Treatment Failure and Long-Term Prescription Risk for Guideline-Recommended Hypnotics in Japan.

Importance: Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. Objective: To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment. Design, Setting, and Participants: This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023. Exposures: Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy. Main Outcomes and Measures: The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively. Results: The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone. Conclusions and Relevance: Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.

Sleep-related adverse events of smoking cessation drugs: A network meta-analysis of randomized controlled trials.

Smoking cessation medications have the potential to affect the functioning of the nervous system, leading to sleep disturbances. Our study aimed to compare the sleep-related side effects (such as insomnia, abnormal dreams, nightmares, and somnolence) induced by different smoking cessation medications in non-psychiatric smokers. We conducted a thorough search of five electronic databases (Cochrane, EMBASE, PubMed, PsycInfo, and Web of Science) for randomized controlled trials. This study was registered with the PROSPERO (registration number CRD42022347976). A total of 79 full-text articles, encompassing 36,731 participants, were included in our analysis. Individuals using bupropion, bupropion in combination with a nicotinic acetylcholine receptor agonist (NRA), and bupropion in conjunction with nicotine replacement therapy (NRT) exhibited a higher likelihood of experiencing insomnia compared to those using NRT alone. Bupropion plus NRA had the highest ranking on the surface under the cumulative ranking curve (SUCRA) for insomnia risk, while placebo had the lowest ranking. Additionally, NRA plus NRT ranked first for abnormal dream outcomes, NRA alone for nightmares, and nortriptyline for somnolence, based on the SUCRA results. Healthcare providers should exercise caution when prescribing smoking cessation drugs, particularly in consideration of their potential sleep-related side effects.

Orexinergic Receptor Antagonists as a New Therapeutic Target to Overcome Limitations of Current Pharmacological Treatment of Insomnia Disorder.

Insomnia disorder is a common condition that is considered a risk factor for multiple physical and mental disorders, contributing to reduced quality of life and increased healthcare expenditures. Although cognitive behavioral therapy (CBT) is typically recommended as the primary intervention, its accessibility is hindered by limited resources, prompting the prevalent use of pharmacological interventions as the primary treatment in clinical settings. This study reviews the benefits and risks of current pharmacological treatments for insomnia, with special reference to the orexinergic system as a novel therapeutic target for treatment. The prescription of GABAergic mechanism enhancers (benzodiazepine (BZD) and "Z drugs") has shown efficacy in short-term insomnia treatment (less than 4 weeks), however, concerns arise regarding their long-term effectiveness, unfavorable tolerability and safety profiles, including the potential for dependency. Drugs with antihistamine properties, including certain antidepressants and antipsychotics, exhibit short-term efficacy but have documented tolerability limitations, especially in the elderly. The use of melatonin, available in various formulations, lacks comprehensive long-term data. Dual orexin receptor antagonists (DORAs) such as daridorexant, lemborexant, and suvorexant, represent a novel approach to insomnia treatment by inhibiting wakefulness rather than enhancing sedation. As the only DORA approved for insomnia treatment by the European Medicines Agency (EMA) and Food and Drug Administration (FDA), daridorexant has demonstrated sustained efficacy over a 12-month period, improving nocturnal sleep parameters and daytime functionality, with a favorable safety and tolerability profile.

