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Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36–0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27–0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52–0·99; moderate], 0·70 [0·51–0·95; moderate] and 0·71 [0·52–0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28–3·13; very low]; zolpidem: 1·79 [1·25–2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01–3·33; low]), daridorexant (3·45 [1·41–8·33; low), and suvorexant (3·13 [1·47–6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27–2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36–0·90; very low]; lemborexant: 0·41 [0·04–0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16–1·10; very low]) and zolpidem (0·60 [0·00–1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20–0·93; very low]; zolpidem: 0·43 [0·19–0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11–3·70; very low]). Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Background: Many individuals in the community are prescribed psychoactive drugs with sedative effects. These drugs may affect their daily functions, of which automobile driving is a major component. Objective: To examine the association of three classes of commonly used psychoactive drugs ( viz. benzodiazepines and newer non-benzodiazepine hypnotics, antidepressants and opioids) with (i) the risk of traffic accidents (as indexed by epidemiological indicators of risk); and (ii) driving performance (as indexed by experimental measures of driving performance). Methods: A literature search for material published in the English language between January 1966 and January 2010 in PubMed and EMBASE databases was combined with a search for other relevant material referenced in the retrieved articles. Retrieved articles were systematically reviewed, carrying out meta-analyses where possible. Twenty-one epidemiological studies (13 case-control and 8 cohort studies) fulfilled the inclusion criteria by estimating the accident risk associated with drug exposure (ascertained by blood/urine analysis or prescription records). Sixty-nine experimental studies fulfilled the inclusion criteria by testing actual or simulated driving performance after administering a single dose or multiple doses. Results: Two meta-analyses showed that benzodiazepines are associated with a 60% (for case-control studies: pooled odds ratio [OR] 1.59; 95% CI 1.10, 2.31) to 80% (for cohort studies: pooled incidence rate ratio 1.81; 95% CI 1.35, 2.43) increase in the risk of traffic accidents and a 40% (pooled OR 1.41; 95% CI 1.03, 1.94) increase in ‘accident responsibility’. Co-ingestion of benzodiazepines and alcohol was associated with a 7.7-fold increase in the accident risk (pooled OR 7.69; 95% CI 4.33, 13.65). Subgroup analysis of case-control studies showed a lower benzodiazepine-associated accident risk in elderly (>65 years of age) drivers (pooled OR 1.13; 95% CI 0.97,1.31) than in drivers <65 years of age (pooled OR 2.21; 95% CI 1.31, 3.73), a result consistent with age-stratified risk differences reported in cohort studies. Anxiolytics, taken in single or multiple doses during the daytime, impaired driving performance independent of their half-lives. With hypnotics, converging evidence from experimental and epidemiological studies indicates that diazepam, flurazepam, flunitrazepam, nitrazepam and the short half-life non-benzodiazepine hypnotic zopiclone significantly impair driving, at least during the first 2–4 weeks of treatment. The accident risk was higher in the elderly (>65 years of age) who use tricyclic antidepressants (TCAs); however, the evidence for an association of antidepressants with accident risk in younger drivers was equivocal. Sedative but not non-sedative antidepressants were found to cause short-term impairment of several measures of driving performance. Limited epidemiological research reported that opioids may be associated with increased accident risk in the first few weeks of treatment. Conclusions: Benzodiazepine use was associated with a significant increase in the risk of traffic accidents and responsibility of drivers for accidents. The association was more pronounced in the younger drivers. The accident risk was markedly increased by co-ingestion of alcohol. Driving impairment was generally related to plasma half-lives of hypnotics, but with notable exceptions. Anxiolytics, with daytime dosing, impaired driving independent of their half-lives. TCAs appeared to be associated with increased accident risk, at least in the elderly, and caused short-term impairment in driving performance. Opioid users may be at a higher risk of traffic accidents; however, experimental evidence is limited on their effects on driving.

Abstract 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.

