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.

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.

Efficacy of Zhumian Tang formula granules combined with eszopiclone for the treatment of poor sleep quality: a multi-center, randomized controlled, superiority trial.

OBJECTIVE: To evaluate the efficacy and safety of Zhumian Tang formula granules combined with eszopiclone for treating poor sleep quality. METHODS: This multi-center, dynamic block-randomized, parallel-group superiority clinical trial included 130 patients. The combined treatment group received Zhumian Tang formula granules combined with eszopiclone treatment, and the control group received eszopiclone treatment only. The group allocation ratio was 1∶1. The duration of treatment was 2 weeks. Participants were asked to complete questionnaires before treatment, after 1 week of the intervention, after 2 weeks of the intervention, and at the follow-up on week 3. The primary outcomes were the Pittsburgh Sleep Quality Index (PSQI) score and the total effective rate of treatment. The secondary outcome was the rate of adverse effects. RESULTS: Compared with the eszopiclone treatment group, the PSQI score of the combined treatment group was significantly lower after 2 weeks of the intervention (6.98 vs 8.26, P < 0.05). However, there was no significant difference in the mean PSQI score after 1 week of the intervention (9.89 vs 9.15, P = 0.124). After the follow-up on week 3, the PSQI score of the combined treatment group remained significantly lower than that of the eszopiclone treatment group (6.12 vs 8.31, P < 0.001). The total effective rates of treatment of the combined group and the eszopiclone group were 36.92% vs 35.38% (Z = 0.033, P = 0.855) after 1 week of the intervention, 83.08% vs 58.46% (Z = 9.519, P < 0.05) after 2 weeks of the intervention, and 83.08% vs 61.54% (Z = 7.530, P < 0.05) and after the follow-up on week 3, respectively. There was no significant difference in the overall rate of adverse reactions between the combined and eszopiclone treatment groups (21.53% vs 31.8%, P = 0.318). CONCLUSION: The combination of Zhumian Tang formula granules with eszopiclone was found to be safe and more effective in improving sleep quality than eszopiclone alone. Traditional Chinese medicine can enhance the effectiveness of Western medicine in the treatment of insomnia.

Improved Sleep Affects Epigastric Pain in Functional Dyspepsia by Reducing the Levels of Inflammatory Mediators.

INTRODUCTION: The pathogenesis of epigastric pain in functional dyspepsia (FD) is complex. The study aims to explore the effect of sleep improvement on this symptom. METHODS: In total, 120 patients with FD-associated epigastric pain and insomnia were randomly divided into experimental and control groups using the envelope method. After applying the exclusion criteria, 107 patients were enrolled in the experimental (56 patients) and control (51 patients) groups. Insomnia was graded according to the Pittsburgh Sleep Quality Index (PSQI). In the experimental group, eszopiclone 3 mg, eszopiclone 3 mg + estazolam 1 mg, and eszopiclone 3 mg + estazolam 2 mg were given to patients with mild, moderate, and severe insomnia, respectively. In the control group, patients were given 1, 2, or 3 tablets of vitamin B complex. Patient sleep quality was monitored with Sleepthing. Epigastric pain was evaluated with a Numeric Rating Scale. The serum levels of IL-1ß, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. Pain scores, sleep parameters, and serum levels of inflammatory mediators were compared before and after treatment. RESULTS: After treatment, the pain scores, sleep parameters, and TNF-α and IL-6 levels in the experimental group were significantly lower than those in the control group (p < 0.05). PSQI insomnia scores were significantly associated with pain scores, IL-6, and TNF-α (p < 0.05) but not in IL-8 and IL-1ß levels (p > 0.05) among the three groups. CONCLUSIONS: Improving sleep with eszopiclone and/or estazolam alleviates FD-associated epigastric pain, possibly by inhibiting related downstream transmission pathways and reducing the release of inflammatory mediators.

Evaluation of anticholinergic burden in elderly outpatients and the risk factors. / è€å¹´é—¨è¯Šæ‚£è€ æŠ—èƒ†ç¢±èƒ½å¤„æ–¹è´Ÿæ‹ è¯„ä»·åŠå ¶å±é™©å› ç´ .

