Maternal exposure to zolpidem and risk of specific birth defects.

Zolpidem is a non-benzodiazepine agent indicated for treatment of insomnia. While zolpidem crosses the placenta, little is known about its safety in pregnancy. We assessed associations between self-reported zolpidem use 1 month before pregnancy through to the end of the third month ("early pregnancy") and specific birth defects using data from two multi-site case-control studies: National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study. Analysis included 39,711 birth defect cases and 23,035 controls without a birth defect. For defects with ≥ 5 exposed cases, we used logistic regression with Firth's penalised likelihood to estimate adjusted odds ratios and 95% confidence intervals, considering age at delivery, race/ethnicity, education, body mass index, parity, early-pregnancy antipsychotic, anxiolytic, antidepressant use, early-pregnancy opioid use, early-pregnancy smoking, and study as potential covariates. For defects with three-four exposed cases, we estimated crude odds ratios and 95% confidence intervals. Additionally, we explored differences in odds ratios using propensity score-adjustment and conducted a probabilistic bias analysis of exposure misclassification. Overall, 84 (0.2%) cases and 46 (0.2%) controls reported early-pregnancy zolpidem use. Seven defects had sufficient sample size to calculate adjusted odds ratios, which ranged from 0.76 for cleft lip to 2.18 for gastroschisis. Four defects had odds ratios > 1.8. All confidence intervals included the null. Zolpidem use was rare. We could not calculate adjusted odds ratios for most defects and estimates are imprecise. Results do not support a large increase in risk, but smaller increases in risk for certain defects cannot be ruled out.

Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report.

BACKGROUND: Zolpidem is a non-benzodiazepine hypnotic widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before. CASE PRESENTATION: A 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril/valsartan 12/13 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no significant change. The night before admission, the patient attempted suicide by overdosing on 40 mg of zolpidem after an argument, which resulted in severe lethargy. Upon admission, his ECG revealed new-onset AF, necessitating immediate cessation of zolpidem. Nine hours into admission, AF spontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that AF was not detected. CONCLUSIONS: This study provides valuable clinical evidence indicating that zolpidem overdose may induce AF in patients with cardiomyopathy. It serves as a critical warning for clinicians when prescribing zolpidem, particularly for patients with existing heart conditions. Further large-scale studies are needed to validate this finding and to explore the mechanisms between zolpidem and AF.

Immediate Postoperative Zolpidem Use Increases Risk of Falls and Implant Complication Rates Following Total Hip Arthroplasty: A Retrospective Case-Control Analysis.

BACKGROUND: Zolpidem is the most widely used hypnotic in the United States and has known side effects. However, the morbidity of zolpidem use following total hip arthroplasty (THA) is not well-defined. Thus, the aim of this study was to assess the effects that zolpidem use has on medical and implant complications, falls, lengths of stay, and medical utilizations following THA. METHODS: A retrospective query of a nationwide insurance claims database was conducted from 2010 to 2020. All cases of THA and hypnotic use were identified using procedural and national drug codes. Patients who were prescribed zolpidem within 90 days of surgery were matched to hypnotic naive patients 1:5 based on demographic and comorbidity profiles. The 90-day medical complications, falls, fragility fractures, costs, and readmission rates, as well as 2-year implant complications were compared between cohorts. A total of 50,328 zolpidem patients were matched to 251,286 hypnotic naive patients. RESULTS: The zolpidem group had significantly higher rates of medical complications, falls, and fragility fractures when compared to the hypnotic-naive group. The zolpidem group had significantly higher rates of dislocation, mechanical loosening, and periprosthetic fracture. Likewise, healthcare utilization was significantly greater in the zolpidem group. CONCLUSION: Zolpidem use following THA is associated with significant risk of medical and implant complications, as well as fall risks, increased costs, lengths of stay, and readmissions. The findings of this study may affect discussions between orthopaedic surgeons and their patients on the benefits of sleep quality in their recovery versus the incurred risks of zolpidem use. LEVEL OF EVIDENCE: III, retrospective case-control study.

Comparative efficacy of hypnotics in young and middle-aged adults with insomnia: a systematic review and network meta-analysis.