Aim/Objective: This study aims to analyse the real-world safety profile of DORAs and compare it with the one observed for Z-drugs, using data from the WHO Individual Case Safety Reports (ICSRs) database. Methods: ICSRs collected in Vigibase between its inception and 01/09/2023, presenting as suspected or interacting drugs DORAs (suvorexant, lemborexant or daridorexant), or Z-drugs (zaleplon, zolpidem, zopiclone, eszopiclone) were evaluated. Characteristics of cases were first described, then quantitative differences between DORA and Z-drugs were assessed using reporting odds ratios (RORs) and 95% confidence intervals (CIs) as measures of disproportionality. Possible Adverse Drug Reactions (ADRs) were evaluated as Preferred Terms (PT) and Standardized MedDRA Queries (SMQs) of the MedDRA dictionary. Class disproportionalities were further assessed considering each DORA individually compared to the Z-drugs. Results: Data regarding 82,043 ICSRs were retrieved, 9,669 related to DORA, and 72,374 related to Z-drugs. When compared to Z-drugs, DORA ICSRs showed a higher frequency of women (n = 5,415; 62.8% vs n = 41,175; 60.6%), but most importantly, older patients: 64 to 74 years 23.1% vs. 16.3%; C75 years 23% vs. 18.1%, in DORA and Z-drugs respectively. A total of 109 positive ROR values were found; the most frequent and disproportional ADRs were drug ineffective (n = 2,996; ROR = 3.3; 95% CI [3.1, 3.5]), nightmare (877; 6.8; [6.2, 7.4]), abnormal dreams (668; 11.7; [10.4, 13.2]), somnolence (630; 1.1; [1.0, 1.2]), and headache (486; 1.7; [1.5, 1.9]). Any meaningful differences were confirmed among individual DORAs, except for Lemborexant which was the only one significantly related to somnolence (n = 41; ROR = 1.7; 95% CI [1.2, 2.3]). Regarding SMQs, Lack of efficacy and medication errors were disproportional (ROR = 3.3; [3.1, 3.4] and 1.7; [1.5, 1.8], respectively). While depression and suicide/self-injury were not disproportional for all DORAs. The ROR for lack of efficacy was found positive for every DORA, while the ROR for medication errors was positive for suvorexant and daridorexant. Conclusion: The present data show slight differences in the safety profile of DORAs compared to Z-drugs. Nightmares and headaches, which could worsen patient sleep quality, and the disproportional reporting of lack of efficacy merit further investigation. This analysis does not suggest potential signals concerning depression or suicidality.

Background Pharmacological treatment is common in practice and widely used for the management of insomnia. However, evidence comparing the relative effectiveness, safety, and certainty of evidence among drug classes and individual drugs for insomnia are still lacking. This study aimed to determine the relative effectiveness, safety, and tolerability of drugs for insomnia. Methods In this systematic review and network meta-analysis we systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and ClinicalTrials.gov, from inception to January 10, 2022 to identify randomized controlled trials that compared insomnia drugs with placebo or an active comparator in adults with insomnia. We conducted random-effects frequentist network meta-analyses to summarize the evidence, and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty, categorize interventionsand present the findings. Results A total of 148 articles met our eligibility criteria; these included 153 trials which enrolled 46,412 participants and assessed 36 individual drugs from eight drug classes. Compared with placebo, both subjectively and objectively measured total sleep time were significantly improved with non-benzodiazepine (subjective: mean difference [MD] 25.07, 95% confidence interval [CI] 15.49–34.64, low certainty; objective: MD 22.34, 95% CI 7.64–37.05, high certainty), antidepressants (subjective: MD 54.40, 95% CI 34.96–75.83, low certainty; objective: MD 35.64, 95% CI 13.05–58.24, high certainty), and orexin receptor antagonists (subjective: MD 21.62, 95% CI 0.84–42.40, high certainty; objective: MD 31.81, 95% CI 2.66–60.95, high certainty); of which doxepin, almorexant, suvorexant, and lemborexant were among the relatively effective drugs with relatively good tolerability and lower risks of any adverse events (AEs). Both subjectively and objectively measured sleep onset latency were significantly shortened with non-benzodiazepines (subjective: MD − 10.12, 95% CI − 13.84 to − 6.40, moderate certainty; objective: MD − 12.11, 95% CI − 19.31 to − 4.90, moderate certainty) and melatonin receptor agonists (subjective: MD − 7.73, 95% CI − 15.21 to − 0.26, high certainty; objective: MD − 7.04, 95% CI − 12.12 to − 1.95, moderate certainty); in particular, zopiclone was among the most effective drugs with a lower risk of any AEs but worse tolerability. Non-benzodiazepines could significantly decrease both subjective and objective measured wake time after sleep onset (subjective: MD − 16.67, 95% CI − 21.79 to − 11.56, moderate certainty; objective: MD − 13.92, 95% CI − 22.71 to − 5.14, moderate certainty). Conclusions Non-benzodiazepines probably improve total sleep time, sleep onset latency, and wake time after sleep onset. Other insomnia drug classes and individual drugs also showed potential benefits in improving insomnia symptoms. However, the choice of insomnia drugs should be based on the phenotype of insomnia presented, as well as each drug’s safety and tolerability. Protocol registration PROSPERO (CRD42019138790).

