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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and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials.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 -
Neuroscience and Biobehavioral Reviews May 2020Akinetic mutism (AM) is a rare neurological disorder characterized by the presence of an intact level of consciousness and sensorimotor capacity, but with a simultaneous... (Review)
Review
Akinetic mutism (AM) is a rare neurological disorder characterized by the presence of an intact level of consciousness and sensorimotor capacity, but with a simultaneous decrease in goal-directed behavior and emotions. Patients are in a wakeful state of profound apathy, seemingly indifferent to pain, thirst, or hunger. It represents the far end within the spectrum of disorders of diminished motivation. In recent years, more has become known about the functional roles of neurocircuits and neurotransmitters associated with human motivational behavior. More specific, there is an increasing body of behavioral evidence that links specific damage of functional frontal-subcortical organization to the occurrence of distinct neurological deficits. In this review, we combine evidence from lesion studies and neurophysiological evidence in animals, imaging studies in humans, and clinical investigations in patients with AM to form an integrative theory of its pathophysiology. Moreover, the specific pharmacological interventions that have been used to treat AM and their rationales are reviewed, providing a comprehensive overview for use in clinical practice.
Topics: Adrenergic Uptake Inhibitors; Akinetic Mutism; Animals; Dopamine Agonists; Dopamine Uptake Inhibitors; Dopaminergic Neurons; GABA-A Receptor Agonists; Gray Matter; Humans; Motivation; Zolpidem
PubMed: 32044373
DOI: 10.1016/j.neubiorev.2020.02.006 -
Handbook of Experimental Pharmacology 2019Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABA receptors. Pharmacogenetic experiments...
Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABA receptors, continue to be some of the most effective compounds to treat primary insomnia.
Topics: Hypnotics and Sedatives; Receptors, GABA; Receptors, GABA-A; Sleep; Zolpidem
PubMed: 28993837
DOI: 10.1007/164_2017_56 -
Health Psychology Research 2021Insomnia is a common type of sleep disorder defined by an ongoing difficulty initiating or maintaining sleep or nonrestorative sleep with subsequent daytime impairment.... (Review)
Review
PURPOSE OF REVIEW
Insomnia is a common type of sleep disorder defined by an ongoing difficulty initiating or maintaining sleep or nonrestorative sleep with subsequent daytime impairment. The sleep disturbances in insomnia usually manifest as difficulty in falling asleep, maintaining the continuity of sleep, or waking up too early in the morning well before the desired time, irrespective of the adequate circumstances to sleep every night. Insomnia can significantly impact daytime functioning resulting in decreased workplace productivity, proneness to errors and accidents, inability to concentrate, frequent daytime naps, and poor quality of life.The treatment of insomnia should involve a multi-disciplinary approach, focusing on implementing behavioral interventions, improving sleep hygiene, managing psychological stressors, hypnotic treatment, and pharmacological therapy. The most effective therapies utilize cognitive behavioral therapy in conjunction with pharmacotherapy to minimize the needed dose and any resulting side effects. Non-benzodiazepine hypnotics such as zolpidem, eszopiclone, zaleplon are the most used as adjunctive treatment. One of the most used of these hypnotics is zolpidem. However, zolpidem has a wide variety of adverse effects and has some special considerations noted in the literature.
RECENT FINDINGS
Zolpidem has been associated with an increased risk of falls in hospitalized patients with an OR of 4.28 (P <0.001) when prescribed short-term for insomnia. The relative risk (RR) for hip fractures in patients taking zolpidem was described as 1.92 (95% CI 1.65-2.24; P<0.001), with hip fractures being the most commonly seen. A case series of 119 inpatients aged 50 or older demonstrated that a majority (80.8%) of ADRs were central nervous system (CNS)-related such as confusion, dizziness, and daytime sleepiness. A systematic review of 24 previous studies of sleepwalking associated with zolpidem demonstrated that the association was not dependent on age, dose, medical history, or even a history of sleepwalking at any time before zolpidem use. Suicide attempts and completion have been successfully linked with zolpidem use (OR 2.08; 95% CI 1.83-2.63) in patients regardless of the presence of comorbid psychiatric illness. There have been multiple cases reported of seizures following the withdrawal of zolpidem. Most cases have demonstrated that withdrawal seizures occurred in patients taking daily dosages of around 450-600mg/day, but some reported them as low as 160mg/day. Rebound insomnia has been a concern to prescribers of zolpidem. Sleep onset latency has been demonstrated to be significantly increased on the first night after stopping zolpidem (13.0 minutes; 95% CI 4.3-21.7; P<0.01). Women had a non-significantly higher mean plasma concentration than men after 8 hours for the 10mg IR (28 vs. 20 ng/mL) and the 12.5mg MR (33 vs. 28ng/mL). The FDA has classified zolpidem as a category C drug based on adverse outcomes seen in animal fetal development. In the mothers exposed to zolpidem, there was an increased incidence of low birth weight (OR = 1.39; P<0.001), preterm delivery (OR 1.49; P<0.001), small for gestational age (SGA) babies (OR = 1.34; P<0.001), and cesarean deliveries (OR =1.74; P<0.001). The rate of congenital abnormalities was not significantly increased with zolpidem (0.48 vs 0.65%; P = 0.329).
