• Ludovico Messineo, Scott A Sands, and Gonzalo Labarca.
• Spedali Civili di Brescia, Malattie dell'Apparato Respiratorio, Brescia, Italy; Dr.ludovico.messineo@gmail.com.
• Am. J. Respir. Crit. Care Med. 2024 Jul 23.

RationaleLow arousal threshold and poor muscle responsiveness are common determinants of obstructive sleep apnea (OSA). Hypnotics were hypothesized as an alternative OSA treatment via raising the arousal threshold and possibly genioglossus responsiveness.ObjectivesEffect of common hypnotics on arousal threshold, OSA severity and genioglossus responsiveness.MethodsWe searched MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov for randomized clinical trials, and ran meta-analyses to determine the effect of oral hypnotics on arousal threshold, OSA severity and genioglossus responsiveness. GRADE was used to rate the quality of evidence (QoE). The association between post-treatment AHI and arousal threshold percent reductions was explored in individual patient data (IPD) metanalyses (overall sample and low arousal threshold subgroups).Measurements And Main ResultsBased on our analysis (27 studies; 25 for AHI, 11 for arousal threshold, 4 for genioglossus responsiveness), hypnotics minimally raised arousal threshold (mean difference [95% CI]: 2.7 [1.5, 3.8] cmH2O epiglottic pressure swings; moderate QoE), but did not change OSA severity (1.4 [3.5, 0.7] events/h; moderate QoE). IPD meta-analysis (N=114) showed no association between changes in arousal threshold and AHI, independent of low arousal threshold subgrouping. However, people with very-low arousal threshold or those who exhibited 0-25% arousal threshold increase from placebo experienced the greatest-yet still modest-post-treatment AHI reductions (10%). Hypnotics did not affect genioglossus responsiveness (high QoE).ConclusionsFurther research testing or clinical use of hypnotics as OSA alternative treatments should be discouraged, unless in the presence of comorbid insomnia or as part of combination therapy in individuals with very-low arousal threshold.

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