Shen Yuan extract exerts a hypnotic effect via the tryptophan/5-hydroxytryptamine/melatonin pathway in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep plays a critical role in several physiologic processes, and sleep disorders increase the risk of depression, dementia, stroke, cancer, and other diseases. Stress is one of the main causes of sleep disorders. Ginseng Radix et Rhizoma and Polygalae Radix have been reported to have effects of calming the mind and intensifying intelligence in Chinese Pharmacopoeia. Traditional Chinese medicine prescriptions composed of Ginseng Radix et Rhizoma and Polygalae Radix (Shen Yuan, SY) are commonly used to treat insomnia, depression, and other psychiatric disorders in clinical practice. Unfortunately, the underlying mechanisms of the SY extract's effect on sleep are still unknown. AIM OF THE STUDY: This study aimed to investigate the hypnotic effect of the SY extract in normal mice and mice with chronic restraint stress (CRS)-induced sleep disorders and elucidate the underlying mechanisms. MATERIALS AND METHODS: The SY extract (0.5 and 1.0 g/kg) was intragastrically administered to normal mice for 1, 14, and 28 days and to CRS-treated mice for 28 days. The open field test (OFT) and pentobarbital sodium-induced sleep test (PST) were used to evaluate the hypnotic effect of the SY extract. Liquid chromatography-tandem mass spectrometry and enzyme-linked immunosorbent assay were utilized to detect the levels of neurotransmitters and hormones. Molecular changes at the mRNA and protein levels were determined using real-time quantitative polymerase chain reaction and Western blot analysis to identify the mechanisms by which SY improves sleep disorders. RESULTS: The SY extract decreased sleep latency and increased sleep duration in normal mice. Similarly, the sleep duration of mice subjected to CRS was increased by administering SY. The SY extract increased the levels of tryptophan (Trp) and 5-hydroxytryptamine (5-HT) and the expression of tryptophan hydroxylase 2 (TPH2) in the cortex of normal mice. The SY extract increased the Trp level, transcription and expression of estrogen receptor beta and TPH2 in the cortex in mice with sleep disorders by decreasing the serum corticosterone level, which promoted the synthesis of 5-HT. Additionally, the SY extract enhanced the expression of arylalkylamine N-acetyltransferase, which increased the melatonin level and upregulated the expressions of melatonin receptor-2 (MT2) and Cryptochrome 1 (Cry1) in the hypothalamus of mice with sleep disorders. CONCLUSIONS: The SY extract exerted a hypnotic effect via the Trp/5-HT/melatonin pathway, which augmented the synthesis of 5-HT and melatonin and further increased the expressions of MT2 and Cry1.

Sedative and hypnotic effects of the saponins from a traditional edible plant Liriope spicata Lour. in PCPA-induced insomnia mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Liriope spicata Lour., a species listed in the catalogue of 'Medicinal and Edible Homologous Species', is traditionally used for the treatment of fatigue, restlessness, insomnia and constipation. AIM OF THE STUDY: This study is aimed to evaluate the sedative and hypnotic effect of the saponins from a natural plant L. spicata Lour. in vivo. MATERIALS AND METHODS: The total saponin (LSTS) and purified saponin (LSPS) were extracted from L. spicata, followed by a thorough analysis of their major components using the HPLC-MS. Subsequently, the therapeutic efficacy of LSTS and LSPS was evaluated by the improvement of anxiety and depression behaviors of the PCPA-induced mice. RESULTS: LSTS and LSPS exhibited similar saponin compositions but differ in their composition ratios, with liriopesides-type saponins accounting for a larger proportion in LSTS. Studies demonstrated that both LSTS and LSPS can extend sleep duration and immobility time, while reducing sleep latency in PCPA-induced mice. However, there was no significant difference in weight change among the various mice groups. Elisa results indicated that the LSTS and LSPS could decrease levels of NE, DA, IL-6, and elevate the levels of 5-HT, NO, PGD2 and TNF-α in mice plasma. LSTS enhanced the expression of neurotransmitter receptors, while LSPS exhibited a more pronounced effect in regulating the expression of inflammatory factors. In conclusion, the saponins derived from L. spicata might hold promise as ingredients for developing health foods with sedative and hypnotic effects, potentially related to the modulation of serotonergic and GABAAergic neuron expression, as well as immunomodulatory process.

