-
Sleep Nov 2020Nonrapid eye movement sleep boosts hippocampus-dependent, long-term memory formation more so than wake. Studies have pointed to several electrophysiological events that... (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVES
Nonrapid eye movement sleep boosts hippocampus-dependent, long-term memory formation more so than wake. Studies have pointed to several electrophysiological events that likely play a role in this process, including thalamocortical sleep spindles (12-15 Hz). However, interventional studies that directly probe the causal role of spindles in consolidation are scarce. Previous studies have used zolpidem, a GABA-A agonist, to increase sleep spindles during a daytime nap and promote hippocampal-dependent episodic memory. The current study investigated the effect of zolpidem on nighttime sleep and overnight improvement of episodic memories.
METHODS
We used a double-blind, placebo-controlled within-subject design to test the a priori hypothesis that zolpidem would lead to increased memory performance on a word-paired associates task by boosting spindle activity. We also explored the impact of zolpidem across a range of other spectral sleep features, including slow oscillations (0-1 Hz), delta (1-4 Hz), theta (4-8 Hz), sigma (12-15 Hz), as well as spindle-SO coupling.
RESULTS
We showed greater memory improvement after a night of sleep with zolpidem, compared to placebo, replicating a prior nap study. Additionally, zolpidem increased sigma power, decreased theta and delta power, and altered the phase angle of spindle-SO coupling, compared to placebo. Spindle density, theta power, and spindle-SO coupling were associated with next-day memory performance.
CONCLUSIONS
These results are consistent with the hypothesis that sleep, specifically the timing and amount of sleep spindles, plays a causal role in the long-term formation of episodic memories. Furthermore, our results emphasize the role of nonrapid eye movement theta activity in human memory consolidation.
Topics: Electroencephalography; Humans; Memory Consolidation; Polysomnography; Sleep; Zolpidem
PubMed: 32330272
DOI: 10.1093/sleep/zsaa084 -
JAMA Network Open Dec 2019Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial.
IMPORTANCE
Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population.
OBJECTIVE
To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder.
DESIGN, SETTING, AND PARTICIPANTS
The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties.
INTERVENTIONS
Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime.
MAIN OUTCOMES AND MEASURES
Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy.
RESULTS
Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, -24.0 min; 95% CI, -30.0 to -18.0 min; P < .001 and for lemborexant 10 mg, -25.4 min; 95% CI, -31.4 to -19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, -6.7 min; 95% CI, -11.2 to -2.2 min; P = .004 and for lemborexant 10 mg, -8.0 min; 95% CI, -12.5 to -3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated.
TRIAL REGISTRATIONS
ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39.
Topics: Aged; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Polysomnography; Pyridines; Pyrimidines; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 31880796
DOI: 10.1001/jamanetworkopen.2019.18254 -
Profiles of Drug Substances,... 2012
Review
Topics: Animals; Chromatography; Drug Stability; Humans; Hypnotics and Sedatives; Pyridines; Spectrum Analysis; Zolpidem
PubMed: 22469325
DOI: 10.1016/B978-0-12-397220-0.00011-8 -
JAMA Neurology Sep 2017Given its selective action on the ω1 subtype of the γ-aminobutyric acid A receptor, zolpidem tartrate presents a potential treatment mechanism for other neurologic... (Review)
Review
IMPORTANCE
Given its selective action on the ω1 subtype of the γ-aminobutyric acid A receptor, zolpidem tartrate presents a potential treatment mechanism for other neurologic disorders.
OBJECTIVE
To synthesize studies that used zolpidem to treat neurologic disorders.
EVIDENCE REVIEW
Eligibility criteria included any published English-language article that examined the use of zolpidem for noninsomnia neurologic disorders in humans for all dates up to March 20, 2015. Searched databases included PubMed, Scopus, Web of Science Core Collection, the Cochrane Library, EMBASE, CENTRAL, and clinicaltrials.gov. Publication bias was mitigated by searching clinicaltrials.gov for unpublished studies. Two rounds of screening were performed based on title and then abstract, and coding was performed by 2 coders. All methods followed the PRISMA Reporting Guidelines for systematic reviews of the literature.
