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Signal Detection Analysis of Hypnotic-induced Respiratory Depression
Saki Hideshima1, Rintaro Sogawa2, Yuki Nakano1
1Department of Pharmacy, Saga University Hospital, Nabeshima, Japan.
In Vivo (Athens, Greece)
|April 28, 2026
Summary
Benzodiazepine receptor agonists (BZRAs) and melatonin receptor agonists (MRAs) were linked to respiratory depression. Newer hypnotics like dual orexin receptor antagonists (DORAs) showed no significant association in this large-scale analysis.
Area of Science:
- Pharmacology
- Clinical Toxicology
- Sleep Medicine
Background:
- Benzodiazepine receptor agonists (BZRAs) are common hypnotics.
- Emerging evidence suggests newer hypnotics, including melatonin receptor agonists (MRAs) and dual orexin receptor antagonists (DORAs), may also pose risks for respiratory depression.
- The clinical association between hypnotic use and respiratory depression requires further investigation.
Purpose of the Study:
- To investigate the association between the use of various hypnotics and the risk of respiratory depression.
- To compare the risk of respiratory depression across different classes of hypnotics, including BZRAs, MRAs, and DORAs.
Main Methods:
- Analysis of 733,296 reports from the Japanese Adverse Event Reporting Database (April 2004-September 2023).
- Calculation of reporting odds ratios (RORs) and 95% confidence intervals (CIs) for respiratory depression associated with each hypnotic class.
- Adjustment for potential confounders including sex, age, reporting year, concomitant medications, and medical history.
Main Results:
- A significant association between respiratory depression and Benzodiazepine receptor agonists (BZRAs) (adjusted ROR=1.34; 95% CI=1.20-1.49) and Melatonin receptor agonists (MRAs) (adjusted ROR=2.03; 95% CI=1.56-2.64) was found.
- No significant association was observed for non-benzodiazepines and dual orexin receptor antagonists (DORAs) (adjusted ROR=0.94; 95% CI=0.70-1.27).
- Stratified analyses indicated BZRAs were associated with respiratory depression across all ages, while MRAs showed an association irrespective of opioid use.
Conclusions:
- The risk of respiratory depression varies among different hypnotic medications.
- Beyond BZRAs, Melatonin receptor agonists (MRAs) represent a potential risk for respiratory depression.
- Clinical vigilance is warranted when prescribing hypnotics, particularly BZRAs and MRAs, due to their association with respiratory depression.
Keywords:
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