Zhumian Granules improves PCPA-induced insomnia by regulating the expression level of neurotransmitters and reducing neuronal apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Sleep problems, according to Traditional Chinese medicine (TCM) philosophy, are attributed to the imbalance between yin and yang. Zhumian Granules, also known as Sleep-aid Granules or ZG, are a traditional Chinese herbal remedy specifically designed to alleviate insomnia. This formula consists of many components, including Wu Wei Zi (Schisandrae Chinensis Fructus), Suan Zao Ren (Ziziphi Spinosae Semen), and other medicinal plants. According to the pharmacology of Traditional Chinese Medicine (TCM), Wu Wei Zi and Suan Zao Ren have the ability to relax the mind and promote sleep. When taken together, they may balance the opposing forces of yin and yang. Therefore, ZG may potentially be used as a therapeutic treatment for insomnia. AIM OF THE STUDY: This research was specifically developed to establish a strong empirical basis for the subsequent advancement and utilization of ZG in the management of insomnia. This research aimed to gather empirical data to support the effectiveness of ZG, thereby providing useful insights into its potential therapeutic advantages for persons with insomnia. MATERIALS AND METHODS: This study utilized Zhumian Granules (ZG), a traditional Chinese herbal decoction, to examine its sedative and hypnotic effects on mice with PCPA-induced insomnia. The effects were assessed using the pentobarbital-induced sleep test (PIST), Morris water maze test (MWM), and autonomic activity test. The levels of neurotransmitters in each group of mice were evaluated using UPLC-QQQ-MS. The impact of ZG on the quantity and structure of hippocampal neurons was seen in brain tissue slices using immunofluorescence labeling. RESULTS: ZG was shown to possess active sedative properties, effectively lowering the distance of movement and lengthening the duration of sleep. ZG mitigated the sleeplessness effects of PCPA by elevating the levels of 5-hydroxytryptamine (5-HT), 4-aminobutyric acid (GABA), and 5-hydroxyindoleacetic acid (5-HIAA), while reducing the levels of dopamine (DA) and norepinephrine (NE), as well as decreasing neuronal death. CONCLUSIONS: This research confirmed the sedative and hypnotic properties of ZG and elucidated its probable mechanism involving neurotransmitters.

[Effectiveness of Anvifen in the treatment of insomnia in elderly patients]. / Effektivnost' preparata Anvifen pri lechenii insomnii u pozhilykh patsientov.

OBJECTIVE: Purpose of the study to determine the effectiveness of Anvifen in the case of insomnia and meteosensitivity as comorbid stress-induced disorders. MATERIAL AND METHODS: 67 patients aged 60-70 years were examined, who were randomly divided into two groups: group 1 - 33 patients (20 men, 13 women), group 2 - 34 patients (19 men, 15 women). The average age of group 1 was 62.7 [61; 65] years, group 2 was 63.1 [60; 66] years (p=0.28). Research methods: questionnaire for scoring subjective characteristics of sleep, assessing the influence of meteosensitivity on daily activity using a numerical rank scale (NRS) for the previous three months. Patients in group 1 took Anvifen 250 mg (capsules) in the morning and afternoon, 500 mg (2 capsules) in the evening at 10 p.m., and upon awakening at night - an additional 250 mg of the drug per capsule. Patients in group 2 took Anvifen powder (extracting it from the capsule) 250 mg in the morning and afternoon, 500 mg in the evening at 10 p.m., and upon awakening at night - an additional 250 mg of the drug. The time from the nightly intake of Anvifen to the onset of sleep was also assessed on a three-degree scale: «fast¼, «long¼, «very long¼. The duration of treatment was 4 weeks. RESULTS: Baseline results of measured parameters did not differ significantly between groups. After completion of treatment, the total score of subjective sleep characteristics improved in 1st (p=0.00001) and 2nd (p=0.000001) groups. Significant differences from group 1 for the better in group 2 were in «quality of sleep¼ (p=0.00027) and «quality of awakening¼ (p=0.00001). Weather sensitivity decreased in 1st (p=0.00001) and 2nd (p=0.000001) groups. CONCLUSION: Anvifen showed good effectiveness in the treatment of two comorbid conditions of elderly people - insomnia and meteosensitivity. Using the drug in powder form allows you to get a faster and better effect without side-effects.

Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study.

INTRODUCTION: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. METHODS: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). RESULTS: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. CONCLUSIONS: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04742699.

A Comprehensive Review of Lemborexant to Treat Insomnia.

Purpose of Review: This is a comprehensive review of the literature regarding Lemborexant for the treatment of insomnia. It covers the background and management of insomnia and then reviews the body of existing evidence evaluating the use of Lemborexant for this purpose. Recent Findings: Insomnia leads to significant decreased in quality of life and economic burden due to decreased workplace performance and increased health care costs. Insomnia manifests as a single common pathway of hyperarousal due to a highly complex network of interactions between activation of the sympathetic system and the endocrine system. Lemborexant is a dual orexin 1/2 antagonist that blocks cortical arousal and promotes sleep state transition. Lemborexant was approved by the FDA in 2019 for use in insomnia. It belongs to a class of orexin neuropeptide inhibitors that is growing in popular clinical application. Summary: Insomnia is a crippling disorder of the sleep wake cycle that drives significant morbidity and mortality in the United States. It carries a high societal and economic toll due to direct and indirect effects to the healthcare system. Lemborexant is a new addition to the orexin antagonist class of drugs that already includes Almorexant and Suvorexant that has superior pharmacokinetic properties. While Lemborexant does have a mild side effect profile, its clinical safety and efficacy make it a promising insomnia drug of the future.

Insomnia and parasomnia induced by validated smoking cessation pharmacotherapies and electronic cigarettes: a network meta-analysis.

We aim to assess the relationship between validated smoking cessation pharmacotherapies and electronic cigarettes (e-cigarettes) and insomnia and parasomnia using a systematic review and a network meta-analysis. A systematic search was performed until August 2022 in the following databases: PUBMED, COCHRANE, CLINICALTRIAL. Randomized controlled studies against placebo or validated therapeutic smoking cessation methods and e-cigarettes in adult smokers without unstable or psychiatric comorbidity were included. The primary outcome was the presence of "insomnia" and "parasomnia." A total of 1261 studies were selected. Thirty-seven studies were included in the quantitative analysis (34 for insomnia and 23 for parasomnia). The reported interventions were varenicline (23 studies), nicotine replacement therapy (NRT, 10 studies), bupropion (15 studies). No studies on e-cigarettes were included. Bayesian analyses found that insomnia and parasomnia are more frequent with smoking cessation therapies than placebo except for bupropion. Insomnia was less frequent with nicotine substitutes but more frequent with bupropion than the over pharmacotherapies. Parasomnia are less frequent with bupropion but more frequent with varenicline than the over pharmacotherapies. Validated smoking cessation pharmacotherapies can induce sleep disturbances with different degrees of frequency. Our network meta-analysis shows a more favorable profile of nicotine substitutes for insomnia and bupropion for parasomnia. It seems essential to systematize the assessment of sleep disturbances in the initiation of smoking cessation treatment. This could help professionals to personalize the choice of treatment according to sleep parameters of each patient. Considering co-addictions, broadening the populations studied and standardizing the measurement are additional avenues for future research.

[Pharmacotherapies for insomnia]. / Traitements médicamenteux de l'insomnie.

PHARMACOTHERAPIES FOR INSOMNIA. The first line of treatment in adult chronic insomnia is cognitive behavioral therapy (CBT). However, its difficult accessibility limited its use and medications are still often prescribed. Considering the drugs with marketing authorization, Z-drugs (zolpidem and zopiclone) if taken at the right hour and dosage promote sleep initiation and have less deleterious effects than benzodiazepines, especially the long-acting ones which should be avoided. This class of drugs cannot be prescribed longer than 28 days. Some antihistaminic licensed drugs are authorized as hypnotics, with a low proof of efficacy and a risk of adverse event as sedation and somnolence the next day. Their prescription should be avoided in old subjects. Some clinicians used antidepressant sedative medications, at low dosage, as hypnotic drugs but "off label", outside authorization. Now melatonin, an endogenous synchronizer of biologic rhythms, has obtained the authorization for the treatment of insomniac troubles, in subjects of at least 55 years old, in its slow- release formula, replacing the physiological decline of this hormone with aging. Melatonin is not a hypnotic, but has soporific properties, inducing sleep, improving sleep efficacy, sometimes sleep duration and morning alertness. When discontinued, it induced no withdrawal syndrome. It has shown no risk of abuse potential and no deleterious side-effects, if used at the right dose and in the absence of hepatic interaction with other compounds. Finally, a new class of hypnotics, "the orexin antagonists" has its first representative on the French market: daridorexant. The place of these molecules in the therapeutic strategy for chronic insomnia needs to be clarified.