FINDINGS
The initial search produced 2314 articles after removing duplicates. After exclusion based on a review of abstracts, 67 articles remained for full manuscript review. Thirty-one studies treated movement disorders, 22 treated disorders of consciousness, and 14 treated other neurologic conditions, including stroke, traumatic brain injury, encephalopathy, and dementia. Study designs included case reports (n = 28), case series (n = 8), single-patient interventional (n = 13), pretest and posttest (n = 9), randomized clinical trials (n = 9), and crossover studies (n = 5). Only 11 studies had more than 10 participants. Effects of zolpidem were wide ranging (eg, improvement on the JFK Coma Recovery Scale-Revised, the Unified Parkinson Disease Rating Scale, and the Burke-Fahn-Marsden Dystonia Rating Scale) and generally lasted 1 to 4 hours before the participant returned to baseline. Sedation was the most common adverse effect.
CONCLUSIONS AND RELEVANCE
Zolpidem has been observed to transiently treat a large variety of neurologic disorders, most often related to movement disorders and disorders of consciousness. Much of what is known comes from case reports and small interventional trials. These findings may represent a new treatment mechanism for these disorders.
Topics: Consciousness Disorders; GABA-A Receptor Agonists; Humans; Movement Disorders; Nervous System Diseases; Pyridines; Zolpidem
PubMed: 28655027
DOI: 10.1001/jamaneurol.2017.1133 -
Psychiatry Research Oct 2022Zolpidem is one of the most commonly prescribed nonbenzodiazepine hypnotic drugs for insomnia. Published epidemiological studies linked zolpidem with the risk of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Zolpidem is one of the most commonly prescribed nonbenzodiazepine hypnotic drugs for insomnia. Published epidemiological studies linked zolpidem with the risk of suicide. However, to date, no meta-analysis investigated this association. Hence, we systematically reviewed and meta-analysed the current evidence from real-world studies reporting the risk of suicide with the use of zolpidem.
METHODS
Medline (Ovid), Embase (Ovid), and PsycINFO databases were searched from inception till June 2021 for real-world evidence studies reporting the risk of suicide with the use of zolpidem. The quality assessment of included studies was assessed using the New-Castle Ottawa Scale (NOS). Random-effect meta-analysis was performed using a generic inverse variance method.
RESULTS
This meta-analysis was based on four studies with 344,753 participants, of which 42,279 were zolpidem users. The methodological quality of all the included studies was of high quality. A significantly increased risk of suicide or suicide attempt was found in zolpidem users compared to non-users, with a pooled relative risk of 1.88 (95% CI: 1.54 - 2.30). Furthermore, an increased risk of suicidal death was observed in zolpidem users compared to non-users, with a pooled relative risk of 1.82 (95% CI: 1.43 - 2.30). Dose-response analysis also revealed a significantly increased risk of suicide in patients receiving ≥ 180cDDD (cumulative defined daily doses) of zolpidem (124 times), followed by 90-179cDDD (113 times) and <90cDDD (93 times) of zolpidem compared to non-users.
CONCLUSION
In conclusion, zolpidem use was associated with an increased risk of suicide or suicide attempt and suicidal death. Therefore, careful prescribing practices must be followed by considering the risk-benefit profile.
Topics: Humans; Risk Assessment; Sleep Initiation and Maintenance Disorders; Suicidal Ideation; Suicide, Attempted; Zolpidem
PubMed: 35985088
DOI: 10.1016/j.psychres.2022.114777 -
The Journal of Nervous and Mental... Jan 2020A post-2000 literature search reviewed prevalence of health consequences associated with zolpidem, plus two salient case reports. Common zolpidem-related harms... (Review)
Review
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.
Topics: Adult; Aged; Delirium; Hallucinations; Homicide; Humans; Male; Rage; Risk Factors; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Violence; Zolpidem
PubMed: 31834190
DOI: 10.1097/NMD.0000000000001074 -
Revista Colombiana de Psiquiatria... 2023Zolpidem is a non-benzodiazepine hypnotic agent used most frequently in the treatment of insomnia, indicated for short-term use. It is not indicated for the chronic... (Review)
Review
Zolpidem is a non-benzodiazepine hypnotic agent used most frequently in the treatment of insomnia, indicated for short-term use. It is not indicated for the chronic treatment of sleep disorders, despite which there is evidence in clinical practice that a large number of patients receive it for years. Although it has been described that it presents a better profile of adverse effects than benzodiazepines and that it generates a lower risk of dependence and withdrawal than these, there are significant reports of cases of dependence and withdrawal from zolpidem. A report of a case of generalized tonic-clonic seizures due to withdrawal at a dose of 300 mg per day of zolpidem is presented and a brief review of the literature is carried out.