OBJECTIVES: The use of anticholinergic drugs in the elderly may lead to negative events such as falls, delirium, urinary retention and cognitive decline, and the higher the number of anticholinergic drugs use, the more such negative events occur. This study aims to analyze the risk factors associated with the prescription of total anticholinergic drugs in elderly outpatients and evaluate the rationality of anticholinergic drugs, and to provide a reference for reducing the adverse effects of anticholinergic drugs. METHODS: A list of drugs with anticholinergic activity based on the Beers criteria was established. The basic information (such as age and gender), clinical diagnosis, and medications of elderly outpatient were extracted from hospital electronic medical records, and the Anticholinergic Cognitive Burden (ACB) Scale was used to calculate the anticholinergic burden for each patient. Logistic regression analysis was used to identify the potential risk factors for the occurrence of problems such as multiple medication and insomnia. RESULTS: A total of 1 840 prescriptions for elderly patients were reviewed. Of these patients, ACB score was more than or equal to 1 in 648 (35.22%) patients. Number of prescription medication (95% CI: 1.221 to 1.336) and insomnia (95% CI: 3.538 to 6.089) were independent factors affecting ACB scores (both P<0.01). Medications for patients of ACB scores were most commonly treated with the central nervous system drugs (such as alprazolam and eszopiclone) and for the cardiovascular system drugs (such as metoprolol and nifedipine). CONCLUSIONS: There is a high rate of ACB drugs use in geriatric patients, and the clinical focus should be on multiple medication prescriptions, especially on the central nervous system drugs (such as alprazolam and eszopiclone) and cardiovascular system drugs (such as metoprolol and nifedipine). The prescription review should be emphasized to reduce adverse reactions to anticholinergic drugs in elderly patients.

Network meta-analysis comparing the effectiveness of a prescription digital therapeutic for chronic insomnia to medications and face-to-face cognitive behavioral therapy in adults.

OBJECTIVE: The purpose of this study was to compare the effectiveness of the only Food and Drug Administration-authorized prescription digital therapeutic (PDT) Somryst versus face-to-face cognitive behavioral therapy for insomnia (CBT-I), or FDA-approved prescription medications for insomnia. METHODS: A systematic literature review was undertaken to identify relevant studies. A Bayesian network meta-analysis (NMA) was conducted to examine (1) mean change in insomnia severity index (ISI); (2) proportional change in ISI remitters; (3) mean change in wake after sleep onset (WASO); and (4) mean change in sleep onset latency (SOL). RESULTS: Twenty studies provided data on the PDT, CBT-I, CBT-I in combination with self-help (SH), or two prescription medications (eszopiclone and zolpidem). The PDT was associated with significant mean change in ISI (-5.77, 95% Credible Interval [CrI] - 8.53, -3.07) and ISI remitters (OR 12.33; 95% CrI 2.28, 155.91) compared to placebo, and had the highest probability of being the most effective treatment overall for ISI mean change (56%), and ISI remitters (64%). All evaluated interventions significantly outperformed placebo for WASO but no significant differences were observed for SOL (five interventions). Sensitivity analyses excluding medications and meta-regression (assessing type, duration, delivery method for CBT-I) did not affect NMA results. CONCLUSIONS: This network meta-analysis demonstrated that a PDT delivering CBT-I had the highest probability of being most effective compared to face-to-face CBT-I, prescription sleep medications, or placebo, as measured by reductions in mean ISI score from baseline and ISI-determined remittance.

Chronic insomnia is the long-term inability to fall asleep easily or to stay asleep. This condition is much more serious than most people realize, raising the risk of many health problems including depression, heart disease, and injuries.Although sleep medications are commonly used to treat insomnia, these drugs may not be effective and can lead to harms such as accidents or clouded thinking. Clinical guidelines recommend a treatment called cognitive behavioral therapy for insomnia (CBT-I) that is safe and effective. Unfortunately, there is a shortage of clinicians trained to provide CBT-I.Prescription digital therapeutics (PDTs) are FDA-approved software programs available on mobile devices such as smartphones. A PDT for insomnia (Somryst) delivers CBT-I and can overcome barriers to access for this important type of therapy. To compare the effectiveness of this PDT with FDA-approved sleep medications and face-to-face CBT-I a special kind of study was conducted called a network meta-analysis. This is a statistical method of combining data from numerous studies in a way that allows the results to be fairly compared.This network meta-analysis of 20 studies found that the PDT was more effective at reducing insomnia symptoms than any of the sleep medications studied and was even more effective than face-to-face CBT-I as measured by scores on a clinically valid scale of insomnia symptoms. These results are encouraging because they suggest that digital delivery of CBT-I could help the millions of people who currently do not have access to this effective treatment.

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network 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.