OBJECTIVE/BACKGROUND: Insomnia is highly prevalent in modern society. However, the hierarchical selection of hypnotics in young and middle-aged adults with insomnia remains unclear. We aimed to compare the efficacy and daytime drowsiness associated with different hypnotics for treating insomnia in young and middle-aged adults. METHODS: We searched Embase, PubMed, Cochrane Library, and ProQuest Dissertations and Theses A&I databases from inception until December 15, 2021. We also manually searched reference lists and relevant publications. The literature search, data collection, and risk of bias evaluation were all carried out separately by pairs of reviewers. We included randomized control trials (RCTs) that compared hypnotics approved by the Food and Drug Administration. The R and Stata software were both used to perform the meta-analysis. RESULTS: In total, 117 RCTs comprising 22,508 participants with the age of 18 to 65 years were included. Assessment of the efficacy of the hypnotics and adverse events (drowsiness) revealed that zolpidem improved all objective sleep parameters (oTST, oSOL, oWASO, and oSE), zopiclone increased oTST and oSE and reduced oSOL, and daridorexant increased oTST and reduced oWASO. Regarding subjective sleep outcomes, zolpidem exhibited beneficial effects on sTST, sSOL, and sWASO. Zaleplon reduced sSOL, and zopiclone was the recommended hypnotic for improving SQ. Zolpidem was associated with drowsiness effect (odds ratio = 1.82; 95% confidence interval = 1.25 to 2.65). The results of sensitivity analysis remained unchanged after the exclusion of studies reporting long-term effects. CONCLUSION: Zolpidem is recommended for managing sleep-onset insomnia and sleep maintenance insomnia but should be used with caution because of daytime drowsiness effects. Daridorexant is recommended as a promising agent for managing sleep maintenance insomnia.

Abuse Potential of Lemborexant, a Dual Orexin Receptor Antagonist, Compared With Zolpidem and Suvorexant in Recreational Sedative Users.

BACKGROUND: Lemborexant (LEM) is a dual orexin receptor antagonist approved for the treatment of insomnia in adults in multiple countries including the the United States, Japan, Canada, Australia and several Asian countries. PROCEDURES: This was a randomized, single-dose, single-center, double-blind, active-control, 6-way crossover study to evaluate LEM abuse potential. The study assessed oral doses of LEM 10 mg (LEM10), 20 mg (LEM20), and 30 mg (LEM30) compared with placebo (PBO), zolpidem (ZOL) immediate release 30 mg, and suvorexant (SUV) 40 mg. Subjects were healthy, nondependent, recreational sedative users able to discriminate/like the effects of both SUV and ZOL from PBO during a qualification phase. RESULTS: Abuse potential endpoints were analyzed in qualified subjects who received and completed all treatments (n = 32). On the "at this moment" drug-liking visual analog scale (VAS), mean maximum (peak) effect (primary endpoint) values were 78.4, 80.5, and 83.6 for LEM10, LEM20, and LEM30, respectively, which were all significantly greater than PBO (57.8; all P > 0.05) but not different from SUV (76.1) or ZOL (78.3). Similarly, for secondary endpoints overall drug-liking VAS and take-drug-again VAS, mean maximum (peak) effect values for all LEM doses were significantly greater than PBO ( P > 0.05) but not different compared with ZOL or SUV. CONCLUSIONS: For all doses, LEM demonstrated abuse potential versus PBO and appeared to have a similar abuse potential profile to ZOL and SUV in this study population. Lemborexant was well tolerated. Lemborexant has been placed in Schedule IV, the same drug schedule as ZOL and SUV.

Falls, healthcare resources and costs in older adults with insomnia treated with zolpidem, trazodone, or benzodiazepines.

