Meta-Analyses of Hypnotics and Infections: Eszopiclone, Ramelteon, Zaleplon, and Zolpidem

Abstract

Recent meta-analyses raising concern about risks of hypnotics suggest a need for more clarification of these risks. Methods: Because of preliminary suggestions that eszopiclone causes infections, we studied US Food and Drug Administration files on the 4 most-recently approved hypnotics, combined with published studies, to compile the risk ratios of infections for groups randomly assigned to receive hypnotics versus those assigned to receive placebos in controlled trials. Parallel controlled clinical trials of eszopiclone, ramelteon, zaleplon, and zolpidem were included when data on subjects, duration of exposure, and adverse effects were available. Results of trials were combined by meta-analyses. Results: Of 8828 participants assigned to the 4 hypnotics and 4383 participants who randomly received placebos, 606 in the hypnotics groups and 200 in the placebo groups were reported to develop some kind of infection (risk ratio = 1.44, 95% confidence interval 1.25-1.64, p < 0.00001). Most infections were apparently mild and did not lead to dropouts. Subanalyses for individual drugs indicated that eszopiclone and zolpidem individually were associated with reported infections. There were insufficient data concerning individual studies of zaleplon and ramelteon for valid secondary meta-analyses of zaleplon or ramelteon by themselves. Conclusions: Research is needed to objectively determine whether the use of hypnotics increases the risk of infections. Immune compromise or esophageal reflux and aspiration should be studied as possible mechanisms.

The association between benzodiazepines and influenza‐like illness‐related pneumonia and mortality: a survival analysis using UK Primary Care data

“…13 In the community, meta-analysis of evidence from randomised controlled trials of commonly prescribed Z-drugs (zopiclone, zolpidem, ramelteon and zaleplon) found increased risk of infection with Zdrugs compared with placebo (risk ratio 1.44; 95%CI [1.25, 1.64]). 14 In a recent general population study, benzodiazepine use was associated with increased pneumonia risk (odds ratio (OR) 1.54; 95%CI [1.42, 1.67]). 15 On the other hand, a study in elderly patients did not find a statistically significant association between benzodiazepines and pneumonia (OR 1.08; 95%CI [0.84, 1.47]), although wide CIs were reported, which may partly be due to low numbers of patients exposed to benzodiazepines in this study.…”

Use of Zolpidem and Risk of Acute Pyelonephritis in Women: A Population‐Based Case‐Control Study in Taiwan

“…25,26 Similar to benzodiazepine, zolpidem binds to benzodiazepine receptors, which have also been associated with immunity and inflammation; therefore, this interaction might further increase the risk of infection. 5,8,[11][12][13][14] Given that APN is an infectious disease, we can provide a plausible explanation for the correlation of zolpidem use with an increased risk of APN. On the other hand, zolpidem has a short elimination t 1/2 value (approximately 2.6 hours in women) 21,22 and produces inactive metabolites 4,6 and therefore does not exert accumulating effects with repeated administration.…”

“…In 1 meta-analysis, Joya et al reported an infection risk ratio of 1.99 (95%CI 1.21-3.26; P = .006) for zolpidem users but did not report APN risk data. 12 In a recent 3-year follow-up study, Huang et al reported that the proportion of pyelonephritis was higher among patients using zolpidem than among those not using zolpidem (0.36% vs 0.19%, P = .035). 11 However, these authors did not consider some risk factors associated with APN, such as pregnancy, renal transplant, HIV/AIDS, diabetes mellitus, nephrolithiasis, and urinary tract infection, and did not calculate odds ratios or hazard ratios of the pyelonephritis risk.…”

“…3,4,6 However, some observational studies reported significant morbidity with zolpidem use, including suicide or suicide attempt, 7 cancer, 8 acute pancreatitis, 9 pyogenic liver abscess, 10 and common infections. 11,12 Furthermore, zolpidem was shown to act as an inflammatory mediator in the experimental study, 5,13 and it may suppress immune function, 8,14 which could increase the probability of infection. [10][11][12] Acute pyelonephritis (APN), a type of renal parenchymal infection, often occurs consequent to a urinary bladder infection that involves the kidney and predominantly affects women.…”

“…11,12 Furthermore, zolpidem was shown to act as an inflammatory mediator in the experimental study, 5,13 and it may suppress immune function, 8,14 which could increase the probability of infection. [10][11][12] Acute pyelonephritis (APN), a type of renal parenchymal infection, often occurs consequent to a urinary bladder infection that involves the kidney and predominantly affects women. [15][16][17] In South Korea, the overall incidence of APN from 1997 to 1999 was 35.7 cases per 10,000 person-years (women, 59.0; men, 12.6); approximately 14.3% of all APN cases (1 of every 7 patients) were hospitalized, and the associated in-hospital mortality rate was 2.1 per 1000 hospitalized patients (women, 1.7; men, 5.3).…”