Construction of sublingual trilaminated Eszopiclone fast dissolving film for the treatment of Insomnia: Formulation, characterization and In vivo clinical comparative pharmacokinetic study in healthy human subjects.

BACKGROUND: Disturbed sleep can cause to m health problems such as cognitive impairment, depressed mood, and negative effects on cardiovascular, endocrine, and immune function. This study formulates and optimizes Eszopiclone trilaminate fast dissolving film. METHODS: Prepared Eszopiclone trilaminate fast dissolving film (Eszopiclone TFDF) was characterized by disintegration time, drug release, tensile strength (TS), percentage elongation (EB%), folding endurance, taste masking test, and in vitro dissolution test. The selected formulas were F2 (0.5% xanthan gum, 10% propylene glycol), F4 (3% sodium alginate, 10% propylene glycol) and F6 (1.5% pullulan, 10% propylene glycol) were subjected to in vivo study compared to conventional Lunesta® tablet. RESULTS: The results indicated that disintegration time was in the range of 940 m. Drug release was found to be in the field of 78.51%-99.99%, while TS values and EB% differed from 11.12 to 25.74 (MPa) and 25.38%-36.43%, respectively. The folding endurance went between 200 and 300 times. All formulas exhibited acceptable uniformity content, surface pH, film thickness, and a good taste feeling. CONCLUSION: F4 had the highest Cmax (39.741 ± 6.785-µg/l) and lower Tmax (1.063 hr) among other formulas and conventional tablets. Therefore, FDFs' technology could increase the therapeutic effect of Eszopiclone.

Assessment of Suvorexant and Eszopiclone as Alternatives to Benzodiazepines for Treating Insomnia in Patients With Major Depressive Disorder.

OBJECTIVES: We investigated the utility of switching from benzodiazepines to suvorexant or eszopiclone to manage benzodiazepine-unresponsive insomnia in patients with major depressive disorder (MDD) in a randomized, open-label study. METHODS: Patients with MDD who have insomnia symptoms (a score of >7 on the Insomnia Severity Index Japanese version [ISI-J]), who had received benzodiazepine treatment for more than 2 weeks (n = 18) were randomized to 4 weeks of suvorexant (20 or 15 mg/d) or eszopiclone (3 or 2 mg/d) treatment. The primary endpoint was an improvement in insomnia severity from baseline assessed by the ISI-J score at 2 and 4 weeks after switching from benzodiazepines. The secondary endpoints included changes in the scores of the Pittsburgh Sleep Quality Index Japanese version, the Beck Depression Inventory II, Generalized Anxiety Disorder 7, the digit span test, and the digit symbol substitution test from baseline. Adverse events were recorded throughout the study. RESULTS: Patients taking suvorexant or eszopiclone had improved ISI-J scores (-4.3 for suvorexant and -4.1 for eszopiclone at week 4; P = 0.04 for eszopiclone). Both drugs tended to improve the Beck Depression Inventory II and Generalized Anxiety Disorder 7 scores 2 and 4 weeks after switching. The Pittsburgh Sleep Quality Index Japanese version, digit symbol substitution test, and digit span test scores and the incidence of adverse events did not change from baseline. CONCLUSIONS: Switching to suvorexant or eszopiclone was well tolerated and improved the severity of benzodiazepine-unresponsive insomnia in MDD patients. Both drugs could be beneficial alternatives to benzodiazepines for treating insomnia in MDD patients.

Effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimer's disease and sleep disorder: A randomized controlled trial.

OBJECTIVE: To investigate the effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimer's disease (AD) and sleep disorders. METHODS: This study was a prospective study of 96 elderly patients with AD and sleep disturbance treated in our hospital from April 2019 to December 2020. All patients were divided into a control group (48 patients, given alprazolam tablets) and a study group (48 patients, given eszopiclone) according to the random number table method. RESULTS: After treatment, compared with the control group, the study group had lower sleep latency, daytime function, sleep disturbance, sleep efficiency, sleep quality, sleeping time, and hypnotic medication scores (p < .05). After treatment, sleep progression and sleep architecture improvement were more obvious in the study group compared with the control group (p < .05). After treatment, compared with the control group, the rhythm disturbance, psychotic disorder, hallucination, phobic anxiety, and disorder in the study group improved more significantly (p < .05). After treatment, compared with the control group, the scores of orientation, attention, memory, calculation, recall, and language ability in the study group improved more significantly (p < .05). After treatment, the scores of the physical life self-care scale and instrumental activities of daily living scale in the study group were improved more obviously compared with the control group, with significant differences (p < .05). CONCLUSION: Eszopiclone can effectively improve the quality of sleep and cognitive function in elderly patients with AD and sleep disorder.

