Efficacy of treatment of insomnia in migraineurs with eszopiclone (Lunesta®) and its effect on total sleep time,headache frequency,and daytime functioning: A randomized,double-blind,placebo-controlled,parallel-group,pilot study

Aims:

A review on headache and insomnia revealed that insomnia is a risk factor for increased headache frequency and headache intensity in migraineurs. The authors designed a randomized, double blind, placebo-controlled, parallel-group, pilot study in which migraineurs who also had insomnia were enrolled, to test this observation.

Methodology:

In the study, the authors treated 79 subjects with IHS-II migraine with and/or without aura and with DSM-IV primary insomnia for 6 weeks with 3 mg eszopiclone (Lunesta^®) or placebo at bedtime. The treatment was preceded by a 2-week baseline period and followed by a 2-week run-out period.

Results:

Of the 79 subjects treated, 75 were evaluable, 35 in the eszopiclone group, and 40 in the placebo group. At baseline, the groups were comparable except for sleep latency. Of the three remaining sleep variables, total sleep time, nighttime awakenings, and sleep quality, the number of nighttime awakenings during the 6-week treatment period was significantly lower in the eszopiclone group than in the placebo group (P?=?0·03). Of the three daytime variables, alertness, fatigue, and functioning, this was also the case for fatigue (P?=?005). The headache variables, frequency, duration, and intensity, did not show a difference from placebo during the 6-week treatment period.

Conclusions:

The study did not meet primary endpoint, that is, the difference in total sleep time during the 6-week treatment period between eszopiclone and placebo was less than 40 minutes. Therefore, it failed to answer the question as to whether insomnia is, indeed, a risk factor for increased headache frequency and headache intensity in migraineurs.     

The acute cognitive effects of zopiclone,zolpidem, zaleplon,and eszopiclone: A systematic review and meta-analysis

The “z-drugs” zopiclone, zolpidem, eszopiclone, and zaleplon were introduced in the 1980s for the treatment of insomnia, as it was observed that the side effect profile associated with these medications were more benign than those related to the benzodiazepines. This meta-analysis set out to ascertain which domains of cognitive function, if any, were affected by the ingestion of these medications. A total of 20 studies met the study inclusion criteria. Results revealed medium effect sizes for zopiclone and zolpidem on measures of verbal memory. An additional medium effect size was observed for zolpidem on attention. Finally, smaller effect sizes were observed for zolpidem speed of processing and for zopiclone on working memory. It is clear from these data that the use of a single dose of the z-drugs in healthy adults as measured in the morning following the exposure does produce a specific rather than a generalized negative effect on cognitive function. However, there were only enough studies to evaluate the individual cognitive effects of the zolpidem and zopiclone medications; the specific effects of zaleplon and eszopiclone cannot be ascertained because only one study met the inclusion and exclusion criteria for the review.     

A 12-Week,Randomized, Double-Blind,Placebo-Controlled Study Evaluating the Effect of Eszopiclone 2 mg on Sleep/Wake Function in Older Adults with Primary and Comorbid Insomnia

Background:

Longer-term pharmacologic studies for insomnia in older individuals are sparse.

Objective:

To evaluate the efficacy and safety of 12 weeks of nightly eszopiclone in elderly outpatients with insomnia.

Methods:

Participants (65–85 years) met DSM-IV-TR criteria for insomnia with total sleep times (TST) ≤ 6 h, and wake time after sleep onset (WASO) ≥ 45 min. Participants were randomized to 12 weeks of eszopiclone 2 mg (n = 194) or placebo (n = 194), followed by a 2-week single-blind placebo run-out. Subject-reported measures of sleep (sTST, sleep latency [sSL], sWASO) and daytime function (alertness, concentration, well-being, ability to function) were assessed. AEs were monitored.

Results:

Subjects treated with 2 mg eszopiclone slept longer at night on average and at every individual time point compared to baseline than placebo subjects, as measured by TST over the 12-week double-blind period (P < 0.0001). Mean sTST over the double-blind period for eszopiclone-treated subjects was 360.08 min compared to 297.86 min at baseline, a mean change of 63.24 min. Over the double-blind period, eszopiclone-treated subjects also experienced a significantly greater improvement in sSL compared to placebo, with a mean decrease of 24.62 min versus a mean decrease of 19.92 min, respectively (P = 0.0014). Eszopiclone subjects also experienced a significantly greater decrease in WASO (mean decrease of 36.4 min) compared to placebo subjects (decrease of 14.8 min) (P < 0.0001). Post-discontinuation, sleep parameters were statistically improved versus baseline for eszopiclone (P-values ≤ 0.01), indicating no rebound. The most common AEs (≥ 5%) were headache (eszopiclone 13.9%, placebo 12.4%), unpleasant taste (12.4%, 1.5%), and nasopharyngitis (5.7%, 6.2%).