BACKGROUND: Falls are the leading cause of injury-related death among older Americans. While some research has found that insomnia heightens falls, health care resource utilization (HCRU) and costs, the impact of insomnia treatments on fall risk, mortality, HCRU and costs in the elderly population, which could be of substantial interest to payers, has not been fully elucidated. This study evaluated the risk of falls and related consequences among adults ≥ 65 years of age treated with common prescription medications for insomnia compared with non-sleep disordered controls. METHODS: This was a retrospective cohort analysis of deidentified Medicare claims from January 2011 through December 2017. Medicare beneficiaries treated for insomnia receiving zolpidem extended-release, zolpidem immediate-release, trazodone, or benzodiazepines were matched with non-sleep disordered controls. The main outcomes were falls, mortality, healthcare resource utilization (HCRU), and medical costs during the 12 months following the earliest fill date for the insomnia medication of interest. Generalized linear models controlled for several key covariates, including age, race, sex, geographic region and Charlson Comorbidity Index score. RESULTS: The study included 1,699,913 Medicare beneficiaries (59.9% female, mean age 75 years). Relative to controls, adjusted analyses showed that beneficiaries receiving insomnia medication experienced over twice as many falls (odds ratio [OR] = 2.34, 95% CI: 2.31-2.36). In adjusted analyses, patients receiving benzodiazepines or trazodone had the greatest risk. Crude all-cause mortality rates were 15-times as high for the insomnia-treated as controls. Compared with controls, beneficiaries receiving insomnia treatment demonstrated higher estimated adjusted mean number of inpatient, outpatient, and emergency department visits and longer length of inpatient stay. All-cause total adjusted mean costs were higher among insomnia treated patients ($967 vs $454). CONCLUSIONS: Individuals receiving insomnia treatment had an increased risk of falls and mortality and higher HCRU and costs compared with matched beneficiaries without sleep disorders. Trazodone and benzodiazepines were associated with the greatest risk of falls. This analysis suggests that significant risks are associated with common, older generation insomnia medication treatments in the elderly. Nonetheless, these results should be interpreted with caution as the use of these medications may be indicative of underlying morbidity with potential for residual confounding.

Effects of Bedtime Dosing With Suvorexant and Zolpidem on Balance and Psychomotor Performance in Healthy Elderly Participants During the Night and in the Morning.

PURPOSE/BACKGROUND: This study was designed as an early assessment of the safety of the orexin receptor antagonist suvorexant, but also included exploratory assessments of balance and psychomotor performance that are the focus of this report. METHODS/PROCEDURES: This was a double-blind, randomized, 3-period, crossover, phase 1 study. Balance and psychomotor performance were evaluated during the night in 12 healthy elderly participants after bedtime administration of suvorexant 30 mg (a supratherapeutic dose), the GABAergic agonist zolpidem 5 mg (the recommended dose in the elderly), or placebo. Balance (body sway measured by platform stability) and psychomotor performance (measured by choice reaction time) were assessed predose and at 1.5, 4, and 8 hours postdose in each period. Memory (measured by word recall) was assessed predose and at 4 hours postdose. FINDINGS/RESULTS: At 1.5 hours after nighttime administration of each drug (the approximate time of their anticipated maximal plasma concentrations), both zolpidem and suvorexant increased body sway versus placebo, with a greater increase for zolpidem than suvorexant. Suvorexant increased choice reaction time compared with placebo or zolpidem at 1.5 hours. There were no treatment differences on body sway or choice reaction time at 4 or 8 hours, or on word recall at 4 hours. IMPLICATIONS/CONCLUSIONS: These exploratory data suggest that a 30-mg dose of suvorexant (supratherapeutic) and a 5-mg dose of zolpidem (recommended dose in the elderly) impaired balance at 1.5 hours in healthy elderly people, with potentially less impairment for suvorexant relative to zolpidem, but no treatment differences on body sway or psychomotor performance at 4 and 8 hours. Because of their exploratory nature, these findings and their clinical relevance, if any, require confirmation in a prospective study.

Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study.

BACKGROUND: Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia. METHODS: We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates. RESULTS: The mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13-2.46), 1.96 (1.16-3.31), 1.33 (1.06-1.66), and 1.88 (1.14-3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64-0.83]). CONCLUSIONS: Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed. TRIAL REGISTRATION: ENCePP e-register of studies, EUPAS18006.

Association of eszopiclone, zaleplon, or zolpidem with complex sleep behaviors resulting in serious injuries, including death.