[Standardization of Hypnotic Agents for Prevention of Falls: A Pharmacoeconomic Study].

To reduce the number of falls caused by hypnotic agents, the standardization of insomnia treatment was carried out at Yamaguchi University Hospital from April 2019. There were concerns that medical costs would increase due to the selected medicines-suvorexant and eszopiclone-being more expensive than conventional benzodiazepines. In this study, the standardization of insomnia treatment was evaluated by pharmacoeconomics. The costs of the hypnotic agents was considered, as was the cost of examination/treatment following falls. Effectiveness was evaluated as the incidence of falls within 24 hours of taking hypnotic agents. This analysis took the public healthcare payer's perspective. Propensity score matching based on patient background, showed that, per hospitalization the medicine costs of the recommended group increased by 1,020 yen, however, the examination/treatment costs following falls decreased by 487 yen when compared with the non-recommended group. Overall, the recommended group incurred costs of 533 yen more per hospitalization for patients prescribed hypnotic agents compared to the non-recommended group, but the incidence of falls for the recommended group was significantly lower than that in the non-recommended group (1.9% vs. 6.3%; p<0.01). These results suggest that in order to prevent the incidence of falls by 1 case, it is necessary to increase costs by 12,086 yen which is the subthreshold cost for switching to the recommended medicine as standardization. The selection of recommended medicines may be a cost-effectiveness option compared with non-recommended medicines.

Prevalence of and factors associated with acute withdrawal symptoms after 24 weeks of eszopiclone treatment in patients with chronic insomnia: a prospective, interventional study.

BACKGROUND: Although long-term use of benzodiazepines and benzodiazepine receptor agonists (BZDs) has been associated with an increased risk of dependence, the incidence, details of clinical manifestations, and triggering factors of withdrawal symptoms associated with long-term BZD use at common clinical doses remain unclear. METHODS: In a multicenter, open-label study of 123 Japanese patients with insomnia, patients were given a common clinical dose of eszopiclone (2 mg) for 24 weeks, and then treatment was abruptly discontinued. Withdrawal symptoms were evaluated using the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS). The Insomnia Severity Index (ISI) was used to rate insomnia severity during treatment and 2 weeks after discontinuation. Dependence and poor compliance during treatment without strict medication controls were evaluated with the Benzodiazepine Dependence Self Report Questionnaire short version (Bendep-SRQ SV) subscale sum scores for problematic use, preoccupation, and lack of compliance. Associations between the presence of clinically relevant withdrawal symptoms (BHWSS≥7) and demographic measures, ISI scores at Week 24, and Bendep-SRQ SV subscale sum scores were evaluated by multivariable stepwise logistic regression analyses. RESULTS: Seventy-six patients completed treatment and 2 weeks of withdrawal; eight (10.5%) had clinically relevant withdrawal symptoms. On multiple logistic regression analysis, Bendep-SRQ SV subscale sum scores were correlated with withdrawal symptoms (odds ratio, 1.650; 95% confidence interval, 1.105-2.464; p = 0.014). Exacerbation of post-discontinuation insomnia was not significantly different between patients who showed clinically relevant withdrawal symptoms and those who did not (p = 0.245). CONCLUSIONS: Dependence and poor compliance may contribute to withdrawal symptoms with long-term BZD use. Providing guidance to ensure proper compliance is thought to be the best way to mitigate withdrawal symptoms. TRIAL REGISTRATION: UMIN000024462 (18/10/2016).

The effect of non-benzodiazepine sedative hypnotics on CPAP adherence in patients with OSA: a systematic review and meta-analysis.