Conclusion:

In this Phase IV trial of older adults with insomnia, eszopiclone significantly improved patient-reported sleep and daytime function relative to placebo. Improvements occurred within the first week and were maintained for 3 months, with no evidence of rebound insomnia following discontinuation. The 12 weeks of treatment were well tolerated.

Clinical Trial Information:

A Long-Term Safety and Efficacy Study of Eszopiclone in Elderly Subjects With Primary Chronic Insomnia; Registration #{"type":"clinical-trial","attrs":{"text":"NCT00386334","term_id":"NCT00386334"}}NCT00386334; URL - http://www.clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00386334","term_id":"NCT00386334"}}NCT00386334?term=eszopiclone&rank=24

Citation:

Ancoli-Israel S; Krystal AD; McCall WV; Schaefer K; Wilson A; Claus R; Rubens R; Roth T. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. SLEEP 2010;33(2):225-234.     

右佐匹克隆定时释放片的制备研究

目的制备右佐匹克隆定时释放片,并考察其体外释药特性。方法分别以HPMC作为溶胀层包衣材料,以乙基纤维素水分散体作为控释层包衣材料,采用高效包衣机制备右佐匹克隆定时释放片,考察影响释放度的主要因素,并测定体外释放度以考察体外释药行为。结果确定了影响右佐匹克隆释放的处方因素,体外释放度研究结果表明,该制剂可达到脉冲式释放。结论右佐匹克隆定时释放片可以达成两次定时脉冲释放,符合让失眠患者快速入睡并维持6 h以上睡眠状态的设计初衷。     

认知行为疗法联合右佐匹克隆片治疗ICU转出患者睡眠障碍的疗效观察

目的比较认知行为疗法联合右佐匹克隆片与单用右佐匹克隆片治疗ICU转出患者睡眠障碍的临床疗效与安全性。方法采用随机数字表法将符合DSM-5失眠诊断标准、年龄18~55岁的58例患者分为研究组和对照组各29例,两组均服用右佐匹克隆片1~3mg/d;研究组加用4周认知行为疗法。入组患者均接受问卷调查,记录患者在ICU住院期间存在疼痛、焦虑、失眠等不适经历,希望家属陪护,以及对机械通气、各种侵入性操作的疼痛记忆比例。治疗前后分别进行多导睡眠监测（PSG）、匹兹堡睡眠质量指数（PSQI）量表、焦虑自评量表（SAS）、抑郁自评量表（SDS）、不良反应量表（TESS）评估。结果治疗后,研究组入睡时间、觉醒时间、睡眠时间均优于对照组（均P＜0.05）;研究组PSQI总分低于对照组（P＜0.05）,睡眠效率、Ⅲ期和快速眼动睡眠时间均优于对照组（均P＜0.05）。治疗后,研究组SAS、SDS评分均显著低于对照组;研究组及对照组治疗后SAS、SDS评分均显著低于治疗前（均P＜0.01）。结论认知行为疗法联合右佐匹克隆片治疗ICU转出患者睡眠障碍的疗效更优。     

Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia

SUMMARY

Objective: Eszopiclone is a new, single-isomer, non-benzodiazepine, cyclopyrrolone agent under investigation for the treatment of insomnia. The present study was a randomized, double-blind, multicenter, placebo-controlled trial conducted to assess the efficacy and safety of eszopiclone in adults with chronic primary insomnia.

Research design and methods: Patients (n = 308) were randomized to receive placebo or eszopiclone (2?mg or 3?mg) for 44 consecutive nights, followed by 2 nights of single-blind placebo. Efficacy was evaluated with polysomnography (Nights 1, 15 and 29) and patient-reports (Nights 1, 15, 29 and 43/44). Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST).

Results: Eszopiclone 3?mg had significantly less time to sleep onset (?p ≤ 0.0001), more total sleep time and sleep efficiency (?p ≤ 0.0001), better sleep maintenance (p ≤ 0.01), and enhanced quality and depth of sleep (?p < 0.05) across the double-blind period compared with placebo. Eszopiclone 2?mg had significantly less time to sleep onset (?p ≤ 0.001), more total sleep time (?p ≤ 0.01) and sleep efficiency (?p ≤ 0.001), and enhanced quality and depth of sleep (?p < 0.05) compared with placebo, but did not significantly improve sleep maintenance. There was no evidence of tolerance or rebound insomnia after therapy discontinuation. Median DSST scores showed no decrement in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group. Treatment was well tolerated; the most common adverse event related to eszopiclone was unpleasant taste.

