-
Frontiers in Pharmacology 2023Systematic comparisons of the doses of the Food and Drug Administration (FDA)-approved dual orexin receptor antagonists (DORAs) for people with insomnia are limited....
Systematic comparisons of the doses of the Food and Drug Administration (FDA)-approved dual orexin receptor antagonists (DORAs) for people with insomnia are limited. PubMed, Embase, Cochrane Library, and Clinicaltrials. gov were systematically searched to identify relevant studies published before 31 October 2022. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. We pooled 7257 participants from 9 randomized controlled trials (RCTs). Moderate to high certainty evidence demonstrated suvorexant (20 and 40 mg) and daridorexant (10 and 50 mg) as the most effective in latency to persistent sleep (LPS) reduction. Lemborexant at 5 and 10 mg was the most effective in subjective sleep onset time (sTSO) reduction. For wake time after sleep onset (WASO), all drugs except daridorexant 5 mg were more effective than placebo. Lemborexant 5 mg was among the best in subjective WASO (sWASO) (moderate to high certainty) and had the highest surface under the curve ranking area (SUCRA) values for sWASO (100%). For total sleep time (TST), suvorexant and daridorexant, except the respective minimum doses, were more effective than placebo, while suvorexant 40 mg and lemborexant 10 mg may have been the most effective for subjective TST (sTST) (low to very low certainty). Suvorexant 40 mg (RR 1.09), suvorexant 80 mg (RR 1.65), and daridorexant 25 mg (RR 1.16) showed a higher safety risk than placebo. Suvorexant 20 mg, lemborexant 5 mg, lemborexant 10 mg, and daridorexant 50 mg represent suitable approaches for insomnia. clinicaltrials.gov, PROSPERO (CRD42022362655).
PubMed: 37261282
DOI: 10.3389/fphar.2023.1175372 -
Arquivos de Neuro-psiquiatria May 2023Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the superiority of one particular DORA over the others remains unclear.
OBJECTIVE
To perform a network meta-analysis to evaluate the efficacy of different DORAs in patients with chronic insomnia.
METHODS
The Medline, Embase, and Cochrane Central databases were searched for RCTs that compared DORA with placebo in patients ≥ 18 years of age with a diagnosis of insomnia disorder. We pooled outcomes for wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time (TST), and adverse events (AEs).
RESULTS
We included 10 RCTs with 7,806 patients, 4,849 of whom received DORAs as the intervention. Overall, we found that DORAs were associated with the improvement of all analyzed efficacy outcomes. Concerning TST, an apparent dose-dependent pattern was noticed, with higher doses relating to a longer TST. Lemborexant 10mg provided the largest reduction in WASO (at month 1) in minutes (standardized mean difference [SMD] = -25.40; 95% confidence interval [95%CI] = -40.02--10.78), followed by suvorexant 20/15mg (SMD = -25.29; 95%CI = -36.42--14.15), which also appeared to provide the largest decrease in long-term WASO (SMD = -23.70; 95%CI = -35.89--11.51). The most frequent AEs were somnolence, nasopharyngitis, and headache, with rates of up to 14.8%.
CONCLUSION
Our results suggest that DORAs are associated with greater efficacy when compared with placebo in the treatment of insomnia, a complex 24-hour sleep disorder. Additionally, dosing might play an important role in the management of chronic insomnia.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Orexin Receptor Antagonists; Network Meta-Analysis; Sleep; Wakefulness
PubMed: 37257468
DOI: 10.1055/s-0043-1768667 -
International Journal of Molecular... Apr 2023The sleep-wake cycle is a complex multifactorial process involving several neurotransmitters, including acetylcholine, norepinephrine, serotonin, histamine, dopamine,... (Review)
Review
The sleep-wake cycle is a complex multifactorial process involving several neurotransmitters, including acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexin and GABA, that can be, in turn, regulated by different nutrients involved in their metabolic pathways. Although good sleep quality in children has been proven to be a key factor for optimal cognitive, physical and psychological development, a significant and ever-increasing percentage of the pediatric population suffers from sleep disorders. In children, behavioral interventions along with supplements are recommended as the first line treatment. This systematic review was conducted, according to the PRISMA guidelines, with the purpose of assessing the principal nutrients involved in the pathways of sleep-regulating neurotransmitters in children and adolescents. Our focus was the utilization of over the counter (OTC) products, specifically iron, hydroxytryptophan, theanine and antihistamines in the management of different pediatric sleep disorders with the intention of providing a practical guide for the clinician.
