Signal Detection Analysis of Hypnotic-induced Respiratory Depression

Discussion

The JADER database was used to examine the association between hypnotic use and respiratory depression. The results indicated that the association between hypnotics and respiratory depression varied by drug type. The BZRAs and MRAs detected significant signals for respiratory depression, even after adjusting for diseases and opioids that put patients at risk for respiratory depression.

Respiratory depression risk associated with BZRAs has been reported previously (14). BZRAs increase respiratory depression risk in patients with certain diseases. Specifically, Wang et al. (5) demonstrated that the use of BZRAs in patients with OSA increased the risk of acute respiratory failure. The mechanisms by which BZRAs adversely affect OSA include central ventilatory drive suppression, decreased upper airway muscle tone, and increased arousal threshold (15, 16). Interestingly, this study found a significant signal for respiratory depression in patients administered BZRAs, even in those <60 years of age. Previous studies of the general population have suggested that hypnotics, usually BZRAs, are associated with an increased risk of mortality in patients <60 years of age (17). These factors increase the death rate for cardiovascular diseases, which may be influenced by OSA. Furthermore, BZRA use may increase the risk of respiratory depression in patients with COPD (6, 18). Sleep-related hypoventilation may be exacerbated by BZRA use (19). Although these comorbidities had a significant impact on BZRA-induced respiratory depression, our results showed that the association persisted even after adjustment. When stratified by opioid use, an association was not found between BZRAs and respiratory depression in patients who received opioids. The strong effect of opioids on respiratory depression may mask the relevance of BZRAs. Although several reports have suggested that respiratory depression risk is increased by the combination of opioids and BZRA (3, 4), the present results should be interpreted with caution because the association could hold even in the absence of opioids.

Respiratory depression caused by MRAs is uncommon in clinical practice. Previous reports have shown that ramelteon does not exacerbate OSA in older adult patients (20). However, our results suggest that MRAs may be associated with respiratory depression. Basic research has revealed that ramelteon potentiates the contraction of human airway smooth muscle by suppressing cAMP production and increasing intracellular Ca²⁺ concentration via the MT2 receptor (7). Ramelteon, a non-selective MT1/MT2 agonist, may carry a potential risk of respiratory depression through these mechanisms, even in real-world clinical practice. Stratified results showed an association between MRAs and respiratory depression regardless of opioid use, which carries a high risk of respiratory depression, although age-related differences were observed. However, because these analyses were conducted on limited samples, additional studies are needed to interpret the finding that under certain conditions, hesitation in choosing ramelteon for respiratory depression may not be necessary. Notably, ramelteon is the drug of choice for the prevention of perioperative and intensive care unit delirium; however, the potential risk of respiratory depression requires caution.

In the analyses of this study, we addressed the potential influence of concomitant hypnotic use by including all reported cases, regardless of whether the drugs were used alone or in combination, and by incorporating each hypnotic class as covariates in the multivariable model. This approach was necessary because restricting an analysis to monotherapy cases would have substantially limited the number of reports. Nevertheless, in real-world clinical practice, combinations of hypnotics are common, and additive or synergistic effects on respiratory depression cannot be ruled out. Additionally, adjusted RORs for Z-drugs and DORAs were not significant. This may reflect their pharmacological characteristics, such as the short half-life of Z-drugs and the relatively low use of these agents in high-risk populations (patients with OSA or COPD). For DORAs, the limited number of reports, owing to their relatively recent introduction, may have reduced statistical power. Further research using larger datasets or prospective clinical studies is warranted to clarify these associations.

The strengths of this study are that the database for spontaneous reports of adverse events is superior because it contains the information of many reports from a large number of facilities that allowed for analyses of the association between drugs and adverse events, even for adverse events that occurred relatively infrequently.

Limitations. First, it was impossible to quantify respiratory depression risk because the analyses only included data on reported adverse events and there was no information for the denominator of patients who use hypnotics (21). Second, spontaneous adverse drug reaction reporting systems have inherent limitations including substantial underreporting and reporting biases. Reporting frequency often follows the Weber effect, where reports increase shortly after a drug’s approval and then decline over time. Additionally, media coverage or safety alerts can trigger temporary spikes in reporting, which may distort the true incidence of adverse events. According to the FAERS, adverse event reports typically increase for the first two years after a drug’s approval and then decline rapidly (22). To mitigate these temporal effects, we included the reporting year as an adjustment factor in our analyses. Third, there is a potential for indication bias related to the clinical context in which certain hypnotics, such as MRAs or DORAs, were administered. In recent years, these agents have been discussed regarding their potential to reduce delirium, particularly in critical care settings such as intensive care units (23). Consequently, patients who received these medications may represent a population with higher baseline severity, including those who were in the post-extubation phase or with multiple comorbidities. This clinical background could introduce confounding factors not fully captured in the database, potentially influencing the observed associations. Finally, there were limitations to the items obtained and measurement errors may have been introduced by factors other than those selected as confounders. In particular, the key clinical variables such as obesity, renal issues, neurologic conditions, and substance/alcohol use were not included. However, the large sample size data, which included drug information and adverse events could be useful for statistical adjustment of the covariates. In the field of psychiatry, several studies have reported associations between drugs and adverse events using the JADER database (24-26). We believe the results of this study have the potential to inform future clinical studies.