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Efficacy and Safety of Zopiclone and Eszopiclone in the Treatment of Primary and Comorbid Insomnia

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GABA and Sleep

Abstract

Drug enantiomers with chiral factors exhibit different effects on pharmacological activity, metabolism, and toxicity in the human body, and thus may differ in their pharmacokinetic and pharmacodynamic properties. Many currently used medications in clinical practice are mixtures of enantiomers (racemates), and replacing existing racemates with single isomers has resulted in improved efficacy and/or safety profile of the racemic mixtures. This “chiral switch” allows the existing racemate to be switched to one of its isomers and provides a safer, better-tolerated, and more efficacious alternative medication. Since the introduction and widespread use of asymmetric synthesis and chiral separation technologies, as well as the publication of formal FDA guidelines, which encourage the development of chiral drugs, many pharmaceutical manufacturers have developed single-enantiomer drugs.

Zopiclone [(R,S)-zopiclone] is a hypnotic, which has been available in countries outside the United States (US) for over 20 years, while eszopiclone (S-zopiclone) is the dextrorotatory enantiomer of racemic zopiclone, approved as a hypnotic in the United States in 2004. Both zopiclone and eszopiclone are pyrrolopyrazine derivatives of the cyclopyrrolone class, and are both active at GABAA receptors, whereas (S)-zopiclone has a relatively higher affinity and accounts for much of the action of racemic zopiclone.

The hypnotic effects of zopiclone and eszopiclone have been demonstrated in numerous clinical trials in healthy subjects and patients with insomnia. Both hypnotics are utilized in the management of insomnia in patients who either experience difficulty initiating sleep or are unable to maintain sleep through the night.

Clinical studies utilizing zopiclone at a dose of 7.5mg administered nightly have demonstrated the hypnotic’s efficacy in reduced sleep onset latency, increased total sleep time, and a reduction in the number of night-time awakenings. In treating insomnia, 7.5mg zopiclone nightly is at least effective as the benzodiazepine hypnotics, flurazepam, flunitrazepam, nitrazepam, temazepam, triazolam, and midazolam, used at approved therapeutic doses. Trials with zopiclone administered for up to 6 weeks duration as well as EEG analysis of sleep parameters in a 17-week study have revealed no marked tolerance to the effects of the hypnotic. Additionally, studies with zopiclone have demonstrated that it does not have a high dependence potential or cause rebound insomnia, and does not cause significant next-day psychomotor impairment.

In clinical trials, eszopiclone 2mg and 3mg in adults with chronic insomnia significantly improved subjective and objective sleep measures including improved sleep efficiency, sleep latency, total sleep time, wake time after sleep onset, number of awakenings, number of nights awakened weekly, and quality and depth of sleep. In elderly patients, eszopiclone 2mg was associated with significantly shorter sleep latency compared to placebo and significantly improved ratings of sleep quality and depth, wake time after sleep onset, sleep duration, and decreased cumulative number of naps. Long-term treatment of primary insomnia with eszopiclone for 6 months improved daytime functioning and health-related quality of life. In clinical trials of up to 12 months duration, eszopiclone 3mg showed a sustained beneficial effect on sleep induction and sleep maintenance, was well tolerated, with no clinically significant evidence of tolerance, rebound insomnia or dependence noted. Nightly use of eszopiclone 3mg did not impair next-day driving-related skills or measures of cognition relative to placebo. Randomized, double-blind trials have demonstrated that eszopiclone 3mg administered once nightly for 4–8 weeks produced significantly greater improvements in measures of sleep induction and maintenance compared to placebo in patients with insomnia and comorbid conditions, as well as improvements in certain measures of the comorbid conditions compared to standard therapies alone. In 2005, eszopiclone was the first sedative hypnotic approved by the US Food and Drug Administration (FDA) for the long-term management of chronic insomnia.

Both zopiclone and eszopiclone appear to be well tolerated in short-term and in longer-term studies in nonelderly and elderly patients. Numerous studies performed on a self-reporting basis show the absence of serious adverse events. The most commonly reported adverse events in clinical trials with both zopiclone and eszopiclone are unpleasant or bitter taste, headache, dizziness, and dry mouth.

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  1. Division of Pharmacy Practice, Arnold & Marie Schwartz College of Pharmacy, Long Island University, HS Building, 5th Floor, 75 DeKalb Avenue, Brooklyn, NY, 11201, USA

    Jadwiga S. Najib

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  1. Jadwiga S. Najib
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  1. School of Medicine, Dept. Pharmacology & Therapeutics, Clinics Hospital Montevideo, Zudanez Street 2833/602/602, Montevideo, 11300, Uruguay

    Jaime M. Monti

  2. Somnogen, Inc., Lansdowne Avenue 200, Toronto, M6K 2V9, Ontario, Canada

    Seithikurippu Ratnas Pandi-Perumal

  3. Institut für Pharmakologie und, Toxikologie, Universität Zürich, Winterthurerstr. 190, Zürich, 8057, Switzerland

    Hanns Möhler

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Najib, J.S. (2010). Efficacy and Safety of Zopiclone and Eszopiclone in the Treatment of Primary and Comorbid Insomnia. In: Monti, J., Pandi-Perumal, S., Möhler, H. (eds) GABA and Sleep. Springer, Basel. https://doi.org/10.1007/978-3-0346-0226-6_18

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