PURPOSE: To identify and analyze postmarketing cases of complex sleep behaviors (CSBs) resulting in serious injuries, including death, associated with eszopiclone, zaleplon, or zolpidem (Z-drugs). METHODS: Retrospective analysis of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 16 December 1992 through 27 February 2018 and medical literature using PubMed and EMBASE. We used random sampling and descriptive statistics. RESULTS: We identified 66 cases that met inclusion and exclusion criteria, four of which were identified in the medical literature. Twenty cases reported death and 46 cases reported serious injuries in association with CSBs occurring after the use of a Z-drug. Fatal cases described events, such as carbon monoxide poisoning, drowning, falls, hypothermia, motor vehicle collisions, and apparent completed suicide. Nonfatal cases resulting in serious injuries described events, such as accidental overdoses, falls, gunshot wounds, hypothermia, third-degree burns, and self-injuries or suicide attempts. Twenty-two cases reported a previous episode of a CSB while taking a Z-drug prior to the event reported in this case series. CONCLUSIONS: The FAERS and medical literature cases support the need for increased awareness of the consequences that may occur because of CSBs associated with the use of Z-drugs. Therefore, to protect public health, regulatory actions were taken, including adding a Boxed Warning, a Contraindication in patients who have experienced a prior episode of a CSB with a Z-drug, and updating the existing Warnings and Precautions. An FDA Drug Safety Communication was also disseminated to alert healthcare professionals and the public of this potential risk.

Zolpidem-Associated Consequences: An Updated Literature Review With Case Reports.

A post-2000 literature search reviewed prevalence of health consequences associated with zolpidem, plus two salient case reports. Common zolpidem-related harms encompassed accidents, falls, overdoses, delirium, and infections. Risks to others included assaults, vehicular accidents, various crimes, and civil actions that occurred during zolpidem-induced delirium, withdrawal, and other impediments. Remarkably, much harm occurred while patients were taking therapeutic doses of licitly prescribed zolpidem (10-30 mg). Zolpidem-associated health, behavioral, and social problems comprise an international pandemic of preventable heath misfortunes.

Use of short-acting and long-acting hypnotics and the risk of fracture: a critical analysis of associations in a nationwide cohort.

Numerous observational studies suggest that hypnotics increase the risk of fractures, and long-acting hypnotics are suggested to be especially harmful. This study showed that the highest risk of fracture was found before start of treatment and remained after end of therapy, suggesting that the increased risk during treatment is influenced by other factors, such as underlying disease. INTRODUCTION: The purpose of this study was to evaluate associations between the use of short-acting and long-acting hypnotics and the risk of fracture. METHODS: Four cohorts were formed from all individuals living in Sweden aged ≥ 50 years in 2005 (n = 3,341,706). In the first cohort, individuals prescribed long-acting propiomazine (n = 233,609) were matched 1:1 with controls. In the second cohort, individuals prescribed short-acting z-drugs (zopiclone, zolpidem, and zaleplon, n = 591,136) were matched 1:1 with controls. The third and fourth cohorts consisted of full sibling pairs with discordant propiomazine (n = 83,594) and z-drug (n = 153,314) use, respectively. RESULTS: The risk of fracture was greatest among users of hypnotics in the 90 days before the initiation of treatment, both for propiomazine (odds ratio [OR], 2.52; 95% confidence interval [CI], 2.28-2.79) and z-drugs (OR, 4.10; 95% CI, 3.86-4.35) compared with that in matched controls. Furthermore, this risk was significantly reduced after the initiation of treatment with propiomazine (OR, 1.42; 95% CI, 1.27-1.60) and z-drugs (OR, 1.67; 95% CI, 1.56-1.80) and remained the first year following the last prescribed dose both for propiomazine (OR, 1.28, 95% CI, 1.21-1.36) and z-drugs (OR, 1.19, 95% CI, 1.16-1.23). The pattern was similar in the sibling cohorts, with the greatest risk of fracture seen in the 90 days before treatment with hypnotics was initiated. CONCLUSION: The use of short-acting and long-acting hypnotics is associated with an increased risk of fracture. This risk was highest before initiation of treatment and remained after end of therapy. The results suggest that the increased risk during treatment is influenced by other factors such as underlying disease.

An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions.