TRAITEMENTS MÉDICAMENTEUX DE L'INSOMNIE. Le traitement de première intention des adultes atteints d'insomnie chronique est la thérapie cognitivo-comportementale. Toutefois, compte tenu des difficultés d'accès à cette thérapeutique, les prescriptions médicamenteuses restent fréquentes. Considérant les médicaments qui ont une autorisation de mise sur le marché (AMM) dans cette indication, les Z-drugs (zolpidem et zopiclone), prises à bon escient, à la bonne posologie et à la bonne heure, favorisent l'initiation du sommeil et ont moins d'effets indésirables que les benzodiapézines, notamment celles à longue durée d'action, dont la prescription doit être évitée. Cette classe de médicaments est soumise à une réglementation particulière de durée de prescription (28 jours au maximum). Certains antihistaminiques peuvent être utiles comme hypnotiques, avec un faible niveau de preuve d'efficacité et des effets indésirables, notamment sur la vigilance du lendemain ; ils sont à éviter chez les sujets âgés. Certains antidépresseurs sédatifs sont prescrits, à faible dose, hors AMM. Plus récemment, la mélatonine, synchroniseur endogène des rythmes biologiques, a obtenu une AMM dans les troubles du sommeil du sujet âgé de 55 ans ou plus, dans sa formulation à longue durée d'action, suppléant la baisse physiologique de cette hormone avec l'âge. Induisant une somnolence, elle favorise l'endormissement, l'efficacité du sommeil, peut améliorer sa durée et assure un réveil de bonne qualité, sans accoutumance, sans syndrome de sevrage, et sans effet délétère majeur si l'on fait attention à la posologie et aux interactions médicamenteuses. Enfin, une nouvelle classe de médicaments, les anti-orexines, compte un premier représentant commercialisé en France : le daridorexant. La place de ces molécules dans la stratégie thérapeutique de l'insomnie chronique devra être précisée.

Residual effects of medications for sleep disorders on driving performance: A systematic review and network meta-analysis of randomized controlled trials: NMA driving and hypnotics.

Sleep medications often carry residual effects potentially affecting driving safety, warranting network meta-analysis (NMA). PubMed/EMBASE/TRID/Clinicaltrials.gov/WHO-ICTRP/WebOfScience were inquired for randomized controlled trials of hypnotic driving studies in persons with insomnia and healthy subjects up to 05/28/2023, considering the vehicle's standard deviation of lateral position - SDLP (Standardized Mean Difference/SMD) and driving impairment rates on the first morning (co-primary outcomes) and endpoint. Risk-of-bias, global/local inconsistencies were measured, and CINeMA was used to assess the confidence in the evidence. Of 4,805 identified records, 26 cross-over RCTs were included in the systematic review, of which 22 entered the NMA, focusing on healthy subjects only. After a single administration, most molecules paralleled the placebo, outperforming zopiclone regarding SDLP. In contrast, ramelteon 8 mg, daridorexant 100 mg, zolpidem 10 mg bedtime, zolpidem middle-of-the-night 10 mg and 20 mg, mirtazapine 15-30 mg, and triazolam 0.5 mg performed significantly worse than placebo. Lemborexant 2.5-5 mg, suvorexant 15-20 mg, and zolpidem 3.5 mg middle-of-the-night associated with lower impairment than zopiclone. Repeated administration (maximum follow-up time of ten days) caused fewer residual effects than acute ones, except for flurazepam. Heterogeneity and inconsistency were negligible. Confidence in the evidence was low/very low. Sensitivity analyses confirmed the main analyses. Most FDA-approved hypnotics overlapped placebo at in-label doses, outperforming zopiclone. Repeated administration for 15 days or less reduced residual effects, warranting further research on the matter.