Benzodiazepines and ‘Z-drugs’ (including zolpidem and zopiclone) are GABAA receptor (GABAAR) positive modulators commonly prescribed as hypnotics to treat insomnia and/or anxiety. However, alongside sedation, augmenting GABAAR function may also alter coordinated neuronal activity during sleep, thereby influencing sleep-dependent processes including memory consolidation. We used simultaneous recordings of neural population activity from the medial prelimbic cortex (PrL) and CA1 of the dorsal hippocampus (dCA1) of naturally sleeping rats to detail the effects of zolpidem on network activity during the cardinal oscillations of non-REM sleep. For comparison, we also characterized the effects of diazepam and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP/gaboxadol), which acts predominantly at extra-synaptic GABAARs. Zolpidem and THIP significantly increased the amplitudes of slow-waves, which were attenuated by diazepam. Zolpidem increased hippocampal ripple density whereas diazepam decreased both ripple density and intrinsic frequency. While none of the drugs affected thalamocortical spindles in isolation, zolpidem augmented the temporal coordination between slow-waves and spindles. At the cellular level, analyses of spiking activity from 523 PrL and 579 dCA1 neurons revealed that zolpidem significantly enhanced synchronized pauses in cortical firing during slow-wave down states, while increasing correlated activity within and between dCA1 and PrL populations. Of the drugs compared here, zolpidem was unique in augmenting coordinated activity within and between hippocampus and neocortex during non-REM sleep. Zolpidem’s enhancement of hippocampal-prefrontal coupling may reflect the cellular basis of its potential to modulate offline memory processing.

Hae-Jin Ko, Kyungpook National University Hospital, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, Republic of Korea, Tel +82-53-200-6578, Fax +82-53-200-5480, Email liveforme@knu.ac.krIntroduction: Non-benzodiazepine hypnotic drugs known as z-drugs (including zolpidem, eszopiclone, zopiclone, zaleplon) are commonly prescribed for insomnia patients worldwide. Z-drugs have been thought to be safer than benzodiazepines; however, several studies have raised controversy over the side effects of z-drug. This meta-analysis was conducted to evaluate the association between z-drugs and all-cause mortality.Methods: To evaluate the association between z-drugs and all-cause mortality, we conducted a meta-analysis of observational cohort studies identified through PubMed, Embase, and Scopus up to 14 March 2025. The study populations included clinical patients. The pooled hazard ratio of all-cause mortality was calculated using a random-effects model with corresponding 95% confidence of intervals (CI). Sensitivity analysis and subgroup analyses were also performed.Results: Nine cohort studies involving 2,018,397 participants were included for the meta-analysis. Z-drug use was significantly associated with an increased risk of overall mortality (HR = 1.600; 95% CI 1.027− 2.491; P = 0.038), with evidence of substantial heterogeneity (I = 99.642%, P < 0.001). Sensitivity analysis confirmed result stability (HRs 1.440– 1.761; all p < 0.05). Subgroup analyses showed a consistent positive trend across regions, follow-up durations, and study quality (HRs 1.120– 1.780), though not all were statistically significant.Discussion: This meta-analysis showed a positive association between z-drug use and all-cause mortality; however, the substantial between-study heterogeneity (I2 = 99.6%) warrants cautious interpretation of these findings. Clinicians should exercise caution when prescribing z-drugs to high-risk patients.

GPs should consider offering patients with insomnia the Sleepio app as an effective and cost saving alternative to sleeping pills, the National Institute for Health and Care Excellence (NICE) has recommended.1 The app will also reduce patients’ reliance on drugs such as zolpidem and zopiclone that can be dependence forming, said NICE’s medical technologies advisory committee. A data analysis of primary care use, before and after Sleepio was introduced in nine general practices, found that healthcare costs were lower at one year, mainly because of fewer GP appointments and sleeping pills prescribed. Jeanette Kusel, acting director for med tech and digital at NICE, said, “Until now people with insomnia have been offered sleeping pills and taught about sleep hygiene, so our committee’s recommendation of Sleepio provides GPs and their patients with a new treatment option.

No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer’s dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): −0.8, 163.2), a 26 min reduction in WASO (95% CI: −56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: −4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: −52.5, 8.3) and a reduction of 1 awakening each night (95% CI: −3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: −4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: −21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.