BACKGROUND: Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone ("Z-drugs") clinical concerns relating to their potential of abuse, dependence, and withdrawal have been reported over time. We aimed here at assessing these issues analyzing datasets of adverse drug reactions provided by the European Medicines Agency through the EudraVigilance system. METHODS: Analyzing the adverse drug reactions databases of each Z-drug, descriptive analyses have been performed on cases and proportional reporting ratios (PRRs) computed. RESULTS: An overall number of 33 240 (e.g., 23 420 zolpidem; 9283 zopiclone; and 537 zaleplon) misuse-, abuse-, dependence-, and withdrawal-related adverse drug reactions, corresponding to some 6246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data such as concomitant drugs, doses, routes of administration, and outcomes of the reactions (being fatalities recorded). Considering PRR values and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was most involved in overdose adverse drug reactions. Compared with zaleplon, zopiclone presented higher dependence and overdose-related issues but slightly lower misuse/abuse and withdrawal PRR values. CONCLUSION: Current data may only represent a gross underestimate of the real prevalence of Z-drug misuse. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand, and prevent any possible misuse potential of prescribed medications.

Prescription Medications for the Treatment of Insomnia and Risk of Suicide Attempt: a Comparative Safety Study.

IMPORTANCE: Guidelines for the pharmacological treatment of chronic insomnia in adults recognize that trazodone and other off-label medications are commonly prescribed despite poor evidence. The Department of Veterans Health Affairs (VA) fills high volumes of inexpensive, over-the-counter sedating antihistamines and older antidepressants in addition to benzodiazepines and zolpidem. Yet little is known about the comparative safety of these agents with regard to suicidal behavior. OBJECTIVES: To assess the comparative effectiveness of the safety of medications routinely used to treat insomnia in VA. DESIGN: Comparative effectiveness using propensity score-matched samples. SETTING: VA. PARTICIPANTS: VA patients without any history of suicidal ideation or behavior 12 months prior to first exposure. EXPOSURES: VA formularies and data were used to identify prescriptions for insomnia. Agents accounting for at least 1% of total insomnia fill volume were < 200 mg trazodone, hydroxyzine, diphenhydramine, zolpidem, lorazepam, diazepam, and temazepam. Exposure was defined as an incident monotherapy exposure preceded by 12 months without any insomnia medications. Subjects with insomnia polypharmacy or cross-overs in the 12 months following first exposure were excluded. MAIN OUTCOMES AND MEASURES: Suicide attempts within 12 months of first exposure. RESULTS: Three hundred forty-eight thousand four hundred forty-nine subjects met criteria and three well-balanced cohorts by drug class matched to zolpidem were created. After adjusting for days' supply, mental health history, and pain and central nervous system medication history, hazard ratios (compared to zolpidem) were as follows: (< 200 mg) trazodone (HR = 1.61, 95% CI 1.07-2.43); sedating antihistamines (HR = 1.37, 95% CI 0.90-2.07); and benzodiazepines (HR = 1.31, 95% CI 0.85-2.08). CONCLUSIONS AND RELEVANCE: Compared to zolpidem, hazard of suicide attempt was 61% higher with trazodone (< 200 mg). No significant differences in suicide attempt risk were identified between benzodiazepines or sedating antihistamines and zolpidem, respectively. These findings provide the first comparative effectiveness evidence against the use of trazodone for insomnia.

Zolpidem and Gender: Are Women Really At Risk?

BACKGROUND: In 2013 the Food and Drug Administration (FDA) claimed the existence of new data showing women to be at risk for excessive daytime sedation and impaired driving proficiency following bedtime doses of zolpidem. The putative explanation was the reduced metabolic clearance of zolpidem and higher morning blood concentrations in women compared to men. The FDA acted to reduce the recommended dosage for women down to 50% of the dose for men. No other regulatory agency worldwide has taken similar action. METHODS: Gender effects on zolpidem pharmacokinetics, pharmacodynamics, adverse effects, clinical efficacy, and driving performance were evaluated through a further analysis of data from a previous study, together with a literature review. RESULTS: Women had on average 35% lower apparent clearance of zolpidem than men (236 vs 364 mL/min, P < 0.001). This difference was not explained by body weight. In some laboratory studies, women had greater functional impairment than men taking the same dose, but in all studies active drug was not distinguishable from placebo at 8 hours after oral dosage. On-the-road driving studies likewise showed no evidence of driving impairment in men or women at 8 hours after 10 mg of oral immediate-release zolpidem. No clinical trial demonstrated a gender-related difference in clinical efficacy or adverse reactions, and there was no evidence of a particular risk to women. CONCLUSIONS: Dosage reduction in women is not supported by available scientific evidence, and may in fact lead to underdosing and the consequent hazard of inadequately treated insomnia.