STUDY OBJECTIVES: This meta-analysis aimed to explore the effect of non-benzodiazepine sedative hypnotics (NBSH) on continuous positive airway pressure (CPAP) adherence in patients with obstructive sleep apnea (OSA). METHODS: We conducted a systematic search through PubMed, Medline, the Cochrane Library, EMBASE, Scopus and ClinicalTrials (all searched from inception to August 15, 2020). Publications were limited to articles, clinical conferences and letters, including randomized controlled trials and retrospective studies. We used a random-effects model to calculate the odds ratio (OR) and mean difference (MD) with corresponding confidence interval (CI). Subgroup analyses were conducted to analyze the sources of heterogeneity. RESULTS: Eight studies fulfilled the inclusion and exclusion criteria for patients newly diagnosed with obstructive sleep apnea. Overall, the use of NBSH was associated with increased use of CPAP per night (MD = 0.62 h; 95% CI = 0.26-0.98) and use for more nights (MD = 12.08%; 95% CI = 5.27-18.88). When a study seriously affecting heterogeneity was removed, more patients adhered well with CPAP use (pooled OR = 2.48; 95% CI = 1.75-3.52) with good adherence defined as CPAP use for >4 h/night on >70% of nights. Among prescribed NBSHs, eszopiclone showed the most significant effect on CPAP adherence. CONCLUSION: CPAP adherence may increase in OSA patients treated with non-benzodiazepine sedative hypnotics especially eszopiclone. The effect of zolpidem and zaleplon on CPAP adherence requires further investigation by larger scale, randomized, controlled trials.

Comparative efficacy and safety of hypnotics for insomnia in older adults: a systematic review and network meta-analysis.

STUDY OBJECTIVES: To compare the efficacy and safety of various hypnotics for identifying the best treatments for insomnia in older adults. METHODS: We searched the EMBASE, PubMed, ClinicalTrials.gov, and ProQuest Dissertations and Theses A&I databases from the inception to September 12, 2020. Only randomized controlled trials comparing hypnotics with either another hypnotic or placebo for insomnia treatment in elderly people were included. Sleep outcomes, including total sleep time, sleep onset latency, wake after sleep onset, sleep efficiency, were derived from polysomnography, valid questionnaires, or sleep diaries. RESULTS: We identified 24 articles with 5917 older adults. Eszopiclone and low-dose doxepin were ranked the optimal therapy for prolonging objective and subjective total sleep time (26.69 and 28.19 min), respectively, compared to placebo. Zaleplon was the most effective therapy in reducing objective and subjective sleep onset latency (-21.63 and -15.86 min) compared with control. Temazepam was the best treatment for objective and subjective wake after sleep onset (-25.29 and -22.25 min) compared with control. Low-dose doxepin appeared to be the effective treatment for increasing objective sleep efficiency (6.08%) Triazolam showed the higher risk of overall adverse events (odds ratio, 1.96, 95% confidence interval 1.03-3.74) when compared to zaleplon. CONCLUSIONS: Considering study quality and the potential adverse effects of benzodiazepines and nonbenzodiazepines, low-dose doxepin seems to be the optimal pharmacotherapy for the improvements in total sleep time and sleep efficiency. Future RCTs investigating the treatment effects of hypnotics, particularly low-dose doxepin, on insomnia in older adults are warranted. PROSPERO Registration number: CRD42016046301.

Z-drugs and Falls: A Focused Review of the Literature.

OBJECTIVE: To provide a focused review of the literature related to the association between exposure to Z-drugs and the risk of falls, especially in the older population.
DATA SOURCES: A literature search was conducted using Medline, PsychInfo, and the Cochrane Library database for all clinical trials, case series, and case reports published in English up to May 2020. The search terms used consisted of each Z-drug, including "zolpidem," "zopiclone," "eszopiclone," and "zaleplon," matched with "falls."
STUDY SELECTION: The search yielded 295 studies. After review of abstracts, content and references were reviewed, and duplicates removed, a total of 9 articles met inclusion of exposure to at least 1 Z-drug and a primary outcome of falls.
DATA EXTRACTION: The American Geriatrics Society 2019 Beers Criteria Update for Potentially Inappropriate Medication Use in Older Adults recommends to avoid using nonbenzodiazepine hypnotics in this patient population because of the risk of adverse events.
DATA SYNTHESIS: A majority of the literature suggests an increased risk of falls with exposure to Z-drug use, especially zolpidem. Eight trials examined falls as a primary outcome in non-elderly (n=3) and elderly (n=5) patients in different settings, mostly in an inpatient setting (nursing facility or acute care hospital).
CONCLUSION: Exposure to Z-drugs, especially zolpidem, should be evaluated and counseled on continuously as these medications put patients at an increased risk for falls and other complications.

The effects of eszopiclone on sleep spindles and memory consolidation in schizophrenia: a randomized clinical trial.