Meaningful Within-Patient Change in Subjective Total Sleep Time in Patients with Insomnia Disorder: An Analysis of the Sleep Diary Questionnaire Using Data from Open-Label and Phase III Clinical Trials.

BACKGROUND: The Sleep Diary Questionnaire (SDQ), a modified version of the Consensus Sleep Diary, is a 17-item sleep diary for assessing subjective total sleep time (sTST: total time spent asleep at night) and other sleep parameters in insomnia trials. sTST is a key parameter of efficacy in insomnia trials; however, the magnitude of improvement in this parameter that people with insomnia disorder consider clinically meaningful is unclear. OBJECTIVE: The aim of this study was to estimate meaningful within-patient change for sTST using clinical trial data. METHODS: Data were from an open-label trial of zolpidem and pooled data from a phase III placebo-controlled trial of daridorexant. In both trials, adults with moderate to severe insomnia completed the SDQ daily. Meaningful change in sTST was estimated in an anchor-based analysis using outcome measures that were correlated with change in weekly average sTST (Spearman correlation coefficient ≥ 0.30): the Insomnia Severity Index, patient global assessments and impressions of severity and change in daytime and night-time symptoms (PGA-S, PGI-S, PGI-C), and clinician global impressions of severity and change in patients' daytime symptoms (CGI-S, CGI-C). Meaningful within-patient change estimates were 'triangulated' to identify a value where they converged. RESULTS: In the open-label trial (N = 114), subjects with a 1-point or 1-step improvement on the anchors had mean increases in sTST of 60.1-83.2 min at day 8 and 55.5-68.2 min at day 15. For subjects with a 2-point or 2-step improvement on the anchors, mean increases in sTST were 79.6-81.4 min at day 8 and 80.1-93.5 min at day 15. In the phase III trial (N = 930), weekly average increases in sTST for subjects with a 1-point or 1-step improvement on the anchors were 39.3-46.7 min at month 1 and 47.3-58.3 min at month 3. For subjects with a 2-point or 2-step improvement on the anchors, mean increases in sTST were 60.7-76.2 min at month 1 and 70.1-87.7 min at month 3. Triangulation of these values supported a meaningful within-patient change threshold starting at 55 min. CONCLUSION: Increasing sTST is an important treatment outcome for people with insomnia. An increase in sleep time of approximately 55 min is meaningful to patients. CLINICAL TRIALS REGISTRATION: NCT03056053 (17 February 2017) and NCT03545191 (4 June 2018).

Efficacy and safety of eszopiclone combined with drug therapy in the treatment of insomnia after stroke: A network meta-analysis and systematic review.