SUMMARY
Insomnia is linked to fatigue, distractibility, mood instability, decreased satisfaction, and overall decreased quality of life. Optimal therapy can aid patients in returning to baseline and increase their quality of life. Zolpidem is a helpful drug for the treatment of insomnia in conjunction with cognitive-behavioral therapy. When prescribed to elderly patients, the dose should be adjusted to account for their slower drug metabolism. Still, zolpidem is considered a reasonable choice of therapy because it has a lower incidence of residual daytime sleepiness and risk of falls when compared to other drugs. The most concerning adverse effects, which are often the most publicized, include the complex behaviors that have been seen in patients taking Zolpidem, such as sleeping, hallucinations, increased suicidality, driving cars while asleep, and even a few cases of committing homicide. Even so, zolpidem could be a suitable pharmacological treatment for insomnia. Decisions for whether or not to prescribe it and the dosage should be made on a case-by-case basis, considering both the psychical and psychiatric risks posed to the patient with insomnia versus if the patient were to take zolpidem to treat their condition.
PubMed: 34746488
DOI: 10.52965/001c.24927 -
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 -
Paediatric Drugs Jun 2017A large proportion of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) have associated sleep problems which not only affect the child's wellbeing... (Review)
Review
Safety, Tolerability and Efficacy of Drugs for Treating Behavioural Insomnia in Children with Attention-Deficit/Hyperactivity Disorder: A Systematic Review with Methodological Quality Assessment.
OBJECTIVE
A large proportion of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) have associated sleep problems which not only affect the child's wellbeing but also impact family functioning. Management of sleep problems is consequently an important aspect of overall ADHD management in paediatric patients. Although some drugs are being used off-label for the management of paediatric insomnia, there is scant clinical evidence supporting their use. Our aim was to identify and assess the quality of published studies reporting the safety, tolerability and efficacy of drugs used for treating behavioural insomnia in children with ADHD.
METHODS
After an initial screen to determine which drugs were most commonly used, we conducted a systematic review of English-language publications from searches of PubMed, EMBASE, PsycINFO and two trial register databases to February 2017, using keywords 'clonidine', 'melatonin', 'zolpidem', 'eszopiclone', 'L-theanine', 'guanfacine', 'ADHD', 'sleep disorder' and 'children'. For quality assessment of included studies, we used the CONSORT checklist for randomised control trials (RCTs) and the Downs and Black checklist for non-RCTs.
RESULTS
Twelve studies were included. Two case series for clonidine, two RCTs and four observational studies for melatonin and one RCT each for zolpidem, eszopiclone, L-theanine and guanfacine. Of the 12 included studies, only one on eszopiclone scored excellent for quality. The quality of the rest of the studies varied from moderate to low. For clonidine, melatonin and L-theanine, improvements in sleep-onset latency and total sleep duration were reported; however, zolpidem, eszopiclone and guanfacine failed to show any improvement when compared with placebo. Clonidine, melatonin, L-theanine, eszopiclone and guanfacine were well tolerated with mild to moderate adverse events; zolpidem was associated with neuropsychiatric adverse effects.
CONCLUSION
There is generally poor evidence for prescribing drugs for behavioural insomnia in children with ADHD. Further controlled studies are warranted.
Topics: Attention Deficit Disorder with Hyperactivity; Child; Clonidine; Eszopiclone; Glutamates; Guanfacine; Humans; Melatonin; Observational Studies as Topic; Pyridines; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 28391425
DOI: 10.1007/s40272-017-0224-6 -
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 -
Nature Oct 2023Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including...
Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants. However, our understanding of GABAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAR assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1β2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.
Topics: Animals; Mice; Binding Sites; Cryoelectron Microscopy; Depression, Postpartum; Flurazepam; gamma-Aminobutyric Acid; Hypnotics and Sedatives; Ion Channel Gating; Neurosteroids; Photobleaching; Pregnanolone; Protein Conformation; Protein Subunits; Receptors, GABA-A; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 37730991
DOI: 10.1038/s41586-023-06556-w