Sleep spindles, defining oscillations of stage 2 non-rapid eye movement sleep (N2), mediate memory consolidation. Schizophrenia is characterized by reduced spindle activity that correlates with impaired sleep-dependent memory consolidation. In a small, randomized, placebo-controlled pilot study of schizophrenia, eszopiclone (Lunesta®), a nonbenzodiazepine sedative hypnotic, increased N2 spindle density (number/minute) but did not significantly improve memory. This larger double-blind crossover study that included healthy controls investigated whether eszopiclone could both increase N2 spindle density and improve memory. Twenty-six medicated schizophrenia outpatients and 29 healthy controls were randomly assigned to have a placebo or eszopiclone (3 mg) sleep visit first. Each visit involved two consecutive nights of high density polysomnography with training on the Motor Sequence Task (MST) on the second night and testing the following morning. Patients showed a widespread reduction of spindle density and, in both groups, eszopiclone increased spindle density but failed to enhance sleep-dependent procedural memory consolidation. Follow-up analyses revealed that eszopiclone also affected cortical slow oscillations: it decreased their amplitude, increased their duration, and rendered their phase locking with spindles more variable. Regardless of group or visit, the density of coupled spindle-slow oscillation events predicted memory consolidation significantly better than spindle density alone, suggesting that they are a better biomarker of memory consolidation. In conclusion, sleep oscillations are promising targets for improving memory consolidation in schizophrenia, but enhancing spindles is not enough. Effective therapies also need to preserve or enhance cortical slow oscillations and their coordination with thalamic spindles, an interregional dialog that is necessary for sleep-dependent memory consolidation.

Pharmacological interventions for the treatment of insomnia: quantitative comparison of drug efficacy.

PURPOSE: Although different forms of pharmacological intervention are often prescribed for insomnia disorder, the comparative efficacies among various drugs remain unclear. We therefore conducted this study to quantitatively compare the efficacy of various pharmacotherapies for insomnia by modeling. METHODS: We searched PubMed, EMBASE and Cochrane Library databases for randomized placebo-controlled trials of insomnia medications that were conducted within a designated time period (from the inception dates to May 16, 2019). Pharmacodynamic models were established to describe the time course of changes from baseline in selected sleep parameters. Sleep quality and dropout rates were also compared by a single-arm meta-analysis. RESULTS: In sum, 43 studies covering 44 trials (14,535 patients) were included in the analysis. The drugs evaluated included flurazepam, quazepam, temazepam, triazolam, eszopiclone, zaleplon, zolpidem, extended-release zolpidem, suvorexant, ramelteon and doxepin. The established models revealed eszopiclone had the highest efficacy in terms of sleep latency (SL), total sleep time (TST), and sleep quality, and was also associated with the lowest dropout rates. The effect of suvorexant on the parameter 'wake after sleep onset' (WASO) was significantly higher than that of the other drugs analyzed. CONCLUSIONS: Each drug has its own characteristics in the treatment of insomnia, and this needs to be taken into consideration to meet individual clinical needs. These results serve as a quantitative supplement for clinical practice by reflecting the difference in efficacy of various drugs in the treatment of insomnia.

Development of a novel tandem mass spectrometry method for the quantification of eszopiclone without interference from 2-amino-5-chloropyridine and application in a pharmacokinetic study of rat.

Eszopiclone (E-ZOP), a strictly controlled psychoactive drug, must be accurately quantified in biological matrices. However, because of its rapid degradation and transformation into 2-amino-5-chloropyridine (ACP) during specimen preparation, the concentration of E-ZOP in biological matrices is likely underestimated. In this study, a sensitive and simple high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the accurate determination of the initial concentration of E-ZOP in rat plasma was developed and validated. ACP was monitored simultaneously throughout the method validation process to ensure that it was not produced via E-ZOP hydrolysis. E-ZOP and structurally similar metabolites were stabilized in rat plasma by controlling the pH at 4.2 using a modified phosphate buffer solution (PBS) with acetic acid. Using this method, E-ZOP, ACP and the internal standard (IS), venlafaxine, were extracted from rat plasma via a simple protein precipitation and separated on a C18 column using methanol, 5 mM ammonium acetate, and 0.1 % acetic acid as the isocratic mobile phase. The validated method covered a working range from 0.1-50 ng/mL for E-ZOP, and the lower limit of detection (LLOD) for ACP was 0.2 ng/mL. In conclusion, an accurate, sensitive, and simple HPLC-MS/MS method for E-ZOP quantification was developed and successfully applied to a preclinical pharmacokinetics (PK) study in rats. The toxic product APC was effectively monitored. The HPLC-MS/MS method is a stable and sensitive quantitative method for the determination of E-ZOP in biological matrices.