Topics: Adolescent; Humans; Child; Sleep; Sleep Initiation and Maintenance Disorders; Histamine; Histamine Antagonists; Neurotransmitter Agents; Sleep Wake Disorders
PubMed: 37175525
DOI: 10.3390/ijms24097821 -
Drugs May 2023Pharmacological treatment is common in practice and widely used for the management of insomnia. However, evidence comparing the relative effectiveness, safety, and... (Meta-Analysis)
Meta-Analysis
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).
Topics: Humans; Sleep Initiation and Maintenance Disorders; Network Meta-Analysis; Randomized Controlled Trials as Topic; Antidepressive Agents; Sleep
PubMed: 36947394
DOI: 10.1007/s40265-023-01859-8 -
Medicine Feb 2023Daridorexant is a novel dual orexin receptor antagonist that has shown efficacy as a treatment for insomnia in multiple randomized clinical trials. However, the efficacy... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Daridorexant is a novel dual orexin receptor antagonist that has shown efficacy as a treatment for insomnia in multiple randomized clinical trials. However, the efficacy and safety of daridorexant for treatment of insomnia disorder has not been characterized comprehensively in the literature. Therefore, we performed a meta-analysis of available studies. We performed a meta-analysis to systematically evaluate the efficacy and safety of daridorexant for treatment of insomnia disorder.
METHODS
MEDLINE, Embase, Cochrane Library, and Clinicaltrials.gov for randomized controlled trials were systematically searched up to February 2022. Relative risk and standard mean difference were used to evaluate clinical outcomes.
RESULTS
We pooled 2271 patients from 4 randomized clinical trials, and evaluated efficacy endpoints. We found that 50 mg of daridorexant was superior to placebo for 4 efficacy outcomes including wake time after sleep onset, latency to persistent sleep, subjective total sleep time, and Insomnia Daytime Symptoms and Impacts Questionnaire domain score (P < .05). In addition, there were no significant differences (P > .05) in adverse events between daridorexant and placebo.
CONCLUSIONS
Different dosages of daridorexant were tested for treatment of insomnia; however, 5 and 10 mg are not available because of issues of suboptimal effectiveness. Daridorexant showed better efficacy and safety for treatment of insomnia disorder at doses of 25 and 50 mg.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Randomized Controlled Trials as Topic; Imidazoles; Pyrrolidines
PubMed: 36800596
DOI: 10.1097/MD.0000000000032754 -
Sleep Medicine Reviews Apr 2023Insomnia is one of the most common and burdensome disorders in adults. We compared and ranked insomnia medication on the basis of their efficacy and tolerability. We... (Meta-Analysis)
Meta-Analysis Review
Insomnia is one of the most common and burdensome disorders in adults. We compared and ranked insomnia medication on the basis of their efficacy and tolerability. We performed a systematic review and network meta-analysis of placebo-controlled or head-to-head randomized controlled trials for primary insomnia in adults comparing 20 drugs. We searched eight databases and seven trial registers from inception to March 1st, 2022. Primary outcomes included sleep latency (SL), awake time after sleep onset (WASO) and discontinuation for adverse events (AED), and secondary outcomes included total sleep time (TST), sleep efficiency (SE), sleep quality (SQ) and adverse events (ADE). Pooled standardized mean differences or odds ratios with 95% credible intervals were estimated using pairwise and network meta-analysis with random-effects. Differences among trial findings were explored in subgroup and sensitivity analyses. Confidence in evidence was assessed using GRADE. The PROSPERO registered number is CRD42020182144. We identified 22,538 records and included 69 studies (17,319 patients). Orexin receptor antagonists (ORAs) are more efficacious than benzodiazepine-like drugs (Z-drugs) and placebo for WASO and SE, and better than melatonin receptor agonists (MRAs) for SL, WASO and SE. ORAs ranked the best in SL (SUCRA value: 0.84), WASO (0.93), TST (0.86) and SE (0.96). Lemborexant and daridorexant (two ORAs) showed greater efficacy than placebo for SL, WASO, and TST, with good tolerability. Z-drugs were more efficacious than placebo for SL, WASO, TST and SE, but with higher risk to safety. Zaleplon and eszopiclone had better efficacy than placebo for TST and SQ respectively. MRAs may also be efficacious for sleep-onset insomnia with good safety. However, the long-term adverse effects of all medications are unclear. Insomnia medications differ in their efficacy and tolerability. ORAs have superior efficacy and tolerability. These findings should aid clinicians in matching risk/benefits of drugs available in their countries to insomnia symptoms.