Conclusions: Patients treated with nightly eszopiclone 3?mg had better polysomnographic (through Night 29) and patient-reported measures (through Night 44) of sleep over the 6-week trial. There was no evidence of tolerance or rebound insomnia and no detrimental effects on next-day psychomotor performance using the DSST.     

顶空毛细管气相色谱法测定右旋佐匹克隆残留量

目的建立顶空毛细管气相色谱法测定右旋佐匹克隆中甲醇、丙酮、乙酸乙酯残留量的方法。方法采用ZB-5气相毛细管色谱柱（30m×0.53mm×3μm）;FID检测器;柱温采用程序升温：起始温度40℃,维持6min,再以20℃.min-1速率升至200℃,维持10min,进样口温度130℃;检测器温度230℃;载气为N2,流速为3mL.min-1;分流比：1∶5;进样量：1mL;DMSO为溶解介质。结果甲醇、丙酮、乙酸乙酯分别在14.91～303.12、25.14～500.40和25.20～503.24μg.mL-1浓度范围内,与峰面积线性关系良好（r〉0.99）,检测限分别为1.52、0.71、1.26μg.mL-1;平均回收率分别为100.8%（RSD=3.6%）、99.54%（RSD=3.1%）和98.5%（RSD=3.2%）。结论该方法经济、简便;经方法学验证,灵敏度、准确度均达到有机残留的检测要求,适合用于右旋佐匹克隆残留溶剂的检测。     

甜梦口服液联合右佐匹克隆治疗脑梗死后失眠症的疗效观察

目的探讨甜梦口服液联合右佐匹克隆治疗脑梗死后失眠症临床疗效。方法选取2014年7月—2015年7月在铁岭市中心医院神经内科接受治疗的脑梗死后失眠症患者96例,随机分为对照组和治疗组,每组各48例。对照组患者睡前口服右佐匹克隆片,初始剂量1.5 mg/次,3 d后3 mg/次。治疗组在对照组基础上口服甜梦口服液,20 m L/次,3次/d。两组患者均治疗1个月。观察两组的临床疗效,比较两组改良爱丁堡–斯堪的那维亚卒中量表(MESSS)评分、匹兹堡睡眠质量量表(PSQI)评分和综合医院焦虑抑郁量表(HAD)评分情况。结果治疗后,对照组和治疗组的总有效率分别为83.33%、95.83%,两组比较差异有统计学意义(P0.05)。治疗后,两组MESSS评分、PSQI评分和HAD评分均明显降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的下降程度明显优于对照组,两组比较差异具有统计学意义(P0.05)。结论甜梦口服液联合右佐匹克隆治疗脑梗死后失眠症具有较好的临床疗效,有利于患者神经功能恢复,提高患者睡眠质量,具有一定的临床推广应用价值。     

A polysomnography study of eszopiclone in elderly patients with insomnia

ABSTRACT

Objective: To evaluate the safety and efficacy of eszopiclone 2?mg in elderly patients (aged 64-86 years) with chronic insomnia.

Methods: This was a randomized, double-blind, placebo-controlled 2‐week study. Patients meeting DSM-IV criteria for primary insomnia and screening polysomnography criteria (wakefulness after sleep onset [WASO] ≥ 20?min and latency to persistent sleep ≥ 20?min) were randomized to 2 weeks of nightly treatment with eszopiclone 2?mg (n = 136) or placebo (n = 128). Efficacy was assessed using polysomnography (Nights 1, 2, 13, and 14) and patient reports (Nights 1–14); safety was assessed using adverse events, clinical labs, physical examination, and vital signs. The mean of all efficacy results during the double-blind period was used for the efficacy analysis.

Results: Results indicated that eszopiclone was associated with significantly shorter sleep onset, less WASO, higher sleep efficiency, more total sleep time, and greater patient-reported quality and depth of sleep scores than placebo (?p < 0.05 for all) with a trend in patient-reported morning sleepiness (?p = 0.07). Other measures of daytime functioning (ability to function, daytime alertness, and sense of well-being) were not significantly different between the two treatment groups. Among patients who napped, eszopiclone patients reported fewer naps (?p = 0.03) and less cumulative naptime (median: 98?min placebo, 70?min eszopiclone, p = 0.07). Unpleasant taste, dry mouth, somnolence, and dizziness were higher in the eszopiclone group (12.5%, 8.8%, 6.6%, and 6.6%, respectively) than in the placebo group (0%, 1.6%, 5.5%, and 1.6%, respectively).

Conclusion: In this study, eszopiclone was well tolerated and produced significant improvements in both polysomnographic and patient-reported measures of sleep maintenance, sleep induction, and sleep duration in elderly patients with chronic primary insomnia.