Topics: Humans; Zolpidem; Pyridines; Seizures; Hypnotics and Sedatives; Benzodiazepines
PubMed: 37863763
DOI: 10.1016/j.rcpeng.2021.06.013 -
Osteoporosis International : a Journal... Oct 2016Zolpidem is a representative of non-benzodiazepine hypnotics. Recent epidemiologic studies have reported increased fracture risk in patients taking zolpidem, but the... (Meta-Analysis)
Meta-Analysis Review
UNLABELLED
Zolpidem is a representative of non-benzodiazepine hypnotics. Recent epidemiologic studies have reported increased fracture risk in patients taking zolpidem, but the results have been inconsistent. The present meta-analysis shows that the use of zolpidem is associated with an increased risk of fractures.
PURPOSE
Previous studies have reported inconsistent findings regarding the association between the use of zolpidem and the risk of fractures. We performed a systematic literature review and meta-analysis to assess the association.
METHODS
We identified relevant studies by searching MEDLINE, EMBASE, Cochrane Library, and PsycINFO without language restrictions (until August 2014). Methodological quality was assessed based on the Newcastle-Ottawa Scale (NOS).
RESULTS
A total of 1,092,925 participants (129,148 fracture cases) were included from 9 studies (4 cohort, 4 case-control, and 1 case-crossover study). Overall, the use of zolpidem was associated with an increased risk of fracture (relative risk [RR] 1.92, 95 % CI 1.65-2.24; I (2) = 50.9 %). High-quality subgroups (cohort studies, high NOS score, adjusted for any confounder, or adjusted for osteoporosis) had higher RRs than the corresponding low-quality subgroups (high quality, 1.94-2.76; low quality, 1.55-1.79). Of note, the risk for hip fracture was higher than that for fracture at any site (hip fracture, RR 2.80, 95 % CI 2.19-3.58; fracture at any site, RR 1.84, 95 % CI 1.67-2.03; P < 0.001).
CONCLUSIONS
The use of zolpidem may increase the risk of fractures. Clinicians should be cautious when prescribing zolpidem for patients at high risk of fracture.
Topics: Fractures, Bone; Humans; Pyridines; Risk; Zolpidem
PubMed: 27105645
DOI: 10.1007/s00198-016-3605-8 -
Lancet (London, England) Jul 2022Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently... (Meta-Analysis)
Meta-Analysis
BACKGROUND
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.
METHODS
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.
FINDINGS
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]).
INTERPRETATION
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.
FUNDING
UK National Institute for Health Research Oxford Health Biomedical Research Centre.
Topics: Adult; Benzodiazepines; Doxepin; Eszopiclone; Humans; Melatonin; Network Meta-Analysis; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 35843245
DOI: 10.1016/S0140-6736(22)00878-9 -
The Journal of Family Practice Jul 2023Insomnia is a distinct disorder that is common, yet underrecognized and undertreated in primary care. Treating insomnia has been shown to improve outcomes, including... (Review)
Review
Insomnia is a distinct disorder that is common, yet underrecognized and undertreated in primary care. Treating insomnia has been shown to improve outcomes, including reduced risk of developing cardiovascular and mental health disorders. Insomnia is influenced by the brain's regulation of sleep and wake, which are mutually exclusive events. Insomnia should be treated as a distinct condition, even when occurring with a comorbid diagnosis such as depression or anxiety. Clinicians should implement a multimodal approach to insomnia management, including nonpharmacologic interventions and pharmacologic therapy (when indicated). Pharmacologic agents that are approved by the US Food and Drug Administration for insomnia include benzodiazepine receptor agonists (zolpidem, eszopiclone, and zaleplon), low-dose doxepin (tricyclic antidepressant), ramelteon (melatonin receptor agonist), and dual orexin receptor agonists (DORAs, daridorexant, lemborexant, and suvorexant). Unlike other pharmacologic agents, DORAs inhibit wakefulness rather than induce sedation. Additionally, these medications have no evidence of rebound insomnia or withdrawal, and little to no abuse potential. Daridorexant is the newest DORA, has an ideal half-life of 8 hours, and has demonstrated continued efficacy over a 12-month period. Selection of pharmacologic agent should be based on the patient's comorbid conditions, treatment goals and preferences, and other clinical characteristics.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Sleep; Zolpidem; Doxepin
PubMed: 37549414
DOI: 10.12788/jfp.0620