Topics: Humans; Adult; Sleep Initiation and Maintenance Disorders; Network Meta-Analysis; Sleep; Hypnotics and Sedatives; Wakefulness; Treatment Outcome
PubMed: 36701954
DOI: 10.1016/j.smrv.2023.101746 -
Life (Basel, Switzerland) Jan 2023Background and objective: Obstructive sleep apnea (OSA) can be related to changes in the levels of adipokines and neuropeptides, which in turn may affect the energy... (Review)
Review
Background and objective: Obstructive sleep apnea (OSA) can be related to changes in the levels of adipokines and neuropeptides, which in turn may affect the energy balance components of neuronal cells. Herein, a systematic review and meta-analysis checked the changes in serum/plasma levels of omentin-1 (OM-1: an adipokine) and orexin-A (OXA: a neuropeptide) in adults (age > 18 years old) with OSA (aOSA) compared to controls. Materials and methods: Four databases (Cochrane Library, PubMed, Web of Science, and Scopus) were systematically searched until 14 November 2022, without any restrictions. The Joanna Briggs Institute (JBI) critical appraisal checklist adapted for case−control studies was used to assess the quality of the papers. The effect sizes were extracted using the Review Manager 5.3 software for the blood levels of OM-1 and OXA in aOSA compared with controls. Results: Thirteen articles, with six studies for OM-1 levels and eight for OXA levels, were included. The pooled standardized mean differences were −0.85 (95% confidence interval (CI): −2.19, 0.48; p = 0.21; I2 = 98%) and −0.20 (95%CI: −1.16, 0.76; p = 0.68; I2 = 96%) for OM-1 and OXA levels, respectively. Among the studies reporting OM-1, five were high and one was moderate quality. Among the studies reporting OXA, six were moderate, one was high, and one was low quality. Based on the trial sequential analysis, more participants are needed to confirm the pooled results of the analyses of blood levels of OM-1 and OXA. In addition, the radial plot showed outliers as significant factors for high heterogeneity. Conclusions: The main findings indicated a lack of association between the blood levels of OM-1 and OXA and OSA risk. Therefore, OM-1 and OXA did not appear to be suitable biomarkers for the diagnosis and development of OSA.
PubMed: 36676194
DOI: 10.3390/life13010245 -
Neurological Sciences : Official... May 2023Insomnia is a common condition that may be caused by or coexist with other medical or psychological illnesses. Nearly a quarter of a billion people across the globe... (Review)
Review
INTRODUCTION
Insomnia is a common condition that may be caused by or coexist with other medical or psychological illnesses. Nearly a quarter of a billion people across the globe suffer from insomnia frequently. Lemborexant, a dual orexin receptor antagonist, is a recently authorized hypnotic-based medication for insomnia. The purpose of this systematic review is to further investigate its efficacy and safety profile, with the primary goal of comparing the effects of two FDA-approved doses of lemborexant, 5 mg and 10 mg (LEM5 and LEM10, respectively).
MATERIALS AND METHODS
PubMed, Google Scholar, ClinicalTrials.gov, and Cochrane Central were searched for relevant literature, and studies were considered if they compared the efficacy and safety of lemborexant 5 mg to lemborexant 10 mg. This study comprised clinical trials.
RESULTS
A total of 6 studies were evaluated for efficacy and safety of lemborexant therapy. They reported a significant betterment in values pertaining to sleep efficacy, sleep onset latency, wake after sleep onset, total sleep time, sleep quality, ISI score, and morning alertness. The results presented a dose-dependent pattern and showed slight variation with the different dosages. The most prevalent side effects noted were somnolence, headaches, and dizziness, with infections like UTIs and upper respiratory tract infections also being commonly reported. The incidence is rather ambiguous and not sincerely dose-dependent. The differences between results for LEM5 and LEM10 do not exhibit a wide variation, although slight dose-dependent alterations are noted.