Presentations to the emergency department with non-medical use of benzodiazepines and Z-drugs: profiling and relation to sales data.

BACKGROUND: Non-medical use of benzodiazepines and Z-drugs is common; however, there is limited information available on the extent of harm related to this in Europe, as well as the relationship between misuse and availability. AIM: To describe presentations to the emergency department in Europe related to the recreational use of benzodiazepines and Z-drugs and compare regional differences in these presentations with legal drug sales of benzodiazepines and Z-drugs within each country. METHODS: Emergency department presentations with recreational misuse of benzodiazepines and Z-drugs were obtained from the Euro-DEN dataset for the period from October 2013 to September 2015; data extracted included demographics, clinical features, reported coused drugs, and outcome data. Sales figures obtained by QuintilesIMS™ (Atlanta, Georgia) were used to compare regional differences in the proportion of benzodiazepines and Z-drugs in the emergency department presentations and legal drug sales across Europe. RESULTS: Over the 2 years, there were 2119 presentations to the Euro-DEN project associated with recreational use of benzodiazepines and/or Z-drugs (19.3% of all Euro-DEN presentations). Presentations with 25 different benzodiazepines and Z-drugs were registered in all countries, most (1809/2340 registered benzodiazepines and Z-drugs, 77.3%) of which were prescription drugs. In 24.9%, the benzodiazepine was not specified. Where the benzodiazepine/Z-drug was known, the most frequently used benzodiazepines and Z-drugs were respectively clonazepam (29.5% of presentations), diazepam (19.9%), alprazolam (11.7%), and zopiclone (9.4%). The proportions of types of benzodiazepines/Z-drugs related to ED-presentations varied between countries. There was a moderate (Spain, UK, Switzerland) to high (France, Ireland, Norway) positive correlation between ED presentations and sales data (Spearman Row's correlation 0.66-0.80, p < 0.005), with higher correlation in countries with higher ED presentation rates. CONCLUSION: Presentations to the emergency department associated with the non-medical use of benzodiazepines and/or Z-drugs are common, with variation in the benzodiazepines and/or Z-drugs between countries. There was a moderate to high correlation with sales data, with higher correlation in countries with higher ED presentation rates. However, this is not the only explanation for the variation in non-medical use and in the harm associated with the non-medical use of benzodiazepines/Z-drugs.

Pharmacodynamic and pharmacokinetic profile of SM-1, a triple-drug combination to increase total sleep time.

OBJECTIVE: The primary objective was to characterize the pharmacokinetics and pharmacodynamics of SM-1 after administration of a single oral dose to healthy volunteers in a placebo-controlled double-blind trial of daytime sedation. Secondary objectives were to determine the onset, duration, and offset of the sedative effects using subjective and objective measures of sedation. Safety and tolerability of SM-1 were also investigated. METHODS: Males and females 18-45 years of age received SM-1, a combination drug product comprised of diphenhydramine, zolpidem (delayed release), and lorazepam (delayed release). The pharmacokinetic profile of each drug was determined from blood samples. Sedative effects were assessed by visual analog scale, digit symbol substitution test, memory test, and quantitative electroencephalography. RESULTS: Similar number and severity of adverse events were observed following administration of SM-1 and placebo. Onset of sedation, as determined by subjective, performance, and electroencephalography measures, occurred 0.5-1 hr postdose, lasting about 7-7.5 hr. Plasma concentration curves for the two delayed-release components were altered compared with published data for unmodified drugs. Exposure values obtained with the combination product were in good agreement with published values of the drugs given individually. CONCLUSIONS: SM-1 was well tolerated and has pharmacologic activity starting within an hour of ingestion, lasting approximately 7-8 hr. Sedative activity was seen with subjective, psychomotor, and electroencephalography assays.