OBJECTIVE: To evaluate the efficacy and safety of multi-drug therapy based on eszopiclone in the treatment of insomnia after stroke using a network meta-analysis method and to provide evidence for clinical practice. METHOD: Computer searches of PubMed, Excerpt Medica Database (Embase), Cochrane Library Central Register of Controlled Trials, APA PsycInfo, CNKI, WanFang, Sinomed and other databases were performed to search for clinical randomized controlled studies (RCTs) on multi-drug therapy based on eszopiclone in the treatment of insomnia patients after stroke. The search time was from the establishment of each database until July 2023. The bias risk assessment tool recommended by Cochrane was used to evaluate the quality of the included RCTs. Stata 14.0 was applied to perform network meta-analysis using Review Manager 5.3 software for traditional meta-analysis. RESULT: Eighteen RCTs and 1646 patients were ultimately included, involving 11 treatment options. The results of the network meta-analysis showed that the ranking of Pittsburgh Sleep Quality Index (PSQI) decline was eszopiclone combined with sweet dream oral liquid (ESZ+SDOL)>eszopiclone combined with a shugan jieyu capsule (ESZ+SGJYC)>eszopiclone combined with agomelatine (ESZ+AGO)>eszopiclone combined with flupentixol and melitracen tablets (ESZ+FMT)>eszopiclone combined with yangxue qingnao granules (ESZ+YXQNG)>eszopiclone combined with mirtazapine (ESZ+MIR)>ESZ>FMT; the modified Edinburgh Scandinavia Stroke Scale (MESSS) decline ranking was ESZ+SDOL>ESZ+AGO>ESZ; and the clinical total effective rate ranking was eszopiclone combined with a xuefu zhuyu capsule (ESZ+XFZYC)>ESZ+MIR>ESZ+SGJYC>ESZ+SDOL> ESZ+FMT>ESZ+YXQNG>ESZ>FMT. In terms of clinical adverse reactions, in addition to ESZ therapy, ESZ+ESC had the highest number of adverse reactions, with abdominal pain being the most common. ESZ+YXQNG had the most types of adverse reactions, with 8 types. CONCLUSION: Multi-drug therapy based on eszopiclone can effectively improve the sleep quality of patients with insomnia after stroke, and ESZ+SDOL has significant efficacy and safety. However, due to the limitations of this study, efficacy ranking cannot fully explain the superiority or inferiority of clinical efficacy. In the future, more multicentre, large sample, double-blind randomized controlled trials are needed to supplement and demonstrate the results of this study.

Medications Used for Pediatric Insomnia.

Pediatric insomnia can affect physical and mental health and cause cognitive deficits, social deficits and decrease quality of life. There are no Food and Drug Administration approved medications approved for pediatric insomnia. Pharmacologic interventions derive mostly from adult data or pediatric case reports. This review focuses on Food and Drug Administration approved prescription drugs (in adults), over-the-counter drugs, and off-label pediatric insomnia drugs. This review helps the clinician learn general principles, practice guidelines, and pharmacologic considerations for medication selection in the pediatric population. Pharmacologic management should be considered in combination with behavior therapy, which is proven to have long-lasting outcomes.

UK Medical Cannabis Registry: Assessment of clinical outcomes in patients with insomnia.

INTRODUCTION: The primary aim of this study was to assess changes in sleep-specific health-related quality of life (HRQoL) for those prescribed cannabis-based medicinal products (CBMPs) for insomnia. METHODS: A case series of UK patients with insomnia was analyzed. Primary outcomes were changes in the Single-Item Sleep-Quality Scale (SQS), Generalized Anxiety Disorder-7 (GAD-7), and EQ-5D-5L at up to 6 months from baseline. Statistical significance was identified as a p value < .050. RESULTS: 61 patients were included in the analysis. There was an improvement in the SQS from baseline at 1, 3, and 6 months (p < .001). There were also improvements in the EQ-5D-5L Index value and GAD-7 at 1, 3, and 6 months (p < .050). There were 28 (45.9%) adverse events recorded by 8 patients (13.1%). There were no life-threatening/disabling adverse events. CONCLUSION: Patients with insomnia experienced an improvement in sleep quality following the initiation of CBMPs in this medium-term analysis. Fewer than 15% of participants reported one or more adverse events. However, due to the limitations of the study design, further investigation is required before definitive conclusions can be drawn on the efficacy of CBMPs in treating insomnia.

[Systematic review and Meta-analysis of efficacy and safety of Shumian Capsules in treatment of insomnia].

