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A Review of Its Use in the Treatment of Insomnia

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Eszopiclone (Lunesta®), the S-enantiomer of racemic zopiclone, is a nonbenzodiazepine hypnotic agent that is approved in the US as an oral, once-nightly therapy for insomnia in adults; eszopiclone is also currently under review by the European Medicines Agency.

Eszopiclone is rapidly absorbed after oral administration without any next-day clinical residual effects being detected. Large, well designed trials of up to 6 months’ duration have shown that eszopiclone significantly improves both sleep onset and sleep maintenance compared with placebo in adult and elderly patients with primary insomnia. Eszopiclone for 4–8 weeks also significantly improved sleep parameters compared with placebo in patients with insomnia coexisting with other conditions that also disturb sleep (co-morbid insomnia), and improved certain measures of the co-morbid conditions to a greater extent than the standard therapies alone. Short-term eszopiclone produced improvements in daytime functioning in patients with co-morbid insomnia. Six months’ therapy in adults with primary insomnia improved daytime functioning and health-related quality of life. Eszopiclone was generally well tolerated. There was no evidence of tolerance during 12 months’ treatment with this agent. On discontinuation of eszopiclone, there was no rebound insomnia or serious withdrawal effects. Well designed, comparative trials with other nonbenzodiazepine hypnotics are needed to determine its relative efficacy and tolerability. A cost-utility analysis suggested that eszopiclone is cost effective for the treatment of primary insomnia in the US. Therefore, eszopiclone is a useful therapeutic option in the management of adult and elderly patients with primary or co-morbid insomnia. Unlike most other hypnotics, eszopiclone is not limited to short-term use.

Pharmacological Properties

Eszopiclone, a nonbenzodiazepine cyclopyrrolone, is the S-enantiomer of racemic zopiclone and has a greater affinity than the R-enantiomer for the GABAA/ benzodiazepine receptor complex; the sedative properties of racemic zopiclone are primarily linked to the S-rather than the R-enantiomer.

Eszopiclone 2 and 3 mg significantly improved polysomnography-assessed sleep parameters (sleep latency, wake time after sleep onset and sleep efficiency) compared with placebo in a model of transient insomnia in healthy, adult volunteers. Next-day clinical residual effects of eszopiclone were absent, as determined by standardized tests in healthy volunteers and patients with primary insomnia. Anxiolytic and muscle relaxant effects of eszopiclone have been demonstrated in animal studies.

Eszopiclone is rapidly absorbed after oral administration in healthy volunteers, with maximum plasma concentrations attained in ≈1 hour. Steady-state plasma concentrations were achieved 24–48 hours after initiation of once-daily administration, with no evidence of drug accumulation; pharmacokinetic parameters did not vary appreciably between single-dose and steady-state administration. The binding of eszopiclone to plasma proteins is 52–59%. The drug is metabolized via the cytochrome P450 (CYP) isoenzymes 3A4 and 2E1; metabolites are less active than the parent molecule at GABAa receptors. The mean elimination half-life of eszopiclone 3 mg was 5.8 hours (single dose) or 7 hours (steady state). No in vivo stereoconversion of eszopiclone to R-zopiclone was observed in an animal study. Total drug exposure is greater in elderly than in nonelderly adults, and in patients with severe hepatic impairment than in healthy volunteers; the maximum recommended dosage is less in these patients (2 mg/night) than in nonelderly adults (3 mg/night). No dosage adjustment is required in the US in patients with renal impairment. Coadministration of eszopiclone with inhibitors or inducers of CYP3A4 is likely to affect eszopiclone pharmacokinetics.

Therapeutic Efficacy

In well designed, placebo-controlled trials of ≤6 months’ duration, eszopiclone 2 (elderly patients) or 3 (adult patients) mg/night was effective in improving parameters relating to sleep onset and sleep maintenance in nonelderly and elderly patients with primary insomnia, and nonelderly patients with co-morbid insomnia. The co-morbid conditions were major depressive disorder, generalized anxiety disorder, menopausal transition and rheumatoid arthritis. Ratings for sleep quality, depth of sleep and daytime function also improved with eszopiclone therapy relative to placebo in both primary and co-morbid insomnia. No development of tolerance to eszopiclone 3 mg/night was observed in nonelderly adult patients with primary insomnia over a long-term (12-month) treatment period.

In patients with co-morbid insomnia, on stable standard therapies for their condition where appropriate, eszopiclone produced greater improvements than placebo in certain measures of the co-morbid conditions, such as the Hamilton Depression Rating Scale scores, Hamilton Anxiety Rating Scale scores, arthritis pain and ability to function scores, awakenings due to hot flushes and Greene Climacteric Scale scores.


Eszopiclone was generally well tolerated in clinical trials in adult patients with primary insomnia. The most frequent adverse event was unpleasant taste, which appeared to follow a dose-response relationship. Other common adverse events included headache, somnolence, dizziness and infection. There were few serious adverse events; in a 6-month trial, the proportion of eszopiclone recipients experiencing potentially treatment-related serious events was 0.3%. The rate of discontinuation due to adverse events did not differ between the eszopiclone and placebo groups in trials of ≤6 weeks’ duration or in one 6-month trial, but was significantly higher in the eszopiclone than the placebo group in another 6-month trial. The reasons for discontinuation in the latter trial included somnolence, depression and unpleasant taste. The adverse event profile of eszopiclone in patients with co-morbid insomnia was generally similar to that observed in patients with primary insomnia. Discontinuation of eszopiclone therapy did not result in rebound insomnia and no serious withdrawal syndrome was detected.

Pharmacoeconomic Considerations

A cost-utility analysis performed in the US suggested that 6 months’ treatment with eszopiclone 3 mg/night in adult patients with primary insomnia was cost effective compared with no treatment, especially from the societal perspective, which included productivity gains. The incremental cost-effectiveness ratio for eszopiclone versus no treatment was $US9930 per quality-adjusted life-year (QALY) gained for total costs and $US36 894 per QALY gained for direct costs.

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Corresponding author

Correspondence to Paul L. McCormack.

Additional information

Various sections of the manuscript reviewed by: M. Bonnet, Veterans Affairs Medical Center, Dayton, Ohio, USA; C. Dolder, Wingate University School of Pharmacy, Wingate, North Carolina, USA; M.B. Scharf, Tri-State Sleep Disorders Center, Cincinnati, Ohio, USA; M.G. Terzano, Clinica Neurologica - Centro di Medicina del Sonno, Azienda Ospedaliera Universitaria di Parma, Parma, Italy; G.K. Zammit, Clinilabs, New York, New York, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘eszopiclone’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘eszopiclone’ and ‘insomnia’. Searches were last updated 21 May 2008.

Selection: Studies in patients with insomnia who received eszopiclone. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Eszopiclone, insomnia, pharmacodynamics, pharmacokinetics, therapeutic use, pharmacoeconomics, tolerability.

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Hair, P.I., McCormack, P.L. & Curran, M.P. Eszopiclone. Drugs 68, 1415–1434 (2008).

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