Association between benzodiazepine receptor agonist use and increased mortality among patients hospitalized for COVID-19: results from an observational study

ABSTRACTObjectiveTo examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalized for COVID-19.MethodsWe conducted an observational multicenter retrospective cohort study at AP-HP Greater Paris University hospitals. The sample involved 14,381 adult patients hospitalized for COVID-19. 686 (4.8%) inpatients received a BZRA within at the time of hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (SD=25.4). The study baseline was the date of hospital admission and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for patient characteristics (such as age, sex, obesity and comorbidity) and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW).ResultsOver a mean follow-up of 14.5 days (SD=18.1), the primary endpoint occurred in 186 patients (27.1%) who received a BZRA and in 1,134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (HR=3.20; 95% CI=2.74-3.74; p<0.01) and in the primary IPW analysis (HR=1.61; 95% CI=1.31-1.98, p<0.01), with a significant dose-dependent relationship (HR=1.55; 95% CI=1.08-2.22; p=0.02). This association remained significant in multiple sensitivity analyses.ConclusionsBZRA use was associated with increased mortality among patients hospitalized for COVID-19 with a dose-dependent relationship, suggesting a potential benefit of decreasing dose or tapering off these medications when possible in these patients.

Impact of changes in controlled drugs legislation on benzodiazepine receptor agonist prescribing in Ireland: a repeated cross-sectional study

Purpose To examine the impact of new controlled drugs legislation introduced in May 2017 on benzodiazepine receptor agonist (BZRA) prescribing in Ireland. Methods A repeated cross-sectional analysis was conducted using publically available monthly pharmacy claims data from the General Medical Services (GMS) database. The study population comprised all GMS-eligible individuals aged ≥ 16 years from January 2016 to September 2019. Monthly prevalence rates of individuals receiving BZRA prescriptions per 10,000 eligible population were calculated and trends examined over time. Segmented linear regression of prevalence rates was used to examine changes before and after introduction of the legislation stratified by gender and age groups. Regression coefficients (β) and 95% confidence intervals (CIs) for monthly change were calculated. Results Pre-legislation (January 2016 to April 2017), there was a significant monthly decline in benzodiazepine prevalence rate (β = − 1.18; 95% CI − 1.84, − 0.51; p < 0.001) but no significant change in Z-drug prescribing. Post-legislation (May 2017 to September 2019), increases in prevalence rates were observed for benzodiazepines (β = 1.04; 95% CI 0.17, 1.92; p = 0.021) and Z-drugs (β = 1.04; 95% CI 0.26, 1.83; p = 0.010). Post-legislation trends showed increases in BZRA prevalence rates among the youngest subgroup (16–44 years), with variable changes in the middle-aged subgroup (45–64 years) and no changes in the oldest subgroup (≥ 65 years). Conclusions This study indicates that introduction of new legislation had limited impact on BZRA prescribing on the main public health scheme in Ireland. Interventions targeting specific population subgroups may be required to achieve sustained reductions in prescribing.

Acute cognitive effects of the hypocretin receptor antagonist almorexant relative to zolpidem and placebo: a randomized clinical trial

Study Objectives Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects. Methods Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52). Results ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures. Conclusions The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.

Canadian Guidelines on Benzodiazepine Receptor Agonist Use Disorder Among Older Adults

Background Benzodiazepine receptor agonist (BZRA) use disorder among older adults is a relatively common and challenging clinical condition. Method The Canadian Coalition for Seniors’ Mental Health, with financial support from Health Canada, has produced evidencebased guidelines on the prevention, identification, assessment, and management of this form of substance use disorder. Results Inappropriate use of BZRAs should be avoided by considering non-pharmacological approaches to the management of late life insomnia, anxiety, and other common indications for the use of BZRA. Older persons should only be prescribed BZRAs after they are fully informed of alternatives, benefits, and risks associated with their use. Clinicians should have a high index of suspicion for the presence of BZRA use disorders. The full version of these guidelines can be accessed at www.ccsmh.ca Conclusions A person-centred, stepped care approach utilizing gradual dose reductions should be used in the management of BZRA use disorder.

JM-1232(-) and propofol, a new combination of anesthetics with short-acting and non-cumulative preferable properties

Background Drug interactions are significant in anesthesiology because drug combinations can potentially possess novel properties. The pharmacological advantages of a new combination of the benzodiazepine receptor agonist JM-1232(-) and propofol were investigated in mice.Methods Male adult mice were administered JM-1232(-) or propofol or combinations of the two drugs intravenously. Loss of the righting reflex was evaluated as achieving hypnosis, and the time until recovery of the reflex was measured as hypnosis time. After determining the ED50, doses double and triple the ED50 of propofol were injected with JM-1232(-) to compare hypnosis time. The injections were repeated four times, and the hypnosis times were compared. Flumazenil was administered separately immediately after the last dose was injected.Results The ED50 values ([95% confidence interval]) for hypnosis were 3.76 [3.36–4.10] for JM-1232(-) and 9.88 [8.03–11.58] mg kg-1 for propofol. Co-administration of 0.05 and 0.1 mg kg-1 JM-1232(-) reduced the ED50 values of propofol to 1.76 [1.21–2.51] and 1.00 [0.46–1.86] mg kg-1, respectively. The drug combination for hypnosis produced a supra-additive interaction. Hypnosis time was significantly shorter in the groups given the mixtures compared to each hypnotic administered alone. After repeated injections, hypnosis time with the mixtures showed smaller prolongation than that with the hypnotic alone. Flumazenil completely restored the recovery time after anesthesia.Conclusions The combination of JM-1232(-) and propofol showed a supra-additive interaction, and the reduced hypnotic dose contributed to a faster recovery even after multiple injections.