CONCLUSION
Lemborexant is well integrated with the amelioration of sleep disturbances in insomniac patients, as shown by a decrease in eSOL and sWASO and a rise in sSE, sTST, quality of sleep, and morning alertness. Effects last 12 months after therapy.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Pyridines; Pyrimidines; Hypnotics and Sedatives; Orexin Receptor Antagonists
PubMed: 36633778
DOI: 10.1007/s10072-023-06601-6 -
Frontiers in Psychiatry 2022Recent treatment guidelines for chronic insomnia recommend pharmacological and non-pharmacological therapies. One of the contemporary drug options for insomnia includes...
Dual orexin receptor antagonists for treatment of insomnia: A systematic review and meta-analysis on randomized, double-blind, placebo-controlled trials of suvorexant and lemborexant.
STUDY OBJECTIVES
Recent treatment guidelines for chronic insomnia recommend pharmacological and non-pharmacological therapies. One of the contemporary drug options for insomnia includes dual orexin receptor antagonist (DORA), such as suvorexant and lemborexant. We conducted a systematic review and meta-analysis for the treatment of insomnia with suvorexant and lemborexant based on randomized, double-blind, placebo-controlled Trials.
METHODS
We conducted a comprehensive search on three databases (PubMed/Medline, Web of Science, and Cochrane Library) till August 14, 2021, without any restrictions to retrieve the relevant articles. The effect sizes were computed presenting the pooled mean difference or risk ratio along with 95% confidence interval of each outcome.
RESULTS
Our search showed eight articles (five for suvorexant and three for lemborexant). Results of diary measures, rating scales, polysomnography results, treatment discontinuation, and adverse events were measured. All efficacy outcome measures favorably and significantly differed in the suvorexant compared to placebo. Safety profile did not differ significantly except for somnolence, excessive daytime sleepiness/sedation, fatigue, back pain, dry mouth, and abnormal dreams. Important adverse events including hallucinations, suicidal ideation/behavior and motor vehicle accidents did not differ between suvorexant and placebo. All the efficacy outcomes significantly differed between lemborexant 5 and lemborexant 10 compared to placebo. Somnolence rate for lemborexant 5 and lemborexant 10 and nightmare for lemborexant 10 were significantly higher than placebo.
CONCLUSION
The present meta-analysis reported that suvorexant and lemborexant are efficacious and safe agents for the patients with insomnia. Further data in patients with insomnia and various comorbid conditions are needed.
PubMed: 36578296
DOI: 10.3389/fpsyt.2022.1070522 -
International Clinical... Jan 2023Daridorexant is a novel dual orexin receptor antagonist used in treating insomnia disorder. Daridorexant improves sleep quality without impairing daytime functioning. We... (Meta-Analysis)
Meta-Analysis
Daridorexant is a novel dual orexin receptor antagonist used in treating insomnia disorder. Daridorexant improves sleep quality without impairing daytime functioning. We assess the safety and efficacy of this novel drug in the treatment of insomnia. We performed a systematic search for electronic databases in SCOPUS, PubMed, Web of Science and the Cochrane library. Seven randomized controlled trials were included in this review, with 2425 participants enrolled. Daridorexant was superior to placebo in reducing wake time after sleep onset (MD = -13.26; 95% CI, -15.48 to -11.03; P < 0.00001), latency to persistent sleep (MD = -7.23; 95% CI, -9.60 to -4.85; P < 0.00001), with increasing the total sleep time (MD = 14.80; 95% CI, 11.18-18.42; P < 0.00001) and subjective total sleep time (MD = 14.80; 95% CI, 11.18-18.42], P < 0.00001). The 25 mg and 50 mg were the most officious doses. Treatment with daridorexant has resulted in a slightly higher incidence of adverse events [risk ratio (RR) = 1.19; 95% CI, 1.05-1.35;, P = 0.005], specifically somnolence (RR = 1.19; 95% CI, 1.13-3.23; P = 0.005) and fatigue (RR = 2.01; 95% CI, 1.21-3.36; P = 0.007). Daridorexant is superior to placebo in improving sleep quality. However, the drug resulted in a slightly higher incidence of adverse events, including somnolence and fatigue.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Randomized Controlled Trials as Topic
PubMed: 36473030
DOI: 10.1097/YIC.0000000000000425