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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and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials.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 -
American Family Physician Jul 2017Insomnia accounts for more than 5.5 million visits to family physicians each year. Although behavioral interventions are the mainstay of treatment, pharmacologic therapy... (Review)
Review
Insomnia accounts for more than 5.5 million visits to family physicians each year. Although behavioral interventions are the mainstay of treatment, pharmacologic therapy may be necessary for some patients. Understanding the risks and benefits of insomnia medications is critical. Controlled-release melatonin and doxepin are recommended as first-line agents in older adults; the so-called z-drugs (zolpidem, eszopiclone, and zaleplon) should be reserved for use if the first-line agents are ineffective. For the general population with difficulty falling asleep, controlled-release melatonin and the z-drugs can be considered. For those who have difficulty staying asleep, low-dose doxepin and the z-drugs should be considered. Benzodiazepines are not recommended because of their high abuse potential and the availability of better alternatives. Although the orexin receptor antagonist suvorexant appears to be relatively effective, it is no more effective than the z-drugs and much more expensive. Sedating antihistamines, antiepileptics, and atypical antipsychotics are not recommended unless they are used primarily to treat another condition. Persons with sleep apnea or chronic lung disease with nocturnal hypoxia should be evaluated by a sleep specialist before sedating medications are prescribed.
Topics: Benzodiazepines; Doxepin; Humans; Hypnotics and Sedatives; Melatonin; Sleep Initiation and Maintenance Disorders
PubMed: 28671376
DOI: No ID Found -
Deutsches Arzteblatt International Oct 2019Sleep-related disorders are a group of illnesses with marked effects on patients' quality of life and functional ability. Their diagnosis and treatment is a matter of... (Review)
Review
BACKGROUND
Sleep-related disorders are a group of illnesses with marked effects on patients' quality of life and functional ability. Their diagnosis and treatment is a matter of common interest to multiple medical disciplines.
METHODS
This review is based on relevant publications retrieved by a selective search in PubMed (Medline) and on the guide- lines of the German Society for Sleep Medicine, the German Neurological Society, and the German Association for Psychiatry, Psychotherapy and Psychosomatics.
RESULTS
A pragmatic classification of sleep disorders by their three chief complaints-insomnia, daytime somnolence, and sleep-associated motor phenomena-enables tentative diagnoses that are often highly accurate. Some of these disorders can be treated by primary care physicians, while others call for referral to a neurologist or psychiatrist with special experience in sleep medicine. For patients suffering from insomnia as a primary sleep disorder, rather than a symptom of another disease, meta-analyses have shown the efficacy of cognitive behavioral therapy, with high average effect sizes. These patients, like those suffering from secondary sleep disorders, can also benefit from drug treatment for a limited time. Studies have shown marked improvement of sleep latency and sleep duration from short-term treatment with benzodiazepines and Z-drugs (non- benzodiazepine agonists such as zolpidem and zopiclone), but not without a risk of tolerance and dependence. For sleep disorders with the other two main manifestations, specific drug therapy has been found to be beneficial.
CONCLUSION
Sleep disorders in neurology and psychiatry are a heterogeneous group of disorders with diverse manifestations. Their proper diagnosis and treatment can help prevent secondary diseases and the worsening of concomitant conditions. Care structures for the treatment of sleep disorders should be further developed.
Topics: Humans; Neurology; Psychiatry; Sleep Wake Disorders
PubMed: 31709972
DOI: 10.3238/arztebl.2019.0681 -
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 -
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 -
Journal of Clinical Sleep Medicine :... Feb 2017The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, when such treatment is...
INTRODUCTION
The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual drugs commonly used to treat insomnia. It includes drugs that are FDA-approved for the treatment of insomnia, as well as several drugs commonly used to treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and treatment of chronic insomnia in adults.
METHODS
The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and harms, and patient values and preferences. Literature reviews are provided for those pharmacologic agents for which sufficient evidence was available to establish recommendations. The AASM Board of Directors approved the final recommendations.
RECOMMENDATIONS
The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of chronic insomnia in adults, when such treatment is indicated. Under GRADE, a STRONG recommendation is one that clinicians should, under most circumstances, follow. A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients, but should not be construed as an indication of ineffectiveness. GRADE recommendation strengths do not refer to the magnitude of treatment effects in a particular patient, but rather, to the strength of evidence in published data. Downgrading the quality of evidence for these treatments is predictable in GRADE, due to the funding source for most pharmacological clinical trials and the attendant risk of publication bias; the relatively small number of eligible trials for each individual agent; and the observed heterogeneity in the data. The ultimate judgment regarding propriety of any specific care must be made by the clinician in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources. We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use triazolam as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use doxepin as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use tiagabine as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use melatonin as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use tryptophan as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use valerian as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK).
Topics: Academies and Institutes; Adult; Central Nervous System Depressants; Chronic Disease; GABA Modulators; Humans; Hypnotics and Sedatives; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Sleep Medicine Specialty; United States
PubMed: 27998379
DOI: 10.5664/jcsm.6470 -
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