This study aims to assess the safety and efficacy of Shumian Capsules in the treatment of insomnia. Randomized controlled trial(RCT) about Shumian Capsules for insomnia were retrieved from databases. RevMan 5.4 was used for statistical analysis. A total of 23 articles were included, involving 2 621 patients. Meta-analysis showed that Shumian Capsules had advantages in the treatment of insomnia(RR=1.07, 95%CI[1.03, 1.10], P=0.000 2) and insomnia with depression(RR=1.13, 95%CI[1.02, 1.25], P=0.02) in terms of total response rate. Shumian Capsules had advantages in the treatment of insomnia(MD=-0.75, 95%CI[-1.33,-0.17], P=0.01) and insomnia with depression(MD=-2.51, 95%CI[-2.96,-2.06], P<0.000 01) in terms of PSQI score. The incidence of adverse events in the Shumian Capsules(RR=0.33, 95%CI[0.24, 0.46], P<0.000 01) and Shumian Capsules + conventional western medicine(RR=0.71, 95%CI[0.54, 0.95], P=0.02) was lower than that in the conventional wes-tern medicine alone. In addition, Shumian Capsules had an advantage in treating insomnia complicated with depression in terms of HAMD score(P<0.000 1) and reducing the serum levels of 5-HT, TSH, T3, and T4 in insomnia patients(P<0.05). The quality of evidence was mostly medium or low. The studies demonstrate that Shumian Capsules is effective and safe for treating insomnia, which may be related to the mechanism of lowering the levels of 5-HT, TSH, T3, and T4 in the serum. In view of the quality of evidence, the application of Shumian Capsules should be considered after comprehensive evaluation in clinical practice.

Treatment of Chronic Insomnia in Adults.

Insomnia affects 30% of the U.S. population, with 5% to 15% meeting criteria for chronic insomnia. It can negatively impact quality of life, decrease productivity, increase fatigue and drowsiness, and put patients at higher risk of developing other health problems. Initial treatment focuses on nonpharmacologic therapies such as cognitive behavior therapy, which improves negative thought patterns and behaviors through sleep restriction, stimulus control, and relaxation techniques. Other nonpharmacologic treatments include exercise, mindfulness, and acupuncture. If these approaches are ineffective, pharmacologic agents may be considered. Medications such as benzodiazepines and Z-drugs are often prescribed for insomnia but should be avoided, if possible, due to short- and long-term risks associated with their use. Melatonin receptor agonists are safer and well tolerated but have limited effectiveness. Dual orexin receptor antagonists are effective in patients who have sleep maintenance insomnia or difficulty with sleep onset. Evidence for the use of antihistamines to treat insomnia is generally lacking, but doxylamine is effective for up to four weeks.

Sophora flavescens alcohol extract ameliorates insomnia and promotes PI3K/AKT/BDNF signaling transduction in insomnia model rats.

Active ingredient of Sophora flavescens is reported to promote non-rapid eye movement (NREM) sleep. However, the role of Sophora flavescens alcohol extract in insomnia is elusive, which is addressed in this study, together with the exploration on its potential mechanism. An insomnia model of rats was established by para-chlorophenylalanine induction and further treated with SFAE or Zaoren Anshen capsule (ZRAS; positive control drug). Sleep quality and sleep architecture of rats were evaluated by the sleep test, electroencephalogram and electromyogram. The levels of monoamine neurotransmitters in rat hypothalamus were determined using ELISA, and the transduction of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/brain-derived neurotrophic factor (BDNF) signaling in the brain tissues of rats was examined by Western blot. SFAE and ZRAS increased the sleeping time and decreased the sleep latency of insomnia rats. SFAE reduced waking time and increased NREM and REM time, while changing power density of wakefulness, NREM sleep, and REM sleep in insomnia rats. SFAE and ZRAS upregulated levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, and downregulated those of norepinephrine and dopamine in insomnia rats. Besides, SFAE and ZRAS elevated BDNF expression as well as the ratios of phosphorylated (p)-PI3K/PI3K and p-AKT/AKT. The role of SFAE in insomnia model rats was similar with that of ZRAS. SFAE reduces insomnia and enhances the PI3K/AKT/BDNF signaling transduction in insomnia model rats, which can function as a drug candidate for insomnia.