Use of non-benzodiazepine hypnotics is associated with falls in nursing home residents: a longitudinal cohort study.

BACKGROUND: Falls and related injuries are common among older people, and several drug classes are considered to increase fall risk. AIMS: This study aimed to investigate the association between the use of certain drug classes and falls in older nursing home residents in Sweden, and relate these to different age groups. METHODS: Information on falls that occurred in the previous year and regular use of possible fall risk drugs including non-benzodiazepine hypnotics (zopiclone and zolpidem) was collected from 331 nursing home residents during 2008-2011. Over the following 6 months, the occurrence of serious falls, requiring a physician visit or hospital care, was registered. Association between serious falls and drug use was compared between an older (≥ 85 years) and a younger group. RESULTS: An increased fall risk (Downton Fall Risk Index ≥ 3) was found in 93% of the study subjects (aged 65-101 years). Baseline data indicated an association between falls that occurred in the previous year and regular use of non-benzodiazepine hypnotics (p = 0.005), but not with the other studied drug classes. During the following 6 months, an association between use of non-benzodiazepine hypnotics and serious falls in the older group (p = 0.017, odds ratio 4.311) was found. No association was found between the other studied drug classes and serious falls. DISCUSSION: These results indicate an association between falls and the use of non-benzodiazepine hypnotics, compounds that previously have been considered generally well-tolerated in older people. CONCLUSIONS: Caution is advocated when using non-benzodiazepine hypnotics regularly in older people living in nursing homes.

Highway driving safety the day after using sleep medication: the direction of lapses and excursions out-of-lane in drowsy drivers.

The primary outcome measure of the on-road driving test is the Standard Deviation of Lateral Position. However, other outcome measures, such as lapses and excursions out-of-lane, also need to be considered as they may be related to crash risk. The aim of this study was to determine the direction of lapses and excursions out-of-lane (i.e. towards/into the adjacent traffic lane or towards/into the road shoulder). In total, data from 240 driving tests were re-analysed, and 628 lapses and 401 excursions out-of-lane were identified. The analyses revealed that lapses were made equally frequently over left (49.4%) and over right (43.3%). In contrast, excursions out-of-lane were almost exclusively directed over right into the (safer) road shoulder (97.3%). These findings suggest that drivers are unaware of having lapses, whereas excursions out-of-lane are events where the driver is aware of loss of vehicle control.

Z-drugs and risk for falls and fractures in older adults-a systematic review and meta-analysis.

Objective: zolpidem, zopiclone, eszopiclone and zaleplon, also known as 'Z-drugs', are commonly used as alternatives to benzodiazepines (BZDs) to treat insomnia. Z-drugs are often perceived as safer than BZDs. We conducted a systematic review and meta-analysis evaluating the association between Z-drugs and fracutres, falls and injuries. Methods: a systematic review was performed using MEDLINE, EMBASE and ClinicalTials.gov. Pooled effect-sizes were calculated comparing Z-drugs users with non-users, using fixed and random-effect models with corresponding 95% confidence of intervals (CI). Results: we identified 14 eligible studies reporting on the association between Z-drugs and outcomes of interest. Z-Drugs were associated with a statistically significant increased risk for fractures, with evidence of considerable heterogeneity (OR = 1.63; 95% CI: 1.42-1.87; I2 = 90%; n = 830,877). Likewise, there was a trend suggesting a 2-fold increase in the odds for falls, however, this result was not statistically significant and there was evidence of considerable heterogeneity (OR = 2.40; 95% CI: 0.92-6.27; I2 = 95%; n = 19,505). In an analysis assessing the risk for injuries following exposure to zolpidem we found a statistically significant increased risk of injuries, with no evidence of heterogeneity (OR = 2.05; CI 95%: 1.95-2.15; I2 = 0; n = 160,502). Results were similar in sensitivity analyses, including analyses restricted to studies of high-quality, studies with control groups suffering from insomnia, and with specific Z-drugs. Conclusion: our results indicate that Z-drugs are associated with an increased risk for fractures, and suggest a possible increased risk for falls and injuries as well. However, studies included were observational and susceptible to confounding. Physicians should consider these potential risks before prescribing these medications in older adults.