77%

Obstructive Sleep Apnea without Obesity Is Common and Difficult to Treat: Evidence for a Distinct Pathophysiological Phenotype

Gray

McKenzie

Eckert

2017

Journal of Clinical Sleep Medicine

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116

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“…For example, treatments aimed at improving low respiratory ArTH may only be beneficial in patients who have low respiratory ArTH as part of the pathogenesis of their OSA, while in other patients such treatment may have no impact or even a detrimental effect on AHI. 21,22 In conclusion, the current study by Lee et …”

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confidence: 94%

Ethnic differences in the pathogenesis of obstructive sleep apnoea: Exploring non‐anatomical factors

Tahrani

2017

Respirology

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“…However, hypnotic use is not recommended due to concerns of worsening OSA via pharyngeal muscle relaxation and increased apnea duration and hypoxemia. Recent findings, however, indicate that standard doses of non‐benzodiazepine “z‐drugs” do not reduce upper‐airway muscle activity during sleep (Carberry et al., ; Carter et al., ). Recent studies also suggest that increasing the threshold for arousal with certain hypnotics can stabilise breathing in OSA, especially for the ~30% of patients who have a low respiratory arousal threshold trait (Carberry et al., ; Carter et al., ; Eckert, Malhotra, Wellman, & White, ; Eckert & Younes, ; Eckert et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…Recent findings, however, indicate that standard doses of non‐benzodiazepine “z‐drugs” do not reduce upper‐airway muscle activity during sleep (Carberry et al., ; Carter et al., ). Recent studies also suggest that increasing the threshold for arousal with certain hypnotics can stabilise breathing in OSA, especially for the ~30% of patients who have a low respiratory arousal threshold trait (Carberry et al., ; Carter et al., ; Eckert, Malhotra, Wellman, & White, ; Eckert & Younes, ; Eckert et al., ). Nonetheless, uncertainty regarding the effects of common hypnotics on OSA severity remains, with some studies showing reductions in apnea–hypopnea index (AHI) by ~25%–50% without worsening hypoxemia (Eckert et al., ; Edwards et al., ; Smales et al., ), while others show no change in AHI (Camacho & Morin, ; Carter et al., ; Eckert et al., ; Hoijer et al., ; Quera‐Salva et al., ) or, at high doses and in severe OSA, worse hypoxemia (Berry, Kouchi, Bower, Prosise, & Light, ; Cirignotta et al., ).…”

Section: Introductionmentioning

confidence: 99%

The effects of zolpidem in obstructive sleep apnea – An open‐label pilot study

Carberry

Grunstein

Eckert

2019

Journal of Sleep Research

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New knowledge on hypnotics and their effects on the phenotypic causes of obstructive sleep apnea indicate that zolpidem has therapeutic potential for certain patients. Specifically, zolpidem increases the threshold for arousal threshold and pharyngeal dilator muscle responsiveness. However, the effects of a standard dose of zolpidem (10 mg) on obstructive sleep apnea severity and symptoms have not been investigated. In an open‐label pilot study, 12 unselected people with obstructive sleep apnea were recruited following a diagnostic in‐laboratory sleep study. Participants then returned for a single‐night sleep study in which 10 mg of zolpidem was given just prior to sleep. Tolerability, next‐day sleepiness and the effects of zolpidem on polysomnography variables were assessed. Zolpidem was well tolerated and significantly improved the sleep efficiency compared with the no‐drug night (77 ± 12% versus 84 ± 9%, p = 0.005). Individual responses on obstructive sleep apnea severity to zolpidem in this unselected obstructive sleep apnea patient population were variable with no overall systematic difference in apnea–hypopnea index (29 ± 18.2 events per hr versus 33 ± 28 events per hr, p = 0.45) or other key respiratory parameters (e.g. event duration or hypoxemia). Next‐day sleepiness assessed via the Karolinska Sleepiness Scale was not different between visits (4 ± 1 versus 4 ± 2, p = 0.85). These findings provide the first insight into the effects of a standard dose of zolpidem in obstructive sleep apnea, and highlight its tolerability and potential to improve sleep quality. The variable effects on obstructive sleep apnea severity observed in this pilot also underscore the need for larger trials that incorporate phenotypic characterisation (e.g. arousal threshold, Pcrit and muscle responsiveness) to understand inter‐individual heterogeneity and the therapeutic potential of zolpidem for certain people with obstructive sleep apnea.

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

Abstract: Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, trial ID: ACTRN12614000364673.

Cited by 84 publications

References 33 publications

Obstructive Sleep Apnea without Obesity Is Common and Difficult to Treat: Evidence for a Distinct Pathophysiological Phenotype

Obstructive Sleep Apnea without Obesity Is Common and Difficult to Treat: Evidence for a Distinct Pathophysiological Phenotype

Ethnic differences in the pathogenesis of obstructive sleep apnoea: Exploring non‐anatomical factors

The effects of zolpidem in obstructive sleep apnea – An open‐label pilot study

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